Mapping long-term cortical maturation of the auditory ... · Salima Jiwani Doctor of Philosophy...

Mapping long-term cortical maturation of the auditory system in

adolescents who are deaf and have used a unilateral cochlear implant

to hear

by

Salima Jiwani

A Thesis submitted in conformity with the requirements

for the degree of Doctor of Philosophy

Institute of Medical Sciences

University of Toronto

© Copyright by Salima Jiwani 2015

ii

Mapping long-term cortical maturation of the auditory system in

adolescents who are deaf and have used a unilateral cochlear implant

to hear

Salima Jiwani

Doctor of Philosophy

Institute of Medical Sciences

University of Toronto

2015

Abstract

In the present Thesis, we used novel imaging tools to study maturation of the auditory brain

in adolescents who are deaf and have use a unilateral cochlear implant (CI) to hear for most of their

lives. A CI is a surgically implanted auditory prosthesis that establishes hearing in children who are

deaf. The aims of implantation are to halt any effects of deafness on the brain and promote normal

auditory development. Unfortunately, CIs do not restore normal hearing as they provide only a crude

representation of sounds and eliminate important cochlear processing. It has recently been shown

that unilaterally stimulating the auditory system with a CI and leaving the opposite pathways deprived

of input for longer than 1.5 years compromises bilateral auditory development. We are now exploring

the cortical consequences of missing this sensitive period and driving maturation of the auditory cortex

with unilateral implant stimulation.

We measured electrically-evoked cortical responses in adolescents who had over a decade of

unilateral CI experience before receiving a second implant in the opposite deprived ear. This provided

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an unparalleled opportunity to assess the effects of long-term unilateral stimulation/deprivation on

the auditory pathways in the adolescent brain. We tracked the development of cortical responses with

CI experience and localized underlying areas of cortical activity in the brain using our beamformer

imaging methods. Neural synchrony of these responses was calculated to assess the co-ordination of

activity across brain regions in response to sound.

Our results indicate that long-term unilateral implant stimulation promotes normal-like

maturation of the auditory cortex with good speech perception outcomes, providing a general

impression that some degree of auditory development proceeds normally. However, abnormally

strengthened activity from the hearing ear to the contralateral cortex and increased synchrony in

networks known to be involved in cognitive processing suggests that cortical abnormalities persist

into maturation. In the opposite deprived ear, cortical responses were atypical, had abnormally large

dipoles and abnormal neural synchrony, perhaps reflecting cortical un-coupling/dis-connectivity in

response to sound. We suggest that unilateral maturation of the auditory cortex drives lasting auditory

asymmetries and leaves the deprived pathways unprotected from deafness-induced abnormalities.

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Acknowledgements

The pages of this Thesis hold much more than a culmination of years of studies. This Thesis

is built on the shoulders of more people than I can count, who have had a hand in shaping my personal

and intellectual growth. You have all thought me to push the boundaries of innovative research and

clinical practice to help people hear better and you have shown me how fun this can be! I came to

Archie’s Cochlear Implant Lab as an Audiologist. I now prepare to leave as an Audiologist-Scientist.

For that, I have many people to thank…

First and foremost, I would like to thank all of the children and adolescents who participated in my

studies. Thank you to you and your families for lending us your ears/implants and brains. This work

could not have been done without your generosity, contribution and time.

To my supervisor, Dr. Karen Gordon: Thank you for welcoming me as part of the CI family.

Working with you over the last few years has been an inspiration. You have thought me to think

smarter, write smarter, present smarter, and generally be smarter. Thank you. Thank you for your

incredible mind, your mentorship and your kind heart. Thank you also for always taking the time to

talk through ideas and thoughts with me, for opening doors of opportunity for me, and for becoming

a life-long friend. You truly are a one-of-a-kind Audiologist-Scientist, and I thank you for showing

me the path to success.

To my committee members, Dr. Robert Harrison, Dr. Margot Taylor and Dr. Sam Doesburg: Thank

you for always providing guidance and advice. Bob, you were the first to show me the wonderful

world of research at SickKids and you inspired me to follow a path of research with Karen. Thank

you for always having faith in me, for always asking the right questions, and for pushing me to be

better. Dr. Taylor, Thank you for always being so positive about my work and my abilities, for always

leaving revisions with me, and being so supportive. Sam, Thank you for always having the right ideas

to make the work better and more objective, for always making the time to explain methods to me,

and for always being so encouraging.

To the CI surgeons, Dr. Blake Papsin, Dr. Adrian James and Dr. Sharon Cushing: Thank you for

always sharing your brilliant minds with me, and always welcoming me into your ORs. Dr. Papsin,

Thank you for being an incredible leader, for always sharing your wisdom and for the many life/career

chats. Thank you also for always thinking about our data in terms of the big picture and all the many

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things we can do with it to make a difference in a child’s life. I think the Nobel is on its way! Dr.

James and Dr. Cushing, Thank you for always smiling, for your constant drive to promote better

clinical care, and for teaching me how important it is to ask unique research questions.

To the CI Audiology Team, Vicky Papaioannou, Gina Goulding, Laurie MacDonald, Valérie Simard,

Mary-Lynn Feness, Pat Di Santo, Susan Druker, Rebecca Malcolmson and Cléo Audet-Halde: Thank

you all for your willingness to help and for sharing your knowledge, expertise, and sometimes even

your offices with me. You are an amazing group of people and I am lucky to have had the chance to

work with you all. To Patt Fuller and Debbie Andrade, Thank you for the laughs and all the help in

the clinic and the lab.

To the CI team at Archie’s Cochlear Implant Lab: You became my family and I am so fortunate to

have you in my life. Thank you for your hard work, your high spirits, your inquisitive nature, your

ability to think outside the box and making research so fun! Stephanie Jewell, you and I have shared

way too many laughs and adventures together! Thank you for your good nature and friendship. I am

lucky to have found you. Nikolaus Wolter, Thank you for sharing the Tower with me! Thank you

also for teaching me an abundance of interesting and random facts about science, otolaryngology,

history and animals. Thank you for your constant willingness to help others, for always finding the

good in all situations, for all of your funny jokes and for your friendship. Melissa Polonenko, Thank

you for making everyday more interesting, for always asking the difficult questions, and for pushing

me to do better. Parvaneh Abbasalipour, Thank you for always motivating me to work even harder

and helping me push my limits, as you always do. Thank you also for all of the time spent collecting

data and troubleshooting equipment with me. Patrick Yoo and Daniel Wong, Thank for spending all

of those days and weeks and months working through the Beamformer with me and the fun times in

the Satellite lab. Jerome Valero, Thank you for taking me under your wing early on, showing me the

ropes, and all the delicious lunch dates. Talar Hopyan, Sara Giannatonio, and Shazia Peer, Thank you

for always being so funny, so crazy and so light hearted! Claire Salloum, Sho Tanaka, Michael

Deighton, Morrison Steel, Désirée DeVreede, Lauren Schofield, Hailey Ainley, Catharine McCann,

Cullen Allemang, Bridget Allemang, Gurvinder Toor, Luis Vilchez Madrigal, Tulika Shingal, Heather

Osborn, Tony Eskander, William Parkes, Carmen Knight, Vijayalakshmi Easwar, Joshua

Gnanasegaram, Michael Chaikoff, Patricia Ungureanu, Mikaeel Valli, Eden Amber, Thank you for

making me feel at home in the lab.

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Finally, I would like to thank my family and friends. I am everything that I am because of you. Thank

you. Merci.

To my silent supporters, Dr. Steve Aiken and Philippe Fournier: Thank you for being the best of

cheerleaders and for inspiring me to make a difference in our field of Audiology.

To Akbar and Nasim Dharssi, Karim, Farrah and the boys: Thank you for your constant

encouragement and for always believing in me.

A mon père, ma mère, mes sœurs (Soraya et Sabrina), mes grands-parents (Papaji, Mama, Mama), et

les p’tit chouchous: Merci pour tout. Merci d’avoir toujours cru en moi, de m’avoir toujours

encouragé, et de m’avoir toujours supporté, en particulier dans les moments délicats. Mille Mercis

pour votre patience, générosité, bonne humeur, splendide énergie et bonté de cœur. Je vous dois

absolument tout.

To my dear husband, Salim Dharssi: Thank you for being my true better half over the last few years.

Thank you for always listening to me prep for talks, reading all my applications, and the countless

hours you spent helping me with the beamformer. Thank you for all of your support, all of your

laughs, all of your jokes, all of your kindness, and all of your heart. You inspire me to reach for the

stars and to be better. You have made my life richer than I ever could have imagined.

Contributions

Dr. Karen Gordon and Dr. Blake Papsin were the vision behind the studies presented in this Thesis.

They contributed to all aspects of the work. My Thesis advisory committee, Dr. Robert Harrison, Dr.

Margot Taylor and Dr. Sam Doesburg provided continuing guidance with the data analyses and results

for all studies, particularly the ones in Chapters Four and Five.

Stephanie Jewell and Parvaneh Abbasalipour helped with the EEG recordings for the data presented

in Chapters Three, Four and Five.

Daniel Wong developed the TRACS beamformer imaging method used in Chapter Four. Salim

Dharssi helped me develop an objective method to analyze the beamformer data and visualize dipole

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activity in 63,646 voxels in the brain, shown in Figures 4-2 and 4-4. Alexander Andrews provided

some assistance with this as well. Dr. Sam Doesburg and Marc Lalancette provided assistance with

the permutation analyses used in Chapter Four and shown in Figures 4-3, 4-5 and 4-6. Dr. Sam

Doesburg also provided the Matlab and Mathematica codes for the connectivity analyses in Figures

5-1, 5-2, 5-3. Catharine McCann helped me validate the suppression of the implant artifact using

independent component analyses, shown in Supplementary Figure 5-4.

Funding and Studentships

Studentship funding for my Doctoral work has been provided by an Entrance Award and Open

Fellowship from the Institute of Medical Sciences at the University of Toronto, a Post-Graduate

Medical Award (PGME) from the Faculty of Medicine at the University of Toronto, the Hilda &

William Courtney Clayton Paediatric Research Fund Fellowship, the Margaret & Howard Gamble

Research Grant, several Ontario Graduate Scholarships (OGS) from the Ontario Ministry of Training,

Colleges and Universities, a Sick Kid’s Research Training Competition Studentship (RESTRACOMP)

and a Sick Kid’s Clinician-Scientist Training Program Studentship (CSTP) from the Hospital for Sick

Children Foundation Student Scholarship Program, and a Medical Research Grant from The Hearing

Foundation of Canada. I was also granted a Conference Award from the School of Graduate Studies

at the University of Toronto, two Trainee Travel Awards from The Hospital for Sick Children

Foundation, and numerous Travel Awards from the National Institute of Health – National Institute

of Deafness and Other Communication Disorders (NIH NIDCD).

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Table of Contents

Abstract ..................................................................................................................................................... ii

Acknowledgements ................................................................................................................................ iv

Contributions .......................................................................................................................................... vi

Funding and Studentships.................................................................................................................... vii

Table of Contents................................................................................................................................. viii

List of Tables ......................................................................................................................................... xv

List of Figures ....................................................................................................................................... xvi

List of Abbreviations ........................................................................................................................... xix

Thesis Roadmap .................................................................................................................................... xx

1. Chapter One – Research rationale, questions and hypotheses ................................................... 1

2. Chapter Two – General introduction and background................................................................ 4

2.1 Cochlear implants establish hearing in children who are deaf ................................... 4

2.2 Normal hearing requires intact auditory structures and functions ............................ 9

2.3 Milestones in auditory development ............................................................................ 15

2.4 Auditory experience shapes auditory development ................................................... 19

2.5 Bilateral deafness in childhood drives abnormal reorganization in the brain ........ 22

2.6 Unilateral deafness promotes abnormal changes in the auditory brain .................. 26

2.7 Multiple effects of childhood deafness predict outcomes after cochlear

implantation ..................................................................................................................... 28

2.8 Electrophysiological measures assess auditory cortical development and map

underlying auditory activity in the brain ...................................................................... 33

2.9 Unilateral cochlear implantation restores hearing and promotes auditory

development in the brainstem and midbrain, but the trajectory of cortical auditory

maturation remains unclear ........................................................................................... 37

ix

2.10 Differences from normal persist in auditory processing despite long durations of

unilateral cochlear implant use...................................................................................... 41

2.11 Binaural processing is not available with unilateral hearing ..................................... 43

2.12 Evidence of a short sensitive period for bilateral input in human auditory

development .................................................................................................................... 45

2.13 Does long-term unilateral cochlear implant use have abnormal consequences for

cortical auditory development? ..................................................................................... 51

3. Chapter Three – Central auditory development after long-term cochlear implant use ........ 54

3.1 Abstract .................................................................................................................................... 54

3.2 Introduction ............................................................................................................................. 55

3.3.1 Deafness prior to cochlear implantation alters normal brain development .......... 55

3.3.2 Early auditory cortical development in cochlear implant users follows a normal-

like trajectory ................................................................................................................... 56

3.3.3 Auditory cortical maturation may be altered in cochlear implant users ................. 57

3.4 Methods .................................................................................................................................... 58

3.4.1 Participants ...................................................................................................................... 58

3.4.2 Evoked potential recordings ......................................................................................... 61

3.4.3 Analysis of the electrically-evoked cortical responses ............................................... 62

3.5 Results ....................................................................................................................................... 64

3.5.1 Cortical responses continue to mature with auditory experience in normal hearing

children and in users of cochlear implants.................................................................. 64

3.5.2 Cortical development in users of cochlear implants follows a normal trajectory with

time-in-sound with differences emerging in latencies greater than 150ms ............ 66

3.5.3 Normal-like cortical maturation in the 50 to 150ms latency range is time and

experience dependent..................................................................................................... 69

3.5.4 Cortical abnormalities in the 150 to 300ms latency range is experience dependent .

........................................................................................................................................... 71

3.6 Discussion ................................................................................................................................ 73

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3.6.1 Cortical activity early in development is similar between cochlear implant users and

their normal hearing peers ............................................................................................. 73

3.6.2 Long-term cortical development follows a normal-like trajectory with time-in-

sound ................................................................................................................................ 76

3.6.3 Differences from normal in the later cortical peaks may reflect increased cortical

activity from non-auditory modalities ......................................................................... 78

3.7 Conclusion ............................................................................................................................... 80

4. Chapter Four – Early unilateral cochlear implantation promotes mature cortical asymmetries

in adolescents who are deaf ............................................................................................................ 82

4.1 Abstract .................................................................................................................................... 82

4.2 Introduction ............................................................................................................................. 83

4.3 Materials and Methods ........................................................................................................... 86

4.3.1 Participants ...................................................................................................................... 86

4.3.2 Recording cortical responses ........................................................................................ 87

4.3.3 Localization of cortical evoked peaks .......................................................................... 89

4.3.4 Speech perception tests to assess outcomes with CIs ............................................... 90

4.4 Results ....................................................................................................................................... 91

4.4.1 Tone-bursts preferentially stimulate the right auditory cortex in adolescents with

normal hearing ................................................................................................................ 91

4.4.2 Long periods of unilateral CI use drive abnormal patterns of auditory activity ... 95

4.4.3 Additional cortical areas are recruited by cochlear implant stimulation relative to

normal ........................................................................................................................... 101

4.4.4 Abnormal activity evoked by the naïve side predicts poor speech perception

outcomes ....................................................................................................................... 103

4.5 Discussion .............................................................................................................................. 104

4.5.1 Hemispheric specialization requires normal bilateral hearing ............................... 105

4.5.2 Long periods of unilateral CI use strengthens pathways from the stimulated ear ....

........................................................................................................................................ 107

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4.5.3 Activity evoked by stimulation of the newly implanted ear is abnormal ............. 110

4.6 Conclusion ............................................................................................................................. 111

4.7 Supplementary Information on Methods .......................................................................... 113

5. Chapter Five – Temporally coordinated activity in the brain is promoted by long-term

cochlear implant use in children ................................................................................................. 117

5.1 Abstract .................................................................................................................................. 117

5.2 Introduction ........................................................................................................................... 118

5.3 Methods .................................................................................................................................. 122

5.3.1 Participants and evoked potentials recordings ........................................................ 122

5.3.2 Phase synchronization analysis .................................................................................. 124

5.4 Results ..................................................................................................................................... 126

5.4.1 Less cortical synchrony is evoked from tone-bursts in normal right than left ears ..

........................................................................................................................................ 126

5.4.2 Right cochlear implants promote atypical cortical synchrony and leave deprived

pathways abnormally desynchronized ...................................................................... 130

5.5 Discussion .............................................................................................................................. 135

5.5.1 A specialized cortical hearing network normally matures by adolescence .......... 135

5.5.2 Increased connectivity in long-term unilateral CI users reflects greater processing

demands ........................................................................................................................ 137

5.5.3 Desynchronized activity evoked by the naïve-left CI suggests disorganization in the

deprived pathways ....................................................................................................... 139

5.6 Conclusion ............................................................................................................................. 142

5.7 Supplementary Information for Methods ......................................................................... 143

5.7.1 Independent component analysis to reject cochlear implant artifact .................. 143

5.7.2 Scalp current density to reduce spurious synchronization cause from volume

conduction .................................................................................................................... 146

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6. Chapter Six – General discussion ............................................................................................... 148

6.1 Normal maturation of the auditory system requires hearing in both ears to be

normal ..................................................................................................................................... 150

6.2 Unilateral implant stimulation promotes cortical maturation but leaves the brain with

abnormal organization.......................................................................................................... 154

6.3 Long-term unilateral deprivation drives abnormally altered and disorganized activity in

the unstimulated pathways................................................................................................... 161

7. Chapter Seven – Current and future directions ................................................................... 168

7.1 Does bilateral cochlear implant experience promote auditory development in pathways

from the newly implanted side? .......................................................................................... 168

7.2 Does the presence of residual hearing in the un-implanted ear protect these pathways

from abnormal effects of unilateral deprivation? ............................................................. 169

7.3 Can auditory development in the second implanted ear be promoted by using an aural

patching method? .................................................................................................................. 170

7.4 Is auditory activity evoked by cochlear implants stimulation mediated by mechanisms

of attention or multi-sensory stimulation? ........................................................................ 171

7.5 Can attention-driven and/or multi-modal auditory therapy drive improvements in

auditory processing and ease of listening? ......................................................................... 172

7.6 Can holistic therapies that incorporate music and/or exercise promote improvements

in auditory processing and accelerate auditory development after cochlear implantation?

................................................................................................................................................. 174

8. Chapter Eight – Conclusion ........................................................................................................ 176

References ........................................................................................................................................... 178

Appendices .......................................................................................................................................... 230

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What is the optimal timing for bilateral cochlear implantation in children? ............................. 230

Abstract ............................................................................................................................................ 230

Introduction .................................................................................................................................... 231

Groups of Study Participants ........................................................................................................ 233

Mismatches in bilateral activity following a period of unilateral cochlear implant use ........ 234

Auditory brainstem responses ................................................................................................. 234

Cortical responses ..................................................................................................................... 237

Perception of speech and inter-implant timing and level cues ................................................ 239

Conclusion ....................................................................................................................................... 241

References ........................................................................................................................................ 242

Benefits and detriments of unilateral cochlear implant use on bilateral auditory development in

children who are deaf ................................................................................................................... 246

Abstract ............................................................................................................................................ 246

Introduction .................................................................................................................................... 246

The auditory system reorganizes when bilaterally deprived ..................................................... 247

Unilateral cochlear implantation restores hearing and promotes auditory development .... 249

Differences from normal persist in auditory processing despite long durations of unilateral

cochlear implant use.................................................................................................................................. 255

Binaural hearing is not available to traditional unilateral cochlear implant users .................. 256

Evidence of a short sensitive period for bilateral input in human auditory development .. 258

Long-term unilateral implant use in older children causes lasting asymmetry in the bilateral

auditory pathways ...................................................................................................................................... 264

xiv

Bilateral implantation within a sensitive period improves perception of binaural timing

cues 266

Conclusions ..................................................................................................................................... 268

References ........................................................................................................................................ 269

Copyright Acknowledgements ......................................................................................................... 282

Peer-Reviewed Publications .......................................................................................................... 282

Peer-Reviewed Presentations ........................................................................................................ 283

xv

List of Tables

Table 2-1: Milestones of structural, electrophysiological and behavioural maturation of activity in the

central auditory pathway. Reproduced with permission from Eggermont and Moore (2012) ........... 19

Table 3-1: Mean (X) ± standard deviations (SD) of demographic information of the CI users. ....... 60

Table 5-1: Demographic Information ...................................................................................................... 123

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List of Figures

Figure 2-1: Illustration of the external and internal components of a CI device in a diagram of the

ear. Figure reproduced with permission from Papsin and Gordon (2007). ............................................. 7

Figure 2-2: Diagram of the ascending auditory pathway. Figure reproduced with permission from

(Netter 2010). ................................................................................................................................................... 11

Figure 2-3: Conceptual diagram of ascending projections of the primary auditory pathway (red boxes)

and the non-primary auditory pathways (green boxes). ............................................................................. 15

Figure 2-4: Widespread effects of bilateral deafness in all levels of the auditory pathways. Figure

reproduced with permission from Kral and Sharma (2012). ..................................................................... 24

Figure 2-5: Heterogeneity in the cause and onset of pediatric deafness. Figure reproduced with

permission from Morton and Nance (2006). ............................................................................................... 29

Figure 2-6: P1 latency as a function of age at implantation. Figure adapted then reproduced with

permission from Sharma, Dorman et al. (2002). ......................................................................................... 31

Figure 2-7: Speech perception outcomes as a function of age at implantation. Figure reproduced

with permission from Harrison, Gordon et al. (2005). .............................................................................. 32

Figure 2-8: Development of auditory brainstem responses after cochlear implantation. Figure

reproduced with permission from Gordon, Jiwani et al. (2013). .............................................................. 39

Figure 2-9: Development of auditory middle latency responses after cochlear implantation. Figure

reproduced with permission from Gordon, Jiwani et al. (2013). .............................................................. 41

Figure 2-10: Accuracy and reaction time for CI processing of auditory input with and without visual

input. .................................................................................................................................................................. 43

Figure 2-11: Cortical dipole activity evoked by auditory input in children with different durations of

unilateral implant use. Reproduced with permission from Gordon, Wong et al. (2013). .................... 51

Figure 3-1: Normal hearing mature cortical response. .............................................................................. 62

xvii

Figure 3-2: Development of the cortical response over time. ................................................................. 65

Figure 3-3: Cortical response difference as a function of time after cochlear implantation compared

to the normal hearing mature waveform. ..................................................................................................... 68

Figure 3-4: Difference in latency and amplitude of the P1-N1 complex as a function of time-in-sound

compared to normal hearing peers. ............................................................................................................... 70


compared to normal hearing peers. ............................................................................................................... 72

Figure 4-1: Balanced stimulus levels between the experienced and newly implanted ears determined

by matching peak eV amplitude of the brainstem response. ..................................................................... 88

Figure 4-2: Cortical dipole activity evoked by auditory stimulation of the right and left ears of normal

hearing adolescents. ......................................................................................................................................... 93

Figure 4-3: Aural preference evoked by auditory stimulation of the right and left ears of normal

hearing adolescents. ......................................................................................................................................... 94

Figure 4-4: Cortical dipole activity evoked by auditory stimulation of the experienced-right and naïve-

left ears of CI users. ......................................................................................................................................... 98

Figure 4-5: Cortical lateralization evoked by stimulation of the right/experienced and left/naïve

ear/implant in normal hearing adolescents and CI users. ...................................................................... 101

Figure 4-6: Group differences in cortical dipole activity between normal hearing adolescents and CI

users. ............................................................................................................................................................... 103

Figure 4-7: Speech perception performance on the experienced-right and naïve-left sides in CI users.

......................................................................................................................................................................... 104

Supplementary Figure 4-8: Example from one child with 15.95 years of CI experience in the right

ear indicates activity underlying the mature peak P2. ............................................................................... 116

Figure 5-1: Cortical oscillatory synchronization evoked by auditory stimulation of the right and left

ears of normal hearing adolescents. ........................................................................................................... 129

xviii

Figure 5-2: Cortical oscillatory synchronization evoked by auditory stimulation of the experienced-

right and naïve-left ears in CI users. ........................................................................................................... 133

Figure 5-3: Difference in cortical oscillatory synchronization evoked by auditory stimulation of the

right/experienced and left/naive ears/implant of normal hearing adolescents and CI users. .......... 134

Supplementary Figure 5-4: Independent component analysis to remove contamination of CI

artefact on the cortical response. ................................................................................................................ 146

xix

List of Abbreviations

AEP = Auditory Evoked Potentials

A-V Therapy = Auditory-Verbal Therapy

AVCN = Anteroventral Cochlear Nucleus

CAST = Computer-Assisted Speech Training

CI = Cochlear Implant

GJB-2 protein = Gap Junction Beta-2 protein

EEG = Electro-encephalography

FFW = Fast ForWord

ICA = Independent Component Analysis

LSO = Lateral Superior Olive

MEG = Magneto-encephalography

MNI = Montreal Neurological Institute

MSO = Medial Superior Olive

MRI = Magnetic Resonance Imaging

PBK words = Phonetically Balanced Kindergarden words

PET = Positron Emission Tomography

SOC = Superior Olivary Complex

TRACS Beamformer = Time Restricted Artifact and Coherent Suppression Beamformer

xx

Thesis Roadmap

This Thesis is organized into eight main chapters and one appendix chapter. Chapter One

and Two describe a general introduction to the main research questions explored in Chapters Three,

Four and Five. Background literature in this chapter consists of a description of auditory system

physiology and development both in children with normal hearing and known results from children

using cochlear implants. Chapter Three explores the long-term cortical auditory development in users

of cochlear implants, from infancy to adolescence. The trajectory of cortical auditory development in

this population is compared to that of normal hearing peers who are matched for chronological age

and hearing-age. This chapter has been published in Clinical Neurophysiology. In Chapters Four and

Five, we unwrap the cortical response and use a newly developed beamformer imaging method

(Chapter Four) and analyses of neural synchronization (Chapter Five) to map the activity underlying

the cortical response in both CI users and their peers with normal hearing. The beamformer imaging

method used in Chapter Four is an objective method that allows us to localize the cortical generators

underlying the recorded cortical activity in the temporal, frontal, parietal and occipital lobes in each

hemisphere when the first and second implants are stimulated separately. This manuscript has been

submitted to Human Brain Mapping and is currently under revision. In Chapter Five, we assess

whether different brain regions respond to sound in a synchronized, co-ordinated manner to

determine how different areas of the brain communicate with each other in response to sound.

Interactions across brain areas are believed to reflect cognitive processes that cochlear implant users

recruit to process auditory input. We compare this to normal hearing individuals to map the auditory

cortical network evoked by sound stimulation of the first and second implants. This manuscript has

been submitted to Cerebral Cortex and is currently under revision. Chapter Six draws the three studies

together into a general discussion. Chapter Seven provides a brief outline of relevant research that is

currently being conducted in our laboratory and suggests new directions for future research. Here, I

stress the importance of developing appropriate, effective and targeted auditory rehabilitation

therapies. Finally, I conclude this work in Chapter Eight with a brief recapitulation of the findings

shared in the present Thesis. The Appendix section of this Thesis includes two related review papers

published in Cochlear Implants International and Frontiers in Psychology. These papers are related

to this work but were written with a specific focus to address effects of unilateral CI stimulation on

binaural hearing after bilateral implantation. In these papers, we suggested that cochlear implants

should be provided to children early and in both ears.

1

1. Chapter One – Research rationale, questions and hypotheses

Children with severe to profound sensorineural hearing loss can now hear and develop oral

speech and language abilities with the use of an auditory prosthesis that is surgically placed in the

cochlea (inner ear), called a cochlear implant (CI). A CI is a small and complex electronic device that

sends electrical pulses from a series of electrodes in the cochlea to stimulate the auditory nerve with

auditory input. This input is carried by the auditory pathways to various regions of the cortex. The

user ultimately perceives this signal as sounds. The aims of implantation in children are to halt/reverse

any effects of deafness on the brain and to promote normal auditory development. Unfortunately,

CIs do not restore normal hearing, only provide a crude representation of acoustic sounds and may

not be able to completely reverse the effects of deafness in early life, which is likely to compromise

both of these objectives. It is clear that providing CIs early in life limits deafness-induced

reorganization of the auditory brain, as CI users show increasing activity in the auditory cortex (Suarez

et al., 1999, Pantev et al., 2006) and improvements in speech and language outcomes (Harrison,

Gordon et al. 2005) as they adapt to the artificial electrical stimulation from this unique device.

Unfortunately however, implants were traditionally provided to children in only one ear (i.e.,

unilaterally). Thus, the coupling of atypical electrical input delivered by this device to the stimulated

pathways with the long-term unilateral absence of auditory input to the opposite and deprived side

might drive abnormal maturation of auditory thalamo-cortical and cortico-cortical connections

(Ponton and Eggermont 2001; Eggermont and Ponton 2003) and/or maladaptive reorganization in

the auditory brain (Lee and Winer 2005; Lee, Giraud et al. 2007). These abnormalities could in turn

affect cognitive and perceptual functions such as memory processes, attention, and executive

processes. At the same time, it has recently been shown that leaving the opposite ear deprived of

auditory input beyond an early sensitive period of 1.5 years (Gordon, Wong et al. 2013), which

corresponds to the time-course of brainstem maturation, leaves those pathways unprotected from

abnormal deafness-induced reorganization and compromises bilateral auditory development (Gordon,

Jiwani et al. 2013; Gordon, Wong et al. 2013).

In the experiments of the present Thesis, we explore whether missing this early sensitive period

and driving maturation of the auditory cortex with over a decade of unilateral CI stimulation causes

permanent abnormalities in cortical activity and reorganization in the deprived pathways. In general,

we are asking whether long-term unilateral implant use drives development of pathways from this ear

2

at the expense of pathways from the other ear. Recently, many adolescents that we follow in our CI

Program who had over a decade of unilateral hearing experience with their implant have received a

second device in their opposite-deprived ear. This gave us a unique opportunity to explore the effects

of long-term unilateral implant stimulation/deprivation in the adolescent brain and ask whether the

development of cortical activity in the deprived auditory pathways is compromised by long-term

unilateral implant stimulation/deprivation. Through the course of my Doctorate work, we have

developed the necessary tools to image cortical function in this population using measures of electric

current evoked in the auditory cortex by the implant. We are now in a unique position to answer

important questions regarding the impact of early unilateral cochlear implantation on the development

of the auditory brain network and assess the extent to which our goals of preserving normal auditory

development in children who hear with a unilateral CI have been realized by asking the following

questions in chapters Three, Four and Five:

Chapter Three:

1) Does the auditory system mature in children who are deaf with long-term unilateral CI use?

Chapter Four:

2) Does long-term unilateral CI stimulation promote activity in cortical areas which normally

respond to sound?

3) Is this activity compromised in the deprived contralateral pathways?

Chapter Five:

4) Does long-term unilateral CI stimulation promote coordinated cortical activity (i.e., neural

networks), which is normally activated in response to sound?

5) Are the pathways from the deprived ear segregated from these cortical hearing networks?

We hypothesize that long-term unilateral CI stimulation in children will promote development

of the auditory cortex at normal rates, but will not eliminate reorganization of the brain caused by

bilateral deafness prior to implantation and unilateral deprivation afterward. We expect to find that

CI users will recruit more cortical resources to process sound from the ear they listened to for most

of their lives, reflecting a profound reorganization of the cortical network for CI listening. At the same

3

time, we hypothesize that cortical activity underlying the pathways from the opposite and deprived ear

will be abnormal and segregated from the experienced side, in turn placing this ear at a disadvantage

for auditory processing. This will translate into poor functional outcomes, thereby highlighting the

deleterious effects of unilateral deprivation on the brain. Understanding the effects of deafness and

abnormal hearing during development is important to improve clinical care for children who are deaf

and to guide novel targeted therapies to capitalize on parts of the auditory network that are activated

in CI users to promote optimal CI hearing for children/adolescents who are deaf.

4

2. Chapter Two – General introduction and background

2.1 Cochlear implants establish hearing in children who are deaf

Approximately 1.2 to 5.7 per 1,000 children in developed countries suffer from a permanent

hearing loss (Yoshinaga-Itano, Sedey et al. 1998; Mohr, Feldman et al. 2000; Fortnum, Summerfield et

al. 2001; Smith, Bale Jr et al. 2005; Morton and Nance 2006; Mehra, Eavey et al. 2009; Qi and Mitchell

2012). An estimated 1.33 per 1,000 children are born with a hearing loss that is both bilateral and at

least moderate in severity (thresholds >40dB HL) (Morton and Nance 2006; Mehra, Eavey et al. 2009)

with 4 per 10,000 babies born profoundly deaf each year (Smith, Bale Jr et al. 2005). The prevalence

of hearing impairments increases with age as progressive and acquired hearing losses develop during

childhood and adolescence (Mehra, Eavey et al. 2009; Shargorodsky, Curhan et al. 2010), and reaches

a rate of 2.7 per 1,000 children before the age of five years and 3.5 per 1,000 during adolescence

(Morton and Nance 2006). Such hearing impairments in childhood have detrimental consequences

for the development of hearing and spoken language acquisition (Yoshinaga-Itano, Sedey et al. 1998;

Yoshinaga-Itano, Coulter et al. 2000), educational and professional opportunities (Yoshinaga-Itano,

Coulter et al. 2001; Yoshinaga-Itano 2003; Yoshinaga‐Itano 2003; Qi and Mitchell 2012), and

psychosocial challenges related to low self-esteem and decreased quality of life – all of which lead to

difficulties with social and cultural integration (Bess, Dodd-Murphy et al. 1998) with a high cost to

society (Mohr, Feldman et al. 2000). Children who were identified with a hearing loss early (i.e., by 2

to 3 months) and received appropriate auditory intervention by 6 months of age had significantly better

receptive and expressive language skills (Yoshinaga-Itano, Sedey et al. 1996; Yoshinaga-Itano, Sedey

et al. 1998; Moeller 2000) as well as improved social and emotional development (Morton and Nance

2006) compared to those children who were diagnosed later in life, regardless of the degree of hearing

loss (Mah-rya and Yoshinaga-Itano 1995; Yoshinaga-Itano, Sedey et al. 1996).

For children with severe to profound sensorineural hearing loss who benefit little or not at all

from their hearing aids, hearing can only be established with the use of CIs. The CI is surgically

implanted into the cochlea and allows children who are deaf to develop oral speech and language. The

CI was made available to children in North America in the early 1990s and works by stimulating the

auditory pathways with electrical pulses. An illustration of the external and internal components of

the CI device in Figure 2.1 shows an array of 20 active electrodes (and two external ground electrodes),

which is surgically placed in the scala tympani of the cochlea. These electrodes deliver electrical pulses

5

to stimulate the auditory nerve. This electrical input is then carried by the auditory pathways to regions

of the auditory cortex and allows the user to perceive these signals as sounds. External equipment,

the behind-the-ear speech processor, takes in sounds through the microphone, converts them into a

digital signal, extracts frequency and intensity information from the temporal envelope of the acoustic

signal and sends instructions to an internal device through a transcutaneous radio frequency

transmitting coil.

The speech processor is a key component of the CI system (Zeng 2004; Zeng, Rebscher et al.

2008). It processes and encodes the incoming signal by analyzing its frequency and intensity, and

band-pass filters the sound into 22 independent channels, each corresponding to one implanted

electrode. It also contains a directional microphone that adapts to the sounds in the environment,

wireless capabilities to stream sounds from external commercial devices (i.e., TV, phone, MP3 player,

etc…) and memory which stores patient-specific information including dynamic range settings. The

dynamic range, which is the difference between the lower threshold (T) (minimum) and upper comfort

(C) (maximum loudness) level that a CI delivers to the auditory system is programmed for a number

of electrodes by an audiologist using proprietary programming software from the CI manufacturer

(Vaerenberg, Smits et al. 2014). Instructions regarding the current level and timing of stimulation are

delivered by an external transmitter to an internal receiver-stimulator through a radio frequency signal.

These components are held in place on either side of the scalp by a magnet that is placed underneath

the skin during surgery. The internal receiver-stimulator then sends this information to the electrodes

which are organized to mimic the normal cochlea; high frequency sounds are allocated to basal

electrodes with lower frequencies being allocated to progressively more apical electrodes. The

electrodes stimulate surviving spiral ganglion nerve fibers, which in turn, carry auditory activity through

the auditory pathways to various parts of the cortex. In this way, the child receives an electrical

representation of the acoustic world and learns to understand sounds including speech and language.

7

Unfortunately, the current CI only codes the temporal envelope of the acoustic signal. This

means that the fine-structure of sound that is important for discriminating between pitches, is lost in

CI listening (Zeng 2004; Zeng, Rebscher et al. 2008). CIs also have a much narrower bandwidth than

the normal hearing cochlea (i.e., 20 channels in the CI compared to activity provided by over 3,000

inner hair cells in the normal cochlea which synapse to ~30,000 afferent auditory nerve fibers). The

frequency resolution of CI hearing is therefore significantly poorer than normal (Rubinstein 2004)

particularly given that electrical stimulation excites a much broader/unfocused population of neurons

than acoustic stimulation (Drennan and Rubinstein 2008; Zeng, Rebscher et al. 2008). The limited

spectral selectivity of CI stimulation makes understanding tonal languages and music perception

particularly difficult. Indeed, since musical melodies are composed of complex tones, CI users typically

do not enjoy music, as musical appreciation relies on the ability to extract fine-structure information

from the signal (Drennan and Rubinstein 2008).

Figure 2-1: Illustration of the external and internal components of a CI device in a diagram of the ear.

Figure reproduced with permission from Papsin and Gordon (2007).

The external component houses a microphone, which picks up sounds from the environment and

sends it to the speech processor. The processor converts this acoustic input into an electric signal, and

analyzes the frequency and intensity information of the sound. The digitized signal is then sent by the

transmitting coil to the receiver-stimulator in the internal component via a radio frequency signal,

which in turn sends this information to an array of electrodes that is implanted into the cochlea. The

external transmitter coil and internal receiver-stimulator are connected over the skin flap by a pair of

magnets. The implanted electrodes are organized to mimic the tonotopic arrangement of the cochlea;

high frequencies are allocated to basal electrodes (i.e., electrode 3 in the Cochlear Nucleus device is

roughly equivalent to 1,500Hz) while low frequencies are allocated to more basal electrodes (i.e.,

electrode 20 in the same device corresponds to ~500Hz). The cross section of the cochlea on the top

right corner shows the array of electrodes that are surgically implanted into the scala tympani.

Electrical pulses, which are delivered to the electrode array in the form of biphasic pulses, stimulate

surviving spiral ganglion nerve fibers. This input, in turn, is carried along the ascending auditory system

to various regions of the cortex and allows the listener to perceive sounds.

8

In addition, current devices use a monopolar mode of stimulation, which further hinders the

spatial representation of the implant signal. Monopolar stimulation result in larger spread of electrical

activation/splattering and neural excitation. This occurs because the electric current from activated

electrodes in the cochlea is spread over a larger distance to the return ground electrode, which is placed

outside the cochlea (in bipolar stimulation which is only used in older devices such as the N22 implant,

each active electrode is paired with its own closely situated ground electrode) (Boëx, de Balthasar et al.

2003). A single electrode cannot provide the level of tuning and timing that resembles the normal

pattern of neural activity (Zeng, Rebscher et al. 2008). Thus, activation of a reduced number of

auditory neurons to a potentially abnormal auditory pathway with abnormal auditory input imposes

additional limitations to CI listening. This means that although CIs establish hearing to individuals

who are deaf, listening to sounds with a CI is far from normal.

Despite these limitations, children amaze us by achieving excellent listening and oral

communication abilities, learn and integrate in mainstream environments and communicate effectively.

Chronic auditory stimulation with a unilateral implant promotes development in the auditory

brainstem (Gordon, Papsin et al. 2003; Gordon, Papsin et al. 2006; Gordon, Papsin et al. 2007;

Gordon, Valero et al. 2007; Gordon, Valero et al. 2008; Gordon, Salloum et al. 2012) and thalamo-

cortex (Ponton, Don et al. 1996; Eggermont, Ponton et al. 1997; Ponton and Eggermont 2001; Sharma,

Dorman et al. 2002; Sharma, Dorman et al. 2002; Eggermont and Ponton 2003; Gordon, Papsin et al.

2005; Sharma, Dorman et al. 2005; Sharma and Dorman 2006; Gilley, Sharma et al. 2008; Gordon,

Tanaka et al. 2008; Sharma, Nash et al. 2009; Gordon, Wong et al. 2010; Gordon, Tanaka et al. 2011;

Kral and Sharma 2012; Gordon, Wong et al. 2013) in children who are deaf from infancy. Nonetheless,

performance on auditory processing tasks remains below that of normal hearing listeners even after

years of CI experience, especially in challenging listening situations (Gordon and Papsin 2009).

Children using CIs to hear still require extensive therapy to achieve optimal communication outcomes

and their hearing deteriorates significantly in noise and reverberant environments (Basura et al., 2009;

Gordon and Papsin, 2009a, 2009b; Papsin and Gordon, 2008). Furthermore, we are also finding that

children with CIs use compensatory multi-sensory strategies more effectively than their peers with

normal hearing to facilitate spoken language comprehension and complex auditory processing, such

as understanding subtle emotional cues in speech (Hopyan-Misakyan, Gordon et al. 2009). These

functional differences could be underpinned by strengthening of sensory input (most notably, vision)

into auditory cortices in deaf individuals (Giraud, Price et al. 2001; Dehmel, Cui et al. 2008) due to

9

bilateral deafness prior to cochlear implantation, unilateral deprivation afterwards, and the altered

representation of sound delivered by this unique device.

2.2 Normal hearing requires intact auditory structures and functions

In order to understand the effects of deafness and cochlear implantation on the auditory

system, we must first understand how normal hearing works and develops. Normal hearing requires

that structure and function in all parts of the auditory pathways be intact. Hearing loss of any kind,

whether it be temporary or permanent, conductive or sensorineural, congenital or acquired, stable or

progressive will disrupt the structure and/or function of the auditory system and may ultimately affect

the trajectory of auditory development in children.

Figure 2.2 shows the ascending pathways of the normal auditory system from cochlea to

cortex. Acoustic sound waves are collected by the pinna and travel into the ear canal to cause

vibrations of the tympanic membrane and ossicular chain in the middle ear cavity. Mechanical

vibrations of the stapes footplate against the oval window of the cochlea cause fluid

displacement/waves in the cochlea. The cochlea is a snail-shaped organ which consists of 2.5 turns

and is approximately 35 mm long in humans (Von Békésy and Wever 1960; Pujol and Hilding 1973;

Nadol Jr 1988; Pujol, Lavigne-rebillard et al. 1991). The spiral turns of the cochlea are divided

transversely into three fluid-filled spaces: the scala vestibuli which is anatomically connected to the

oval window, the scala media which houses the organ of corti, and the scala tympani, which is

connected to the round window. The scala media is separated from the scala vestibuli by Reissner’s

membrane and from the scala tympani by the Basilar membrane. The Basilar membrane is tonopically

organized. Its geometry, which is narrower and stiffer at the base (near the oval window) and wider

and flexible at the apical end, allows receptor cells arranged at different places along the basilar

membrane to respond to different frequencies (Von Békésy and Wever 1960; Lim 1980; Lim 1986;

Nadol Jr 1988; Gopen, Rosowski et al. 1997).

Vibrations of the ossicles (i.e., stapes against the oval window) in the middle ear causes waves

of perylimphatic fluid in the scala vestibuli, which in turn drives movement of endolymph in the

cochlear duct (i.e., scala media) and displacement of the basilar membrane into a sheering motion.

Displacement of the basilar membrane stimulates the hair cell receptors in the organ of corti.

10

Approximately 15,000 hair cells are arranged along the cochlear duct as three rows of outer hair cells

and one row of inner hair cells (Lim 1980; Lim 1986; Gopen, Rosowski et al. 1997). Stimulation of

the outer and subsequently, inner hair cells causes them to transduce sound movements into electrical

impulses/potentials which are transmitted to the spiral ganglia and auditory nerve (i.e., axons of the

spiral ganglion neurons form the auditory nerve). Auditory information is then carried along the

auditory pathways to the brainstem, thalamus and cortex via the afferent system.

11

Axons from spiral ganglion neurons enter the brainstem ipsilaterally from the endbulb of Held

in the cochlear nucleus. The cochlear nucleus, whose regions retain the tonotopic organization of the

cochlea, is divided into the dorsal cochlear nucleus, the anteroventral cochlear nucleus (AVCN), and

the posteroventral cochlear nucleus. Signals travel from the cochlear nucleus to both the ipsilateral

and contralateral superior olivary complex (SOC), which form the first relay for binaural processing.

Binaural processing refers to the ability of the auditory system to process and integrate auditory

information by comparing subtle differences in level and timing of sounds reaching the two ears. Inter-

aural level differences are mediated by the head shadow effect, which refers to a mechanism of the

head to partially attenuate sounds coming from one side of head while at the same time improving the

signal-to-ratio on the listening side. As a rule of thumb, only sounds with wavelengths that are shorter

than the size of the head can be reflected. In humans, this typically corresponds to frequencies higher

Figure 2-2: Diagram of the ascending auditory pathway. Figure reproduced with permission from

(Netter 2010).

Diagram of the cochlea and cortex in the top right indicate the tonotopic distribution of activity. High

frequencies are located towards the base of the cochlea and medially in the primary auditory cortex,

whereas low frequency information is distributed on the apical end and towards the lateral end of

Heschl’s gyrus. Transverse cross-section of the cochlea below shows the three fluid spaces of the

cochlea: the scala vestibuli which is connected to the oval window at the top, the scala media which

houses the organ of corti in the middle and the scala tympani which is connected to the round window

at the bottom. The organ of corti is shown in the bottom right. Sound vibrations which are picked

up by the outer ear and causes vibrations of the middle ear ossicles against the oval window create

fluid waves in the cochlea. These movements causes the basilar membrane to move in a shearing

motion and results in the stimulation of outer hair cells and subsequent depolarization of inner hair

cells which in turn release neurotransmitters into a spiral ganglion nerve terminal. Auditory

information is then carried to the ipsilateral auditory nerve, travels through the medial nucleus of the

trapezoid body, project onto the contralateral superior olivary complex, and ascends in this way

through the brainstem, midbrain, medial geniculate body in the thalamus to the auditory cortex in

Hesch’s gyrus in the temporal lobe.

12

than ~1,500Hz. The lateral superior olive (LSO) neurons are the primary site for processing such level

cues between both ears. The LSO is innervated by glutamatergic excitatory input from spherical bushy

cells of the ipsilateral AVCN and inhibitory input from the ipsilateral medial nucleus of the trapezoid

body which receive excitatory input from globular bushy cells of the contralateral AVCN (Grothe,

Pecka et al. 2010). On the other hand, the medial superior olive (MSO) codes for differences in timing

between the ears. Inter-aural timing differences are also mediated in part by the head shadow effect

and relies on differences in phase coding of low frequency sounds (~<1,500Hz) arriving at each ear.

The MSO is innervated by excitatory input from spherical busy cells in both the ipsilateral and

contralateral AVCN as well as binaural inhibitory input from the medial nucleus of the trapezoid body

(Grothe, Pecka et al. 2010).

It is at this stage of the auditory system that the primary (also known as lemniscal) and non-

primary (extra-lemniscal) auditory pathways diverge. A conceptual diagram of afferent projections

from each system is shown in Figure 2.3. In the primary or lemnical pathway, shown by the red boxes

in Figure 2.3, auditory signals from the SOC project to the central nucleus of the inferior colliculus in

the midbrain through the lateral lemniscal fibre tract. Input then ascends to the ventral medial

geniculate body in the thalamus and terminates on middle layers of the primary auditory cortex in

Heshl’s gyrus in the temporal lobe. Signals are then relayed to belt and parabelt association auditory

regions for further processing (Hu, Senatorov et al. 1994). Primary pathway responses to sound are

specific to auditory input, fast, sharply tuned and exhibit great fidelity for temporal and fine-frequency

tuning (Kraus, Smith et al. 1988; McGee, Kraus et al. 1991; Kraus, McGee et al. 1992; LeDoux 1992;

McGee, Kraus et al. 1992; Hu, Senatorov et al. 1994; Kraus, McGee et al. 1994; Moller and Rollins

2002; Hu 2003).

On the other hand, the non-primary or extra-lemniscal auditory pathway receives ascending

activity directly from the SOC to the central nucleus of the inferior colliculus, bypassing the lateral

lemnicus. The ascending trajectory of this pathway is shown by the green boxes in Figure 2.3. Input

then projects to the external nucleus and dorsal cortex of the inferior colliculus. Neurons in these

areas of the inferior colliculus have been shown to respond to both auditory and somatosensory input

(Moller and Rollins 2002). This activity innervates a group of nuclei in the posterior thalamus (Jones

1985) including the medial and caudal portions of the medial geniculate body, the posterior

intralaminar nucleus, the suprageniculate nucleus and the lateral posterior nucleus (Hu 2003). These

neurons all respond to multi-sensory input including auditory, visual and somatosensory information

13

with the latter two, the suprageniculate nucleus and the lateral posterior nucleus, being primarily

devoted to visual processing (Hu 2003). Of note, neurons of this pathway have direct and reciprocal

connections to the mesencephalic reticular formation. This means that activity in this pathway is

particularly sensitive to effects of arousal/sleep (Kraus, Smith et al. 1988; McGee, Kraus et al. 1991;

Kraus, McGee et al. 1992; LeDoux 1992; McGee, Kraus et al. 1992; Hu, Senatorov et al. 1994; Moller

and Rollins 2002; Hu 2003). At the same time, they also send efferent projections to several limbic

structures (i.e, amygdala, insular temporal lobe and striatum), the frontal cortex, the parieto-temporal

regions and the cerebellum (LeDoux 1992; Hu 2003) as they ascend to both the primary and

association areas of the auditory cortex. Because of these connections, neurons of the non-primary

pathway are influenced by changes in arousal/sleep and attention (Kraus, Smith et al. 1988; Kraus,

McGee et al. 1989; McGee, Kraus et al. 1991; Kraus, McGee et al. 1992; McGee, Kraus et al. 1992;

Kraus and McGee 1993; McGee, Kraus et al. 1993; Kraus, McGee et al. 1994), are particularly sensitive

to multi-modal input (Moller and Rollins 2002), are involved in emotional learning and memory

formation of behaviourally relevant sensory input (LeDoux 1992; Hu, Senatorov et al. 1994; Hu 2003),

and are more likely to be affected by plasticity-related changes (i.e., to demonstrate plasticity) (Kraus,

McGee et al. 1994). Of note however, despite these differences in auditory function between the

primary and non-primary auditory pathways, the distribution of inhibitory-excitatory potentials and

the sensory receptive fields of neurons in both pathways are regulated in a similar way (Hu 2003).

15

2.3 Milestones in auditory development

Early exposure to sound shapes auditory development. Normal human auditory development

begins in utero. The ability to hear begins as early as 25 to 29 weeks gestational age. Responses to

sounds, voices (particularly the mother’s voice) and music has been observed by as early as 32 weeks

gestational age (Pujol, Lavigne-rebillard et al. 1991). Exposure to these sounds in the last 10 to 12

weeks of fetal life are necessary for fine tuning of cochlear hair cells and their connections to spiral

ganglion neurons and cochlear nuclei (Graven and Browne 2008). During this time, listening to

meaningful sounds allows babies to form memory circuits in non-primary auditory and language areas

of the cortex which are connected to the limbic system, and create emotional memories that are

associated with speech and music (Graven and Browne 2008). Indeed, newborns show preference for

their mother’s voice at birth (DeCasper and Fifer 1980; DeCasper and Spence 1986), are capable of

discriminating sounds of their native language by 2 days of age (Bosch and Sebastián-Gallés 1997;

Bosch and Sebastián-Gallés 2001), and interestingly, infants younger than 6 months of age are able to

discriminate phonemic contrasts in nearly all languages (Trehub, 1976).

Early auditory discrimination is associated with early maturation of the cochlea, auditory nerve

Figure 2-3: Conceptual diagram of ascending projections of the primary auditory pathway (red boxes)

and the non-primary auditory pathways (green boxes).

Peripherals projections from the cochlea to the contralateral superior olivary complex are similar

between the two pathways. From there, activity of the primary pathway ascends through the lateral

lemniscus tract to the central nucleus of the inferior colliculus, ventral medial geniculate body in the

thalamus and terminates in the primary auditory cortex. The primary pathway serves as the most direct

route to the primary auditory cortex. On the other hand, afferent projections in the non-primary

pathway ascend from the superior olivary complex to both the external nucleus and dorsal portions of

the inferior colliculus and project to the caudal and medial regions of the medial geniculate body.

Activity then innervates both areas of the primary and association auditory cortex. The non-primary

pathway shares direct connections with the limbic system and reticular activating system, and sends

efferent input to the frontal cortex, parietotemporal regions and the cerebellum.

16

fibers, brainstem pathways, reticular activating system and cortical layer I (Moore and Guan 2001;

Eggermont and Moore 2012). Maturation of these processes is largely complete at birth but continues

to be refined until the second to third year of life (Moore and Guan 2001) as developmental increases

in myelin density, dendritic arborization and synaptic modifications occur (Moore and Guan 2001;

Moore 2002). These changes allow for more efficient synapses, increased synchrony and rapid

transmission/conduction velocity in the developing pathways. Functionally, refinement of these

processes has been associated with the ability to attribute meaning to sounds (Eggermont and Moore

2012). At this young age (i.e., 2 to 3 years), the auditory brainstem response (which reflects activity in

the auditory nerve and brainstem pathways) (Salamy and McKean 1976; Starr, Amlie et al. 1977; Jerger

and Hall 1980; Salamy 1984), the middle latency response (which reflects subcortical auditory activity

generated in the thalamus and the primary auditory cortex) (Fifer and Sierra-Irizarry 1988; Frizzo,

Funayama et al. 2007) and the late component P2 of the cortical evoked response (which reflects

auditory activity driven from association auditory areas and the reticular activating system of the non-

primary pathways) (Wunderlich and Cone-Wesson 2006; Wunderlich, Cone-Wesson et al. 2006) are

fully mature. Components of these various responses continue to change with age and maturation,

especially for the cortical response. Table 2.1, reproduced from Eggermont and Moore (2012), shows

a beautiful summary of the structural, electrophysiological and behavioural/functional correlates of

these responses in different stages of development from infancy to adolescence (>12 years of age).

The auditory cortex has the longest developmental time-course. Myelination of thalamo-

cortical projections in deep cortical layers begins around 1 year of age and continues until 4 years

(Moore and Guan 2001; Moore 2002). Superficial layers however, which represent cortico-cortical

connections, take much longer to mature. Dendritic cortical neurofilament proteins which are

necessary for axonal development (i.e., formation of axonal cytoskeleton) only begin to be expressed

in superficial cortical layers around 5 years of age and continue to change until 11 to 12 years when

they are considered mature (Moore and Guan 2001). The maturational time-course of these cortical

structures coincides with the emergence of adult-like polyphasic cortical evoked response waveforms

(peaks P1, N1 and P2) (Albrecht, Suchodoletz et al. 2000; Ponton, Eggermont et al. 2000; Ponton,

Eggermont et al. 2002) and with adult-like development of complex auditory processing skills (such as

processing masked or degraded speech, and listening to sounds in noise or reverberant environments)

(Ponton, Eggermont et al. 2000; Ponton and Eggermont 2001; Ponton, Eggermont et al. 2002;

Eggermont and Ponton 2003; Eggermont and Moore 2012). This indicates that maturation of

17

structure and function in the auditory brain continues well into adolescence and only becomes mature

after the second decade of life (Albrecht, Suchodoletz et al. 2000). Of interest, the human visual

auditory cortex also requires a decade to mature, with the superficial layers only becoming adult-like

around 15 years of age (Moore and Guan 2001), suggesting that adolescence marks an important

maturational period in brain development.

While the primary and non-primary auditory pathways follow a parallel maturational time-

course, each system seems to dominate auditory processing during different times in development.

This has been examined by assessing the contribution of the reticular activating system (Kraus, McGee

et al. 1989; Kraus, McGee et al. 1992; McGee, Kraus et al. 1992; McGee, Kraus et al. 1993) and the

influence of multi-sensory stimulation (Moller and Rollins 2002) on auditory processing in children

and adults. Kraus and colleagues indicated that the middle latency response was clearly detectable

during wakefulness and light stages of sleep in sleeping children but became suppressed as they

transitioned into deeper stages of sleep. Sleep did not affect these responses in adults however, and

their detectability increased with age (Kraus, McGee et al. 1989; Kraus, McGee et al. 1992; McGee,

Kraus et al. 1993). This indicates that the reticular activating system (which regulates states of arousal

and controls the sleep/wake cycles of sleep), which shares reciprocal connections with the non-primary

pathways, mediates auditory activity in children but not in adults. This is consistent with results from

Moller and Rollins who showed that children under 9 years of age, but not adults, perceived sounds as

louder when they received simultaneous auditory and somatosensory stimulation (Moller and Rollins

2002). These findings suggest that the non-primary pathways dominate auditory processing in the

immature brain. Over time however, as the primary pathways develop into maturation around 9 to 12

years of age (Albrecht, Suchodoletz et al. 2000; Ponton, Eggermont et al. 2000; Ponton, Eggermont et

al. 2002), involvement of the non-primary pathways for auditory processing decreases and

contributions from the primary system increases (Kraus, McGee et al. 1989; Kraus, McGee et al. 1992;

McGee, Kraus et al. 1993; Moller and Rollins 2002).

As cortical pathways in the brain mature, so does cortical specialization of each hemisphere.

Adolescents and adults develop brains that are structurally and functionally highly specialized

(Davidson 1984; Zatorre and Belin 2001; Le Grand, Mondloch et al. 2003; Toga and Thompson 2003;

Rivera, Reiss et al. 2005; Gotts, Jo et al. 2013). In the auditory system, a relative specialization for

temporal resolution relevant to speech processing has been observed in the left auditory cortex,

whereas association auditory areas of the right hemisphere are biased for processing spectral patterns

18

of sounds such as tones, melodies and music (Zatorre and Belin 2001; Zatorre, Belin et al. 2002;

Schönwiesner, Rübsamen et al. 2005; Jamison, Watkins et al. 2006). Much of this specialization in the

brain is shaped by sensory experience and perceptual skills that are acquired during development

(Penhune, Zatorre et al. 1996; Johnson 2001; Johnson 2011) and is related to normal neuroanatomical

maturation of the cortex which begin in early life and is mostly complete by adolescence (Giedd, Snell

et al. 1996; Giedd, Blumenthal et al. 1999; Johnson 2001; Blakemore and Choudhury 2006; Lenroot

and Giedd 2006; Johnson 2011; Lebel and Beaulieu 2011; Blakemore 2012; Lohmann and Kessels

2014).

Normal exposure to sounds in utero, during infancy and during childhood is thus important

to the normal development and maturation of the auditory pathways. Indeed, certain auditory

functions such as learning to speak different languages (Johnson and Newport 1989; Flege, Yeni-

Komshian et al. 1999; Birdsong and Molis 2001) or play musical instruments (Hyde, Lerch et al. 2009;

Steele, Bailey et al. 2013) are optimal when learned early in life, when the brain is maximally plastic and

best able to adapt to the environment (Johnson and Newport 1989; Flege, Yeni-Komshian et al. 1999;

Birdsong and Molis 2001; Munte, Altenmuller et al. 2002; Trainor, Shahin et al. 2003; Fujioka, Ross et

al. 2006; Hyde, Lerch et al. 2009; Kraus and Chandrasekaran 2010; Steele, Bailey et al. 2013).

Deprivation of auditory input during initials stages of development may arrest or delay/desynchronize

maturational processes of myelination, dendritic arborization, synaptogenesis, conduction velocities,

etc… – all of which are necessary for normal organization and function in the auditory system. In

addition, since mechanisms of plasticity decrease with increasing age (Lohmann and Kessels 2014),

absence of auditory input during critical periods in development may hinder thalamo-cortical and

cortico-cortical connections (Ponton and Eggermont 2001; Eggermont and Ponton 2003). This may

in turn drive long-lasting abnormalities and reorganization in the central auditory system (Finney, Fine

et al. 2001; Lee, Lee et al. 2001; Bavelier and Neville 2002).

19

2.4 Auditory experience shapes auditory development

The development of the auditory system is shaped by both intrinsic (experience-independent)

and extrinsic (experience-dependent) processes. Activity independent processes such as the growth

of nerve cells and formation of rudimentary tonotopic projections from spiral ganglion neurons (Heid,

Hartmann et al. 1998) to the cochlear nucleus, superior olivary complex, lateral lemniscus, inferior

colliculus (Heid, Jähn-Siebert et al. 1997) and primary auditory cortex (Hartmann, Shepherd et al. 1997)

Table 2-1: Milestones of structural, electrophysiological and behavioural maturation of activity in the

central auditory pathway. Reproduced with permission from Eggermont and Moore (2012)

20

were all preserved in the congenitally deaf auditory pathways of adult cats, despite complete and long-

term absence of auditory input. Rudimentary binaural sensitivity of primary auditory neurons in the

cortex was also maintained (Kral 2007; Kral and Eggermont 2007). This suggests that rudimentary

response properties and feature detection in the auditory cortex are genetically pre-determined and not

influenced by sensory experience (Friauf and Lohmann 1999). Nonetheless, maturation of neuronal

circuits in the brain are shaped and influenced by sensory stimulation/experience during critical

periods in development. “Environmental sounds (e.g., speech) will modulate and increase auditory

nerve activity, conductive hearing loss (e.g., otosclerosis, otitis media) will decrease and desynchronize

nerve activity, and sensorineural loss will reduce and broaden, or abolish nerve activity from damaged

parts of the cochlea” (p.147, Moore 2002).

Hebbian theory of activity-dependent development suggests that successful and repeated

communication/synapses between pre- and post-synaptic neurons strengthens synaptic efficiency

(Hebb 1949) and underlies mechanisms of synaptogenesis, learning, memory and development in the

brain (Abbott and Nelson 2000; Song, Miller et al. 2000). In early development, longer post-synaptic

excitatory potentials (increased NMDA-mediated glutamatergic receptors) support higher levels of

plasticity. With development, the duration of synaptic transmissions decreases (due to changing

proportions of NMDA and AMPA (strength of AMPA-mediated transmission increases and

composition of NMDA changes)) (van Zundert, Yoshii et al. 2004; Elias, Apostolides et al. 2008) and

inhibition (GABA receptors) increases (Gao, Wormington et al. 2000). These developmental changes

in receptor currents promote dendritic elaboration (Cline 2001), are involved with mechanisms of

synaptogenesis in the primary auditory cortex (Huttenlocher and Dabholkar 1997) and support axonal

myelination – all of which serve to generate faster and more efficient synaptic transmission to promote

plasticity during sensitive periods in development (Abbott and Nelson 2000; Song, Miller et al. 2000).

Without stimulation, these receptors do not develop normally. Essential synapses do not get formed,

inappropriate ones may be pruned and normal growth of dendritic arbors may be interrupted (Kral

2007; Kral and Eggermont 2007). Normal auditory activity is thus important to promote activity-

dependent plasticity in the auditory pathways to promote development and maturation of circuits in

the auditory brain, fine-tune the auditory system and allow the brain to adapt to the environment

(Rauschecker 1999).

Interestingly, providing abnormal input to the developing system will still promote plasticity in

the auditory pathways but will impair the structure and function of auditory brain circuits. This has

21

been shown both in cases of sensorineural hearing loss as well as conductive impairments. For

example, sensorineural hearing loss caused from a cochlear lesion induced with ototoxic

aminoglycoside poisoning indicated reduced frequency tuning and frequency selectivity of cortical

neurons in kittens one year after the loss. This frequency deterioration was observed even in areas of

the cochlea which were still intact (Harrison, Stanton et al. 1995). Conductive hearing losses similarly

impaired cortical development. Children suffering from persistent and recurrent otitis media with

effusion, a common intermittent middle ear condition which attenuates and distorts sounds, had

impaired abilities for using binaural cues of timing and level differences between both ears (which in

turn compromised binaural hearing). This deficit was particularly pronounced when the hearing loss

was asymmetric (Moore 2002; Moore, Hartley et al. 2003). Long-term consequences of conductive

hearing loss on auditory processing were also shown in animal models with prolonged bilateral ear

plugging, and similarly indicated that impoverished auditory stimulation resulted in impaired bilateral

auditory function, in particular, poor sound localization and binaural unmasking abilities (Moore 2002;

Moore, Hartley et al. 2003). Abnormal stimulation of the auditory system with a distorted signal thus

has deleterious effects on auditory development and function.

This is a particular concern with CI listening because the implanted electrode array cannot

mimic stimulation provided by a normal cochlea. Specifically, CI processing will extract the envelope

of a speech signal and will transmit temporal information with high fidelity; but because the electrode

array consists of only 22 electrodes, spectral coding is not well represented. This is particularly true

with monopolar stimulation modes, as the CI will stimulate a broader cochlear region. In turn, this

results in broader spread of current excitation, which further limits spectral resolution in CI listeners.

This is unfortunate, given that tonotopic organization is one of the activity-independent mechanisms

that remains preserved in the deaf auditory system (Hartmann, Shepherd et al. 1997; Heid, Jähn-Siebert

et al. 1997; Heid, Hartmann et al. 1998). In addition, electrical pulses delivered by a CI will stimulate

a smaller number of surviving spiral ganglion neurons (because all do not survive cochlear damage

imposed by the hearing loss), and will do so with higher synchrony than normal acoustic hearing

(Rubinstein and Hong 2003). Moreover, the dynamic range of electric hearing is also reduced

compared to acoustic hearing, which means that CI listeners may not have a normal representation of

loudness growth (Zeng, Rebscher et al. 2008). Hearing with a CI is thus not normal. The distorted

signal delivered by this unique device might thus promote maladaptive plasticity in the developing

auditory system, which in turn could hinder expressive and receptive language skills, lead to decreased

22

performance in school and inflict social difficulties.

2.5 Bilateral deafness in childhood drives abnormal reorganization in the

brain

Prior to cochlear implantation, the absence of auditory input from bilateral deafness in early

life drives widespread physiological deficiencies and degeneration in the auditory system. Figure 2.4

summarizes some cortical effects of deafness observed from congenitally deaf adults and animal

models of deafness (i.e., cats) (Kral and Sharma 2012). As shown in A the number of non-responsive

units in the auditory cortex increased from 10% in normal hearing cats (blue bar) to 45% in the

congenitally deaf animal (red bar). The maximum firing rate (B) and dynamic range of responsive

units in the cortex (C) were reduced. Panel D shows that while rudimentary cochleotopy was preserved

in the deaf animal, cochleotopic resolution was weaker compared to the hearing cat. Current

thresholds for generating electrical potential in the auditory system were significantly lower in the

cortex (E), suggesting hypersensitivity to auditory input in the cortical pathways. By contrast,

sensitivity to interaural timing differences in the inferior colliculus and the cortex was decreased (F).

Bilateral deafness also altered the normal organization of activity in the cortex, as shown by the

development of symmetrical aural preference in the congenitally deaf animal in G, indicating a loss of

contralaterality in the auditory system, compared to normal hearing animals who showed preference

for the contralateral ear.

24

In addition to these changes, altered synaptic structures in auditory nerve endings particularly

at spherical and globular bushy cells in the endbulb of Held (Ryugo, Rosenbaum et al. 1998; O'Neil,

Limb et al. 2010), lower spiral ganglion cell count (Nadol Jr, Young et al. 1989; Nadol 1997), smaller

cochlear, vestibular and eight cranial nerve trunk diameter (Nadol Jr and Xu 1992; Nadol 1997),

shrinkage of dendrites and cell bodies (Drennan and Rubinstein 2008), asynchronous glutamate release

from hair cells to spiral ganglion neurons resulting in decreased and sometimes absent spontaneous

activity (Kral 2007) and delayed synaptic pruning (Kral et al., 2005) all also occur with bilateral deafness.

The number of synapses from the lateral lemniscus to the inferior colliculus becomes reduced (Hardie,

Martsi-McClintock et al. 1998; Nishiyama, Hardie et al. 2000) and the density of primary neurons

decreases (Ryugo, Rosenbaum et al. 1998). Bilateral deafness also leads to altered synaptic currents in

the auditory cortex. Activation of auditory cortical columns becomes desynchronized (Kral, et al.

2005), maturation of excitatory post-synaptic potentials becomes abnormal (Kral and Eggermont

2007) and development of inhibitory mechanisms becomes altered (Kral and Eggermont 2007).

Moreover, reduced synaptic activity in loop thalamo-cortical and cortico-cortical connections (Kral,

Hartmann et al. 2001) cause delayed development of supragranular layers and decreased activity in

Figure 2-4: Widespread effects of bilateral deafness in all levels of the auditory pathways. Figure

reproduced with permission from Kral and Sharma (2012).

A number of functional deficits were observed in cats with bilateral deafness compared to normal

hearing control cats. A. Bilateral deafness drives an increased proportion of non-responsive units in

the cortex shown by the red bars compared to normal hearing controls. B. Neural firing rate is

impaired and occurs over a significantly reduced dynamic range as shown in C. (blue). D.

Rudimentary cochleotopy is preserved in the deaf animal, but the resolution is much weaker and much

simpler than in the hearing animal. E. Thresholds of evoked responses are reduced in the cortex of

the deaf animal compared to the hearing animal, providing evidence of cortical hypersensitivity. Of

interest however, sensitivity to inter-aural timing cues is much reduced as shown in F. G. Analyses

of aural preference indicate a contralateral preference in the normal hearing control cat. By contrast,

aural preference is lost in the congenitally deaf animal as shown by similar responsiveness of the

auditory cortices to stimulation of the ipsilateral and contralateral ears.

25

deep infragranular cortical layers (Kral, Hartmann et al. 2001; Kral, Schroder et al. 2003; Kral 2007;

Kral and Eggermont 2007). This reduces connectivity of the primary auditory cortex with higher

cortical centers (Kral 2007; Kral and Eggermont 2007) and alters neural projections to association

auditory areas, leaving the immature and deaf auditory brain vulnerable to cross-modal recruitment by

non-auditory systems (Finney, Fine et al. 2001; Lee, Lee et al. 2001; Bavelier and Neville 2002; Bavelier,

Dye et al. 2006; Lomber, Meredith et al. 2010; Meredith and Lomber 2011).

The primary auditory cortex is spared while association areas of the auditory system become

the targets of other sensory systems (Lomber, Meredith et al. 2010; Meredith and Lomber 2011).

Recent evidence from a cat model of congenital deafness indicated that secondary and association

auditory areas, including parts of the planum temporale, all of which respond to multi-sensory input

including hearing, vision and touch (Pandya and Yeterian 1985; Giard and Peronnet 1999; Calvert,

Hansen et al. 2001; Calvert and Thesen 2004), become recruited by the visual (Finney, Fine et al. 2001;

Lee, Lee et al. 2001; Lee, Truy et al. 2007; Lomber, Meredith et al. 2010; Meredith and Lomber 2011)

and somatosensory (Levänen, Jousmäki et al. 1998; Levänen and Hamdorf 2001; Auer Jr, Bernstein et

al. 2007; Meredith and Lomber 2011) systems to perform non-auditory functions. As a consequence

of early auditory deprivation, processing of visual peripheral localization by the Posterior Auditory

Field (Lomber, Meredith et al. 2010), visual motion detection by the Dorsal Zone of the auditory

cortex (Lomber, Meredith et al. 2010) and somatosensory sensation by the Anterior Auditory Field

(Meredith and Lomber 2011) become enhanced in individuals who are deaf. These changes appear to

result from a direct competition for resources in areas which receive multi-sensory input. If governed

by principals of Hebbian processing (Hebb 1949; Abbott and Nelson 2000; Song, Miller et al. 2000),

neurons in these areas could preferentially form viable connections with non-auditory inputs to the

detriment of inputs carrying auditory information. Depending on how quickly these processes occur,

they may be impossible to reverse and could impair outcomes after cochlear implantation if auditory

input is not restored within sensitive periods in development.

Such cortical reorganization may also be attributed to anatomical changes of the auditory

cortex, occurring as a result of bilateral auditory deprivation in early life (Wong, Chabot et al. 2013;

Kok, Chabot et al. 2014). Indeed, recent findings from deaf cats have indicated that the auditory cortex

in early- or congenitally- deaf brains differs both in size and position from the hearing brain. The

volume of the auditory brain is significantly smaller in deaf cats compared to normal hearing cats and

the borders between the dorsal auditory areas and adjacent somatosensory and visual areas shifts

26

ventrally to allow for a greater representation of non-auditory input (Wong, Chabot et al. 2013). In

humans however, such volumetric changes were not found. While individuals with long-term bilateral

deafness had decreased white matter in the left superior temporal gyrus, the volume of the auditory

brain in either hemisphere was similar between individuals with deafness and normal hearing

(Emmorey, Allen et al. 2003; Shibata 2007). These differences in the cortical effects of early-onset

deafness between animal models and humans may be due to differences in the aetiology and/or onset

of deafness. Unlike children who may have had some hearing in utero, the onset of hearing in cats

occurs post-natally (Heid, Hartmann et al. 1998; Ryugo, Rosenbaum et al. 1998; Ryugo, Cahill et al.

2003). This means that congenitally deaf white cats never had access to sound, which may cause both

anatomical and physiological changes to the auditory pathways that are different from humans.

2.6 Unilateral deafness promotes abnormal changes in the auditory brain

While the effects of early-onset bilateral hearing loss on the auditory brain are well known,

fewer studies have explored the consequences of unilateral deafness on auditory development.

However, individuals with unilateral deafness are not a small population. The prevalence of unilateral

hearing (thresholds >45dB HL) is estimated to be 3 per 1,000 in school-aged children. This rate

increases to 13 per 1,000 when children with milder losses are included (Bess and Tharpe 1984; Bess

and Tharpe 1986; Bess, Dodd-Murphy et al. 1998). Bess and colleagues reported that approximately

one-third of children with unilateral hearing loss failed at least one grade in school, with almost 50%

of them needing access to resource assistance programs. Unilateral hearing impairments also affect

language development, with 38% of children suffering from reading problems, 31% have challenges

with spelling and 23% struggle with arithmetic. In addition to these education and language difficulties,

behavioural problems, low self-esteem and reduced intelligent quotient scores have all been reported

from children with unilateral hearing loss compared to those who have normal hearing in both ears

(Bess and Tharpe 1984; Bess and Tharpe 1986). These deficits might be attributed to functional

changes in the auditory system occurring a result of unilateral deprivation.

Several studies have demonstrated that unilateral hearing loss modifies tonotopic maps in the

auditory cortex (Reale, Brugge et al. 1987; Popescu and Polley 2010), alters the balance of excitation-

inhibition (Nordeen, Killackey et al. 1983; Moore and Kowalchuk 1988; Hashisaki and Rubel 1989;

27

Mossop, Wilson et al. 2000; Vale, Juíz et al. 2004; Kotak, Fujisawa et al. 2005), and drives abnormal

cortical lateralization in the auditory brain (Vasama, Mäkelä et al. 1994; Vasama and Mäkelä 1995;

Vasama, Mäkelä et al. 1995; Vasama and Mäkelä 1997; Scheffler, Bilecen et al. 1998; Ponton, Vasama

et al. 2001; Khosla, Ponton et al. 2003; Langers, van Dijk et al. 2005; Firszt, Ulmer et al. 2006; Hine,

Thornton et al. 2008; Popescu and Polley 2010; Kral, Heid et al. 2013; Kral, Hubka et al. 2013).

Importantly, studies have shown that profound unilateral deafness shifts cortical activation patterns

towards one that is more symmetrical between both the left and right hemispheres (Vasama, Mäkelä

et al. 1994; Vasama and Mäkelä 1995; Vasama, Mäkelä et al. 1995; Vasama and Mäkelä 1997; Scheffler,

Bilecen et al. 1998; Ponton, Vasama et al. 2001; Khosla, Ponton et al. 2003; Langers, van Dijk et al.

2005; Firszt, Ulmer et al. 2006; Hine, Thornton et al. 2008). This occurs as a decrease in normal

contralateral cortical activation and an increase in ipsilateral activation relative to the hearing ear (Firszt,

Ulmer et al. 2006), with earlier ipsilateral latencies (Ponton, Vasama et al. 2001; Khosla, Ponton et al.

2003). This is particularly true when the loss is in the left ear (Scheffler, Bilecen et al. 1998; Khosla,

Ponton et al. 2003), perhaps reflecting hemispheric specialization in the auditory brain (Zatorre and

Belin 2001; Zatorre, Belin et al. 2002). In adults with post-lingual deafness, this loss of contralaterality

in the cortex occurs almost immediately following the onset of hearing loss (Vasama and Mäkelä 1995;

Vasama, Mäkelä et al. 1995). Of interest however, the middle latency response (MLR) and peak N1 of

the cortical response are the least affected in both children and adults (Vasama, Mäkelä et al. 1994;

Vasama and Mäkelä 1997; Hine, Thornton et al. 2008), which suggests that association auditory areas

are most vulnerable to effects of deafness.

Changes in the hemispheric organization of auditory activity in the cortex might be attributed

to a disruption in excitatory-inhibitory activity when input to both ears is unbalanced (Nordeen,

Killackey et al. 1983; Kitzes 1984; Reale, Brugge et al. 1987; Moore and Kowalchuk 1988; Hashisaki

and Rubel 1989; Mossop, Wilson et al. 2000; Moore and Kitzes 2004; Nordeen, Killackey et al. 2004;

Vale, Juíz et al. 2004; Takesian, Kotak et al. 2009; O'Neil, Limb et al. 2010; Popescu and Polley 2010;

Kral, Heid et al. 2013; Kral, Hubka et al. 2013). There is evidence from animal models indicating

better acoustic thresholds and increased excitatory responses in the ventral cochlear nucleus (Kil,

Hkageyama et al. 1995; Kitzes, Kageyama et al. 1995; Moore and Kitzes 2004; Illing, Kraus et al. 2005),

superior olivary complex (Kil, Hkageyama et al. 1995; Kitzes, Kageyama et al. 1995; Moore and Kitzes

2004), inferior colliculus (Nordeen, Killackey et al. 1983; Nordeen, Killackey et al. 1983; Kitzes 1984;

Moore and Kitzes 2004; Nordeen, Killackey et al. 2004), and auditory cortex (Reale, Brugge et al. 1987;

28

Kral, Heid et al. 2013; Kral, Hubka et al. 2013) of the stimulated pathways. This has been attributed

to a loss of inhibitory processes from the opposite-deaf side (Mossop, Wilson et al. 2000; Vale, Juíz et

al. 2004; Takesian, Kotak et al. 2009) that would have normally developed with bilateral hearing (Sanes

and Takács 1993; Gao, Wormington et al. 2000; Grothe 2003; Dorrn, Yuan et al. 2010; King 2010;

Sanes and Kotak 2011). Of note, this strengthening of inputs in the ascending pathways is age-

dependent, occurring only when the loss is present in early life (Nordeen, Killackey et al. 1983; Reale,

Brugge et al. 1987; Moore and Kowalchuk 1988; Nordeen, Killackey et al. 2004) and when it is

unilateral (Moore 1990). These findings thus highlight the deleterious effects of unilateral hearing loss

on the auditory brain.

2.7 Multiple effects of childhood deafness predict outcomes after cochlear

implantation

It is becoming clear that abnormal reorganization of the auditory brain does not occur

uniformly in children who are deaf and may be related to the heterogeneity in the onset and cause of

pediatric deafness (Gordon, Wong et al. 2011; Gordon, Tanaka et al. 2011). This heterogeneity means

that there can be no single animal model to predict the effects and auditory pathway consequences of

childhood deafness (Gordon, Tanaka et al. 2011). More than half of all hearing losses are caused from

a genetic aetiology and approximately one-third have an environmental cause (Morton and Nance

2006; Papsin and Gordon 2007). As shown in Figure 2.5, the most common genetic cause of deafness

is a mutation in the Gap Junction Beta-2 (GJB-2) gene, which accounts for approximately 20% of all

deafness at birth and during childhood (Morton and Nance 2006; Propst, Papsin et al. 2006). Another

30 genes have been associated with syndromic forms of hearing losses, while 50 genes are non-

syndromic (Gordon, Tanaka et al. 2011). In addition, 35% of hearing losses at birth are related to

environmental factors and infections, although this number decreases slightly by 4 years of age. This

is perhaps because newborns have not yet developed immunity to many organisms (i.e., bacteria,

viruses, fungi, parasites) and are more susceptible to infectious agents than toddlers (Gao, Wormington

et al. 2000; Mackay, Rosen et al. 2001; Bach 2002; Openshaw, Yamaguchi et al. 2004). Common

environmental causes of deafness include prematurity, head trauma, infections such a cytomegalovirus

and meningitis, and pharmacologically-induced ototoxicity including aminoglucoside antibiotics and

chemotherapy drugs (Morton and Nance 2006). The heterogeneity of childhood deafness means that

29

there could be multiple effects of hearing loss on the auditory brain, each with its own developmental

trajectory and consequences to the cochlea, brainstem, thalamo-cortical pathways and cortico-cortical

pathways. The various effects of hearing loss on the auditory system could therefore disrupt structure

and function of activity along the auditory pathways and in turn affect how an auditory prosthesis,

such as a CI, stimulates the auditory system and promotes auditory development.

Limiting the period of bilateral deafness in early life is essential to drive maturation in the

auditory pathways (Eggermont, Ponton et al. 1997; O’Donoghue 1999; Kral, Hartmann et al. 2001;

Ponton and Eggermont 2001; Sharma, Dorman et al. 2002; Sharma, Dorman et al. 2002; Sharma,

Dorman et al. 2005; Papsin and Gordon 2007; Gordon, Tanaka et al. 2008; Papsin and Gordon 2008;

Figure 2-5: Heterogeneity in the cause and onset of pediatric deafness. Figure reproduced with

permission from Morton and Nance (2006).

Incidence at birth and prevalence at 4 years of age is shown for different etiologies of deafness. Genetic

mutations are the most common causes of deafness, with GJB-2 associated deafness being the most

common etiology both at birth and during childhood. Environmental factors and infections account

for 35% of deafness at birth, but this number decreases slightly during childhood, as children develop

immunity to infectious agents.

30

Nikolopoulos, O'Donoghue et al. 2009; Gordon, Wong et al. 2011; Gordon, Jiwani et al. 2011), and

promote optimal hearing and speech and language development in children (Beadle, McKinley et al.

2005; Harrison, Gordon et al. 2005; Nicholas and Geers 2007; Geers and Sedey 2011). As shown in

Figure 2.6A and 2.6C, children who were congenitally deaf in both ears and implanted within a critical

period of 3.5 years, when the brain was maximally plastic, followed age-appropriate developmental

changes in the cortical evoked response, compared to children who were implanted at older ages

(Sharma, Dorman et al. 2002). The latency of the P1 component of the cortical evoked response

(considered a biomarker of cortical development) of early implanted children (red circles) decreased

rapidly at initial stages of CI stimulation and reached values which were similar to their normal hearing

peers. By contrast, children who received a CI after 7 years of age (shown in B and by the green

triangles in C) showed abnormal cortical waveform morphologies with persistently delayed peak

latencies despite many of years of CI experience (Sharma, Dorman et al. 2002; Sharma, Dorman et al.

2002; Sharma, Dorman et al. 2005; Sharma, Gilley et al. 2007).

31

These age cut-offs are in line with findings from Harrison and colleagues shown in Figure 2.7

who similarly indicated that children who were implanted at younger ages (<5 years) and within limited

durations of bilateral deafness, shown by the black symbols, achieved higher scores on the open-set

Phonetically Balanced Kindergarden (PBK) words test and at faster rates compared to their peers who

were implanted at older ages and after longer durations of deafness, as shown by the white symbols

(Harrison, Gordon et al. 2005).

Figure 2-6: P1 latency as a function of age at implantation. Figure adapted then reproduced with

permission from Sharma, Dorman et al. (2002).

A. Grand mean cortical response from 18 early implanted children who received a CI by 3.5 years of

age is shown at the bottom and characterized by a large amplitude peak P1, similar to their age-matched

normal hearing peers (top). B. Grand mean cortical response from 13 late implanted children

(bottom) who were implanted later than 7 years of age after long-durations of bilateral deafness has an

abnormal waveform morphology and delayed positive peak latency compared to their age-matched

normal hearing peers (top). C. The latency of peak P1 was used as an index of auditory development

in children who were congenitally deaf and used a CI to hear for an average of 3 years. The solid lines

indicate the lower and upper bound 95% confidence interval of P1 latencies recorded from age-

matched normal hearing peers. Children who were congenitally deaf and received a CI by 3.5 years

had age-appropriate cortical responses as shown by the red circles, but those who were implanted late

after 7 years of age had abnormally delayed latencies (green triangles). Children who received a CI

between 3.5 and 7 years of age had variable responses (blue crosses)

32

Many studies investigating auditory development after cochlear implantation focus on children

who are deaf in infancy, but do not examine the larger heterogeneity in etiology, onset and/or degree

of deafness. These factors may each have unique effects on auditory activity in the brain prior to

implantation. For example, bilallelic mutations of the GJB-2 gene causes deficits in the cochlea at

likely very early stages of development with possible consequences for auditory function after

implantation (Propst, Papsin et al. 2006). The GJB-2 gene normally codes for the connexin-26 protein

which creates gap junctions in the cochlea necessary for the appropriate release and maintenance of

electrochemical gradients. This in turn, generates action potentials and stimulates the auditory nerve

(Kelley, Harris et al. 1998; Cohn and Kelley 1999; Gualandi, Ravani et al. 2002). Electrophysiological

Figure 2-7: Speech perception outcomes as a function of age at implantation. Figure reproduced with

permission from Harrison, Gordon et al. (2005).

Speech perception performance of pre-lingually deaf children who received a CI at ages ranging from

1 to 15 years of age was assessed prior to cochlear implantation and at regular intervals up to 96 months

post implantation using the open-set Phonetically Balanced Kindergarden (PBK) words speech test.

Children implanted prior to 5 years of age shown by the black symbols performed better and showed

faster rates of speech perception improvements compared to their later implanted peers who had

longer durations of bilateral deafness prior to implantation (white symbols).

33

recordings of auditory evoked cortical activity at initial CI activation in children with severe GJB-2

mutations revealed that responses from the cortex were more homogenous in this cohort compared

to those children who did not have such a mutation. Auditory evoked cortical responses in children

with GJB-2 mutations were characteristic of earlier stages of cortical development, perhaps reflecting

restricted spontaneous activity in the auditory system and more limited access to sound prior to

implantation compared to their peers who did not have a GJB-2 related deafness (Gordon, Tanaka et

al. 2011). This was further supported by poorer hearing sensitivity in the low frequencies in the GJB-

2 group (Propst, Papsin et al. 2006).

The degree of residual hearing is another important predictive factor for CI outcomes.

Traditional candidacy criteria for cochlear implantation in children include a diagnosis of permanent

severe-to-profound hearing loss bilaterally with little or limited access to acoustic input through hearing

aids (Osberger, Zimmerman-Phillips et al. 2002). It has recently been reported that children who had

better hearing at 250Hz used their hearing aids for longer durations prior to receiving a CI (Hopyan,

Peretz et al. 2012). Of interest, these children performed significantly better on tests of music

perception with their implants, particularly when detecting differences in rhythm, compared to children

who did not have acoustical access to these low frequencies prior to implantation (Hopyan, Peretz et

al. 2012). Thus, there are advantages of acoustical input for auditory development which can be

capitalized upon after cochlear implantation. In general, we are learning that the cause, onset and

degree of deafness in any one child will be important to understand in order to ensure that he/she

makes the best possible use of his/her device.

2.8 Electrophysiological measures assess auditory cortical development and

map underlying auditory activity in the brain

Auditory activity and development in the brain can be measured with a variety of neuroimaging

techniques, including Positron Emission Tomography (PET), Magnetic Resonance Imaging (MRI),

Magneto-encephalography (MEG) and electroencephalography (EEG), among others. In CI users

unfortunately, only PET and EEG can be used because the CI magnet in the receiver-stimulator

component of the subcutaneous CI component renders it incompatible with the magnetic field of

other imaging modalities (Portnoy and Mattucci 1991; Teissl, Kremser et al. 1998; Teissl, Kremser et

34

al. 1999). EEG imaging provides a non-invasive method to measure changes in the brain as a function

of brain states, as well as during sensory and cognitive processing.

In brief, the brain is composed of a large number of interconnected neurons, each containing

a cell body (soma), an axon and dendritic trees. Neurons are electrically excitable cells, which

communicate with each other via synapses to transmit messages to various parts of the brain through

chemical neurotransmitters. Activation of a cell results in a change in the membrane potential (i.e.,

voltage difference between the inside and outside of the cell). Release of an excitatory

neurotransmitter, reflecting depolarization, will result in an increase of the local intracellular potential.

By contrast, release of an inhibitory neurotransmitter, reflecting hyperpolarization, will cause the cell

interior to become more negative than its resting state. Membrane voltage changes result in small

potential differences between the inside and outside of the cell. Fast voltage changes, reflecting action

potentials, propagate along the axon of pre-synaptic nerve cells. On the other hand, slow voltage

changes are produced in cell dendrites of post-synaptic cells. The flow of ions through the dendrites

forms a primary current. In order to balance the current charge across the membrane, a return current

flows in the extracellular space and forms a secondary current. It is the electric field from this

secondary current that is reflected in EEG recordings.

The electric potential produced by a single neuron is too small to be detected by EEG

electrodes at the surface of the scalp however. Recorded EEG activity thus reflects a summation of

the resulting electrical fields produced by large populations of neurons, which fire in synchrony and

have a parallel spatial orientation. When sound stimulation is delivered to the auditory system, electric

responses in the brain undergo typical fluctuations, but are related in a time-locked fashion to changes

occurring in the auditory signal. These changes, known as auditory evoked potential (AEP) responses,

can be recorded from the brainstem, midbrain or cortex using surface electrodes (i.e., an EEG set-up),

as a waveform whose morphology, peak latencies and peak amplitudes reflect

developmental/maturational changes in the brain and has been used as an index of auditory

development and plasticity in the auditory system (Picton and Hillyard 1974; Eggermont 1985;

Eggermont 1988; Eggermont 2000; Ponton, Eggermont et al. 2000; Ponton and Eggermont 2001;

Eggermont and Ponton 2002; Ponton, Eggermont et al. 2002; Eggermont 2007; Picton and Taylor

2007). Figure 2.8 shows an auditory evoked response recorded from the brainstem in CI users. A

middle latency response to auditory input, which reflects auditory activity in the midbrain (i.e., thalamo-

cortical pathways) is shown in Figure 2.9. The data in Chapter Three describes the cortical response

35

in more depth. Because EEG signals measure the primary effects of neuro-electric activity, their

temporal resolution is very high (i.e., in the order of milliseconds) and can detect brief neuronal events.

Unfortunately, their spatial resolution is particularly poor. In order to record EEG or AEP activity

from distant scalp electrodes, the electric field must travel through tissues of varying conductivities

(i.e., brain, cerebral spinal fluid, skull bone and scalp) (van den Broek, Reinders et al. 1998). This

results in a smeared representation of electric potential at the scalp.

An important caveat with recording cortical evoked responses in CI users, is that the CI device

itself produces a large electrical artifact that is recorded by scalp electrodes (Gilley, Sharma et al. 2006;

Martin 2007; Wong and Gordon 2009; Castaneda-Villa, Manuel Cornejo-Cruz et al. 2010; Friesen and

Picton 2010; Castañeda-Villa and James 2011; Viola, De Vos et al. 2012; Mc Laughlin, Lopez Valdes

et al. 2013). This artifact is generated by the radio frequency transmission of the signal from the

processor to the receiver. It is large in amplitude, time-locked to the stimulus, lasts for at least the

duration of the stimulus, and interferes with recorded response. Methods have been developed to

remove this artifact by suppressing it (used in Chapter Four) or separating it from the cortical response

using independent component analyses (ICA) (used in Chapter Five) to protect the cortical response

from contamination.

Using these artifact suppression/separation methods and cortical responses recorded at 64-

cephalic surface electrodes, we can now objectively spatially localize areas of cortical activity using

beamformer imaging techniques (Dalal, Sekihara et al. 2006; Wong and Gordon 2009) and identify the

interaction of these brain areas with measures of neural oscillatory synchronization. Spatial smearing

of EEG activity recorded at the scalp still occurs with these methods, but using appropriate head

models to account for tissue conductivities and objective normalization techniques to account for

volume conduction and noise, these analyses are now possible. We have developed our unique and

validated ‘Time Restricted Artifact and Coherent Suppression’ (TRACS) beamformer method (Wong

and Gordon 2009; Jiwani, Papsin et al. Submitted) to localize auditory evoked cortical activity in the

hemispheres ipsilateral and contralateral to stimulation. Like many imaging methods, the beamformer

technique divides the brain into thousands of 3-dimensional coordinate spaces known as voxels. The

contribution of the dipole centered in each voxel to the measured field can be assessed by the adaptive

spatial filter of the TRACS beamformer. The signal at each voxel is normalized relative to the baseline

brain activity into a Pseudo-Z statistic (Van Veen, Van Drongelen et al. 1997). Dipole moment activity

can then be visualized topographically on age-appropriate head model templates at different latencies

36

for 63,646 voxels in brain space. In this way, the beamformer allows us to create an image of sound-

induced activity in the brain and assess the strength of activity in each hemisphere and in different

cortical regions, and ask questions regarding the lateralization and aural preference of cortical activity

evoked by sound in users of CIs. This is explored in Chapter Four.

More recently, investigators have indicated that co-ordinated oscillations of the various

frequency components of the cortical response underlie communication of various neural groups

between brain regions. Populations of neurons that are activated by sensory stimuli synchronize their

discharges with high precision, allowing them to oscillate in synchrony (Singer 1999; Uhlhaas, Pipa et

al. 2009). Oscillatory activity is generated by voltage changes in the cell membrane which occur with

de-polarization or hyper-polarization. As previously described, voltage changes can be fast (action

potentials) or slow (post-synaptic potentials). In this way, synchronously oscillating neurons,

particularly pyramidal cells in the cortex, exchange information effectively because their input-output

phases occur at the same time (Fries 2005).

The co-ordinated interaction of large numbers of oscillating neurons in different frequency

bands within and across brain areas is believed to underlie cognitive/perceptual dynamics in the brain,

such as attention, memory, learning, etc…. Different cognitive processes are represented by distinct

oscillatory signatures (Lachaux, Rodriguez et al. 1999; Rodriguez, George et al. 1999; Singer 1999;

Varela, Lachaux et al. 2001; Ward 2003; Doesburg, Kitajo et al. 2005; Uhlhaas and Singer 2006;

Doesburg, Emberson et al. 2008; Doesburg, Roggeveen et al. 2008; Doesburg, Green et al. 2009;

Doesburg and Ward 2009; Uhlhaas, Pipa et al. 2009; Doesburg, Herdman et al. 2010; Uhlhaas, Roux

et al. 2010; Green, Doesburg et al. 2011; Palva and Palva 2012). For example, increased synchrony in

the gamma-band activity (30 to 60Hz) is believed to reflect attention and memory (Doesburg,

Roggeveen et al. 2008; Fougnie 2008; Palva, Monto et al. 2010; Green, Doesburg et al. 2011; Doesburg,

Green et al. 2012). This activity occurs with an increase in theta activity (4 to 7Hz) during active

processing and an increase in alpha activity (10 to 13Hz) during integration and feature binding across

long-distances in the brain (Von Stein and Sarnthein 2000). Assessments of EEG frequency analyses

to auditory input can now be done to identify the regions of the brain which are responding in

synchrony and map interactions/connectivity in the cortex. This is explored in more depth in Chapter

Five.

37

2.9 Unilateral cochlear implantation restores hearing and promotes auditory

development in the brainstem and midbrain, but the trajectory of cortical

auditory maturation remains unclear

We have measured changes in evoked activity in the auditory brainstem and thalamo-cortical

pathways in children who were bilaterally deaf from early life and received a CI to hear within limited

durations of auditory deprivation. Auditory brainstem development, measured by decreasing latencies

of evoked potential peaks, is largely complete by the first year of CI use in children with early onset

deafness (Gordon, Papsin et al. 2003; Gordon, Papsin et al. 2006), indicating increasing efficiency of

neural conduction and improved neural synchrony with exposure to sound (Gordon, Papsin et al.

2003). Similar changes have been reported from the auditory brainstems of normal hearing children

over a similar time-course (Salamy and McKean 1976; Starr, Amlie et al. 1977; Jerger and Hall 1980;

Salamy 1984; Hecox and Burkard 2006). Data from Gordon et al (2006) is shown in Figure 2.8A; on

the left is an example of an electrically evoked auditory brainstem response. The stimulus artifact is

shown at time 0ms followed by waves eII, eIII and eV, and on the right, the latency values of wave eV

are plotted at initial device activation and over the first year following CI use in 44 children who had

early onset deafness and were implanted unilaterally (Gordon, Papsin et al. 2006). Recently, we

recorded these same responses in children who were in the original study once they had over a decade

of unilateral CI experience. Examples of these responses from 2 children are shown in B and C. In

both cases, wave eV latency clearly decreases over the first year of CI use, with no further changes

thereafter. This suggests that activity in auditory brainstem is largely complete by the first year

(Gordon, Papsin et al. 2006).

39

Further studies concentrated on thalamo-cortical activity as measured by the electrically evoked

middle latency response in a cohort of 10 adolescents who had early onset deafness, were implanted

by 3.18 ± 0.52 years of age, and had who had long-term experience with a unilateral CI (13.0 ± 1.65

years). These adolescents were 16.08 ± 1.87 years of age at the time of the test. Etiology of deafness

was heterogenous. Four of the children had genetic mutations associated with hearing loss: 2 had an

abnormal cochlea (1 confirmed mondini malformation), and deafness in 4 children was due to

unknown causes. The grand mean response recorded from the long-term CI group is shown by the

red waveform in Figure 2.9A along with a grand mean response (black waveform) from a group of 8

normal hearing peers matched for duration of hearing (15.1 ± 2.4 years). Upper and lower bound 95%

confidence intervals of the normal hearing acoustically evoked middle latency response are indicated

by the grey dotted lines. This response is characterized by 3 dominant peaks, Na, Pa and Nb, reflecting

auditory projections from the thalamus to the primary auditory cortex (Fifer and Sierra-Irizarry 1988;

Burton, Miller et al. 1989; McGee, Kraus et al. 1991; Kraus and McGee 1993; Frizzo, Funayama et al.

2007). As shown in Figure 2.9A, the middle latency response evoked by long-term CI users is similar

to that of the grand mean normal hearing waveform, with peak amplitudes reaching normal values

across latency. Analyses of peaks latencies and amplitudes are shown in B. No significant differences

Figure 2-8: Development of auditory brainstem responses after cochlear implantation. Figure

reproduced with permission from Gordon, Jiwani et al. (2013).

A. Example of an electrically evoked auditory brainstem response waveform is shown on the left. The

onset of the CI artifact is shown at time 0ms, followed by peaks eII, eIII and eV. Data from Gordon

et al. (2006) are plotted on the right and show the mean wave eV latency values of 44 children recorded

at initial activation of the implant, and at months 2, 6 and 12 following unilateral cochlear implantation.

B. and C. on the right show the changes in the brainstem responses of 2 children who were in the

original study (Gordon et al., 2006), recorded from initial activation of the device to different intervals

over the first year of cochlear implantation use. New responses recorded after 10 years of unilateral

CI experience are also shown further confirming that little change in the eV latency occurs beyond the

first year of implant use. The wave eV latencies at each time-point are represented on the right for

each child.

40

between the groups were found for any peak (Latencies: Na: t(16)=-2.76, p>0.05, Pa: t(16)=-1, p>0.05);

Nb: t(16)=0.12, p>0.05; Amplitudes: Na: t(16)=-2.72, p>0.05, Pa: t(16)=0.70, p>0.05, Nb: t(16)=-1.61,

p>0.05). The development of normal-like middle latency responses with implant use is consistent

with previous reports (Gordon, Papsin et al. 2005). Whilst the children represented in Figure 2.9

were young at the time of implantation, implant driven changes to the middle latency response can be

restricted in children who have long periods of auditory deprivation in early life prior to implantation

(Gordon, Papsin et al. 2005).

These changes suggest that some degree of auditory development proceeds normally at the

level of the brainstem and midbrain in children who are congenitally deaf when CIs are provided within

early durations of bilateral deafness. Of concern however, questions remain regarding the cortical

activity underlying auditory processing in CI users. Little continues to be known about the long-term

development of the auditory system and the neural networks that are activated by auditory input in

adolescents/young adults who have used a CI to hear for most of their lives. Investigators raised

concerns that maturation of axons in superficial layers of the auditory cortex may never occur in CI

users (Eggermont and Ponton 2003; Eggermont 2008). Unfortunately, these studies reported on only

2 children who had over ten years of implant experience (Eggermont and Ponton 2003). In Chapter

Three of the present Thesis, we address these concerns and investigate the long-term developmental

changes of the auditory cortical response with time and experience after unilateral cochlear

implantation in a larger cohort of children and adolescents.

41

2.10 Differences from normal persist in auditory processing despite long

durations of unilateral cochlear implant use

CI users compensate for the abnormal input they receive through the device (Doucet, Bergeron

et al. 2006; Giraud and Lee 2007; Lee, Giraud et al. 2007; Lee, Truy et al. 2007; Hopyan-Misakyan,

Gordon et al. 2009; Strelnikov, Rouger et al. 2010; Hopyan, Gordon et al. 2011; Kral and Sharma 2011;

Lazard, Giraud et al. 2011; Hopyan, Peretz et al. 2012; Lazard, Lee et al. 2012; Sandmann, Dillier et al.

2012). In a recent study, we found that children using CIs depend on visual cues more heavily than

normal when listening for complex information embedded in speech. Twenty-four CI users who

received one implant by 3.89 ± 1.56 years and had 7.91 ± 2.93 years of CI experience at the time of

the test were instructed to listen for and identify 1 of 4 emotions (happy, sad, angry or fearful) conveyed

Figure 2-9: Development of auditory middle latency responses after cochlear implantation. Figure

reproduced with permission from Gordon, Jiwani et al. (2013).

A. Grand mean middle latency response of 10 CI users who have 13.0 ± 1.7 years of hearing

experience (n=10) (red waveform) is plotted against a mature response recorded from 8 normal hearing

individuals who are 15.7 ± 2.2 years of age (black waveform). Lower and upper bound 95% confidence

interval of the normal hearing response is indicated by the grey dotted lines. B. Mean ± standard

deviations of the Na, Pa, Nb absolute latencies and the Na-Pa, Pa-Nb peak-to-peak amplitudes recorded

for the same CI users (n=10)(red bars) and their normal hearing peers (n=8) (grey bars).

42

in the sentence: “I’m going out of the room now and I’ll be back later”. This sentence was presented

via direct auditory input to the child’s CI device by one of four actors (a girl, a boy, a man, a woman)

in an auditory-only or auditory-visual condition. Each emotion was presented twice by each actor, in

each condition, for a total of 64 trials. The listeners were asked to enter their decisions as quickly as

possible using an electronic response pad. Performance accuracy (Figure 2.10A) and reaction time

for accurate responses (Figure 2.10B) were both assessed for each condition and compared to 23

normal hearing controls who were matched for age (9.36 ± 1.01 years of age).

Although children using CIs showed significantly poorer than normal performance on this task

in either condition (Hopyan-Misakyan et al., 2009), they experienced a greater than normal

improvement in accuracy with the addition of visual information as shown in Figure 2.10A. This

means that they relied more on visual cues than their normal hearing peers to identify emotions carried

in speech (Hopyan-Misakyan, Gordon et al. 2009), but did so with longer reaction times, as shown in

Figure 2.10B. Even the accurate decisions took more time for children using CIs to make than their

hearing peers; this was true even when visual cues were available. We thus suggest that children using

unilateral CIs used greater than normal cognitive resources to perform this complex listening task.

The increased reliance on visual cues to process auditory input is consistent with functional

neuroimaging studies, which find abnormally increased activation of the visual cortex in CI users when

listening to meaningful speech (Giraud, Price et al. 2001; Lee, Giraud et al. 2007; Lee, Truy et al. 2007),

perhaps reflecting abnormal development of the auditory and visual systems without normal hearing

(Nishimura, Hashikawa et al. 1999; Lee, Lee et al. 2001; Doucet, Bergeron et al. 2006; Lee, Truy et al.

2007; Meredith and Lomber 2011; Sandmann 2012; Sandmann, Dillier et al. 2012).

These data suggest that unilateral cochlear implantation promotes the development of activity

in the auditory pathways over the long-term, but functional abnormalities persist. Increased

dependence on visual cues in addition to auditory cues when listening with a CI could reflect

compensation for: 1) deleterious or irreversible changes to neural reorganization, which occurred

during the period of auditory deprivation in early life, 2) abnormal representation of sound through

electrical pulses stimulation of the auditory system, and/or 3) absence of auditory input to the deprived

pathways from the opposite un-implanted ear.

43

2.11 Binaural processing is not available with unilateral hearing

Hearing through only one ear or one CI eliminates access binaural hearing. Binaural hearing

is the ability of the auditory system to process and integrate auditory input from both ears to allow

listeners to identify the location of sound sources in space (Basura et al., 2009; Brown and Balkany,

2007; Ching et al., 2007; Litovsky, 2008a, 2008b), increased loudness perception and ease of listening

(Ching et al., 2007; van Hoesel and Tyler, 2003; Steffens et al., 2008) and enhanced speech intelligibility

in the presence of competing noise and in reverberant environments (Basura et al., 2009; Brown and

Balkany, 2007; Ching et al., 2007; van Hoesel and Tyler, 2003). Binaural hearing is especially important

for children because they are rarely in one place and listening to a single speaker at a time. Children

need to attend to and discriminate between several sound sources when playing and learning. The

noise, reverberation and distance, predominant in most learning situations including typical

classrooms, make it challenging for children to listen and learn when binaural cues are not accessible.

Children who use only one CI do not have access to important binaural cues to aid listening in such

Figure 2-10: Accuracy and reaction time for CI processing of auditory input with and without visual

input.

Mean ± 1 standard error of the A. improvement in accuracy when visual input was added and B.

mean reaction time difference of identifying emotions in speech in an auditory only (black bars) and

auditory-visual (grey bars) condition. Responses of 24 CI users (7.9 ± 2.9 years hearing experience)

are compared to those of 23 normal hearing peers matched for hearing age (9.4 ± 1.0 years).

44

challenging conditions. It follows then that we should always strive to provide binaural hearing to

children with hearing loss. For children who are deaf in both ears, binaural hearing might only be

achieved with bilateral cochlear implantation (i.e., CIs in both ears) (van Hoesel and Tyler 2003;

Litovsky, Parkinson et al. 2004; Litovsky, Johnstone et al. 2006; Brown and Balkany 2007; Litovsky

2008; Steffens, Lesinski-Schiedat et al. 2008; Basura, Eapen et al. 2009; Eapen and Buchman 2009;

Gordon, Wong et al. 2010; Salloum, Valero et al. 2010; Chadha, Papsin et al. 2011; Gordon, Jiwani et

al. 2011). Bilateral cochlear implantation is now being increasingly provided to children either in the

same surgery (simultaneously) or in two different surgeries following a period of unilateral implant use

(sequentially).

Bilateral CIs attempt to restore binaural hearing by providing information to both ears.

Normally, the auditory system compares, processes and integrates subtle differences between level and

timing of sounds reaching each ear. In this way, binaural hearing allows: 1) the

identification/localization of sound sources in space (Batteau 1967; Lorenzi, Gatehouse et al. 1999;

Van Deun, Van Wieringen et al. 2009; Grothe, Pecka et al. 2010); 2) increased perception of loudness

and ease of listening through binaural summation (Bocca 1955; Blegvad 1975); and 3) improved

hearing in quiet, noisy and reverberant environments through the head shadow and squelch effects

(Hawley, Litovsky et al. 2004; Van Wanrooij and Van Opstal 2004). Moreover, binaural hearing

reduces the risk of auditory deprivation in the unaided ear (Gordon and Papsin, 2009a, 2009b) and

also makes communication less tiring which enables listening and communication to be a more

pleasant experience. Although restoring binaural hearing is the goal of bilateral implantation, this has

not been completely realized in either adults or children (van Hoesel and Tyler 2003; Seeber and Fastl

2008; Grieco-Calub and Litovsky 2010; Salloum, Valero et al. 2010).

Children who are deaf in both ears hear speech better with bilateral CIs than unilateral implants

(Litovsky, Parkinson et al. 2004; Brown and Balkany 2007; Ching, van Wanrooy et al. 2007; Galvin,

Mok et al. 2007; Peters, Litovsky et al. 2007; Litovsky 2008; Seeber and Fastl 2008; Steffens, Lesinski-

Schiedat et al. 2008; Basura, Eapen et al. 2009; Eapen and Buchman 2009; Gordon and Papsin 2009;

Van Deun, Van Wieringen et al. 2009; Salloum, Valero et al. 2010; Chadha, Papsin et al. 2011), but do

not hear binaural cues normally (Grieco-Calub and Litovsky 2010; Salloum, Valero et al. 2010).

Outcomes improve when both implants are provided with limited delays and at young ages (van Hoesel

and Tyler 2003; Gordon and Papsin 2009; Van Deun, Van Wieringen et al. 2009; Gordon, Wong et al.

2010; Chadha, Papsin et al. 2011). As the duration of inter-implant delay decreases, the two ears

45

develop more symmetric speech perception abilities and children show increasing advantages of

bilateral over unilateral implantation (Gordon and Papsin 2009). Significant improvements on

standardized speech perception tests are seen as early as 6 months following bilateral CI stimulation

in children who receive their second implant simultaneously or within short delays (Gordon and Papsin

2009). Furthermore, children implanted with both CIs simultaneously derive significantly more benefit

from spatial separation of noise compared to children who have longer delays between implants

(Chadha, Papsin et al. 2011). Sound localization improves in children who are provided access to

sound early and in both ears (Van Deun, Van Wieringen et al. 2009). By contrast, children who receive

both CIs sequentially after long inter-implant delays (>2 years) have persistent asymmetries in auditory

function and compromised bilateral benefits for speech perception, even after 36 months of bilateral

CI use (Gordon and Papsin 2009). Sequentially implanted children also seem to depend more on their

first implanted ear than their second for speech perception, and show less bilateral improvement

(relative to unilateral implant use) on speech outcomes than children implanted simultaneously or with

limited delay (Gordon and Papsin 2009). These children localize sound inaccurately and rely heavily

on level cues to do so (Grieco-Calub and Litovsky 2010). The negative effect of inter-implant delay

might be explained by underlying changes to the developing auditory pathways before and after

unilateral and bilateral implantation.

2.12 Evidence of a short sensitive period for bilateral input in human auditory

development

Data presented in Figures 2.8 and 2.9 show that unilateral stimulation promotes development

of the auditory pathways, thus limiting effects of deafness. At the same time, this development might

occur at the expense of pathways from the opposite and deprived ear. This might be explained by the

absence of inhibition, which would normally have come from input from the opposite ear during

binaural hearing (Grothe, Pecka et al. 2010). Without this inhibition, ascending projections from the

stimulated ear may be abnormally strengthened in children who are deaf and use unilateral CIs.

Gordon and colleagues suggested that the stage of unilaterally driven brainstem development

would be an important factor to consider when studying bilateral auditory function in children with

different durations of unilateral implant exposure (Gordon, Salloum et al. 2012; Gordon, Wong et al.

46

2013). Perhaps changes occurring in the brainstem at earlier stages of unilaterally driven development

would have less long lasting consequences on the bilateral pathways than after the unilaterally

stimulated brainstem reached maturity. As shown in Figure 2.8, development in the auditory

brainstem is largely complete by ~1 year of unilateral implant use. Thus, children with >2 years of

unilateral CI experience would be considered to have mature auditory brainstem function and long-

term unilateral use. On the other hand, children who have had <1 year of unilateral experience before

receiving a second implant on the opposite side would be considered to have short-term use with

continuing auditory brainstem development. Gordon and colleagues showed that all children receiving

bilateral implants sequentially produced brainstem responses which were faster when evoked by the

experienced ear compared to the newly implanted ear at initial bilateral implant use (Gordon, Valero

et al. 2008). This was expected and confirmed earlier findings that the first implant promoted

improved neural conduction through the brainstem. Repeated tests completed after (mean ± standard

deviation (SD)) 1.7 ± 1.65 year of bilateral implant use indicated that mismatches in response latencies

persisted in a group of children receiving the second implant after a long delay (>2 years) (Gordon,

Salloum et al. 2012). Increased response latencies in response to sound from the second implanted

side could reflect decreased axonal myelination, longer neural conduction times, slower or weaker

synapses or more asynchronous neural activity – all signs of more limited brainstem development.

Abnormal mismatches between brainstem response latencies were never present in children receiving

bilateral implants simultaneously and resolved with bilateral implant use in children who received both

implants after a short inter-implant delay (<1 year) (Gordon, Valero et al. 2007; Gordon, Valero et al.

2008; Gordon, Jiwani et al. 2011; Gordon, Salloum et al. 2012). Thus, allowing the brainstem to

develop unilaterally for >2 years compromises the later promotion of symmetrically functioning

bilateral auditory brainstem pathways.

Mismatched bilateral auditory development in sequentially implanted children was not

restricted to the brainstem, however. Effects of asymmetric activity in the pathways from the first

stimulated ear were also found in the auditory cortex. Consistent with the brainstem findings, cortical

abnormalities were not resolved by chronic bilateral implant use (3.57 ± 0.74 years) when unilateral

experience exceeded 1.5 years in children who were implanted early (1.87 ± 1.25 years of age). These

findings were recently reported by Gordon, Wong et al. (2013) and are shown in Figure 2.11. Using

a beamformer imaging method (Wong and Gordon 2009) to suppress the electrical artifact from the

CI device and spatially localize areas of cortical activity in the brain (method briefly described in Section

47

1.2.6)., dipole moments for a given voxel in both the left and right auditory cortices were calculated

across latency (virtual sensor) and peak values were used for analyses.

Cortical responses were evoked by unilateral electrical pulse trains delivered from one implant

electrode in 7 children with normal hearing, 8 children who were implanted unilaterally in the right ear

(2.32 ± 1.61 years) and had 7.21 ± 2.48 years of hearing experience and 26 children who used bilateral

CIs for 3.42 ± 0.59 years. Of the bilateral implant users, 10 children received both CIs simultaneously

and 16 were sequentially implanted (right ear implanted first with no hearing aid in the left ear).

Bilateral deafness prior to implantation was limited (1.74 ± 0.90 years) in all children. The children in

this study had less than 12 years of hearing experience, and therefore all produced a cortical evoked

response which was dominated by an immature large amplitude positive peak. The differences

between the dipoles from the left and right auditory cortices were normalized as a percent lateralization

[% lateralization = (dipole right – dipole left) / (dipole right + dipole left) x 100].

A larger than normal variability in the lateralization of cortical dipoles was found in children

receiving bilateral CIs sequentially. A factor analysis of multiple demographic variables identified the

duration of unilateral implant use as the factor, which best accounted for the spread of cortical

responses. Cortical lateralization data was further analyzed for effects of duration of unilateral implant

use occurring prior to bilateral implantation. When responses were evoked by the first (i.e., right)

implant, there was an increase in lateralization of activity to the contralateral left auditory cortex with

unilateral implant use. This became significantly larger than the percent of cortical lateralization in the

simultaneously implanted group at 1.48 years of unilateral implant use. Consistent results were

obtained in data evoked by the second (i.e., left) implant but in this case, cortical lateralization changed

from the normally expected contralateral direction to ipsilateral lateralization with unilateral implant

use. This abnormal switch to larger activity in the ipsilateral auditory cortex became significantly

different from responses in the simultaneously implanted group by 1.37 years of unilateral implant use.

These analyses indicated that children with longer than approximately 1.5 years of unilateral implant

use had experienced an abnormal strengthening of pathways from their first implanted right ear

through the auditory brainstem (Gordon, Valero et al. 2008; Gordon, Salloum et al. 2012) to their left

contralateral cortex. This was not resolved by several years of bilateral implant use and was associated

with poorer speech perception in the second than first implanted ear (Gordon, Wong et al. 2013).

48

The importance of restricting unilateral implant use to less than 1.5 years is further evident in

Figure 2.11. Here, the grand mean lateralization of cortical activity are shown (A), as well as the grand

mean dipole moments identified from the virtual sensors in each hemisphere (B). The group of 16

sequentially implanted children was divided into two groups based on the cut off of 1.5 years of

unilateral implant use. The Short Delay group included 7 children who had 0.86 ± 0.1 years of

unilateral implant experience at the time of testing. The other 9 children, the Long Delay group, had

more than 2 years of unilateral implant use (3.44 ± 1.27 years). The single positive peaked response is

clear in all of the group averaged waveforms shown in Figure 2.11B. The maximum dipoles in the

left and right auditory cortices were marked and analyzed in each child. The left plot of Figure 2.11C

shows that dipoles evoked by stimulation from the first/right implanted ear resulted in significantly

higher dipoles in the left auditory cortex (blue bars) of children who had >1.5 years of unilateral

implant use (Unilateral and Long Delay groups) than other groups of children. The similar findings

for these two groups confirm that unilaterally driven strengthening of projections to the contralateral

left auditory cortex was not reversed by the addition of a second CI. This was true despite the children

in the Long Delay group having had several years of bilateral implant experience at the time of the test.

The right plot in Figure 2.11C shows mean dipoles for each auditory cortex in response to left/second

CI stimulation. The Long Delay group shows significantly higher dipole moments in the left auditory

cortex than the other groups of children. Thus, regardless of which ear was stimulated, the left auditory

cortex (contralateral to the first/right implanted ear) was the more active side of the brain in children

who had used one implant for >1.5 years. One explanation for this finding is that the specialized

processing of language in left auditory cortex (Zatorre and Belin 2001; Zatorre, Belin et al. 2002;

Tervaniemi and Hugdahl 2003; Firszt, Ulmer et al. 2006) may be abnormally increased in unilateral CI

users. An alternate explanation is that unilateral stimulation allowed abnormal strengthening of

pathways from that ear.

Further evidence that the cortical changes were due to unilaterally driven strengthening was

found by assessing which ear preferentially activated the hemisphere contralateral to the ear deprived

during the period of unilateral implant use (i.e., the right auditory cortex). The right auditory cortex

was expected to respond more strongly to input from the left than right ear because the majority of

neurons from one ear normally cross to the contralateral brainstem and ascend ipsilaterally from there.

This was confirmed in the group of children with normal hearing and children with limited unilateral

implant use prior to bilateral implantation (Short Delay and Simultaneous). By contrast, this pattern

49

was reversed in children in the Long Delay group. This means that this group of children had

experienced a strengthening of pathways from their hearing ear to both the ipsilateral right auditory

cortex, as shown by the reversal of aural preference, as well as the contralateral left auditory cortex in

response to long-term stimulation of the experienced right implant. The same reversal of aural

preference in the cortex ipsilateral to the hearing ear has recently been reported in congenitally deaf

white cats (Kral, Hubka et al. 2013).

The abnormal strengthening of pathways from the unilaterally hearing ear to the immature

brain seems to initially occur at the level of the brainstem. This is supported by evidence of

mismatched brainstem latencies observed from children with long (>2 years) unilateral hearing

experience (Gordon, Salloum et al. 2012). The shorter wave eV latencies evoked from the more

experienced ear suggest an increasing efficiency of activity from this side and a weakening of pathways

from the opposite ear, as reflected by slower peak latencies on the second implanted side. This could

result from a lack of inhibitory processes in the brainstem which are normally present during binaural

hearing (Grothe, Pecka et al. 2010). Listening from one side would allow auditory input from the first

right implanted side to be projected to the cortex with abnormally high excitation during development

thus strengthening pathways to the contralateral cortex. It appears that if this is allowed to occur until

the brainstem is largely developed (i.e., >1 year of unilateral implant use), it establishes asymmetric

activity in the auditory pathways, which is not easily reversed by providing a second implant in the

deprived ear. Limiting the period of unilateral hearing in children by providing bilateral CIs with little

or no delay appears to protect the bilateral pathways from this abnormal development. These findings

thus suggest that there is a sensitive period of 1.5 years for binaural auditory development in children

(Gordon, Wong et al. 2013).

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2.13 Does long-term unilateral cochlear implant use have abnormal

consequences for cortical auditory development?

We have reviewed evidence showing that access to sound within limited durations of bilateral

deafness in early life promotes development of activity along the auditory pathways in children who

have many years of hearing experience with a unilateral CI. At the same time however, unilaterally

driven stimulation of the auditory system leaves the opposite pathways deprived of input and

susceptible to reorganization. Thus, both bilateral and unilateral deprivation should be limited to

promote optimal hearing in children who use CIs and enable them to function better and more

naturally in challenging listening situations such as the playground or classroom environments.

Unfortunately, limiting the period of unilateral deprivation has not always been possible, particularly

in the early years of cochlear implantation when the device was provided in only one ear. There are

several reasons why CIs were traditionally provided only unilaterally. These include: 1) benefits of

Figure 2-11: Cortical dipole activity evoked by auditory input in children with different durations of

unilateral implant use. Reproduced with permission from Gordon, Wong et al. (2013).

“A. Per cent cortical lateralization (mean ± 1 standard error) is plotted for each participant group.

Greater than normal contralateral lateralization to right/CI-1 stimuli was found in long delay and

unilateral CI users (P<0.05 and <0.0001, respectively) but not in short delay and simultaneous groups

(P>0.05). The long delay group showed a decrease in contralateral lateralization/increase in ipsilateral

lateralization relative to those with normal hearing in response to left/CI-2 stimulation. This did not

occur in the short delay and simultaneous groups. B. Grand mean virtual sensor data for left and

right hemispheric sources of P1 (normal hearing) and P1ci (CI users for stimulation from right/CI-1

and left/CI-2). Large peaks in responses to CI-1 (right) stimulation can be seen in the long delay and

unilateral group data. C. Left and right hemispheric dipole moments (mean ± 1 SE) for P1/P1ci in

each group in response to right/CI-1 and left/CI-2 stimulation. In response to CI-1 (right)

stimulation, there is a marked increase in left hemispheric dipole moments in participant groups with

>2 years of unilateral hearing experience (long delay and unilateral; P<0.05).” (Gordon et al., 2013,

Brain, Figure 7, p.11).

52

implantation associated to linguistic, psychological, and social development were undetermined in the

early days of cochlear implantation (Lane and Bahan 1998; Svirsky, Robbins et al. 2000), 2) risks related

to the surgical procedure were unclear (Lane and Bahan 1998), 3) since the cost of cochlear

implantation is high, cost-utility analyses were not available at the time, and from a public policy

perspective, net savings to society were unknown (Cheng, Rubin et al. 2000; Mohr, Feldman et al.

2000; O'Neill, O'Donoghue et al. 2000), 4) some parents chose to ‘save’ one cochlea in the hope that

a cure or alternative treatments to deafness (i.e., stem cell therapy or gene therapy) may become

available in the future (Brown and Balkany 2007). Over the past decade, research has addressed many

of these questions related to the safety, efficacy and cost-utility of bilateral over unilateral cochlear

implantation. Positive outcomes for development of the auditory pathways, speech and language

performance, social/cultural integration and improved quality of life with two implants rather than

one all indicate that CIs should be provided to children early and in both ears within very limited or

no delays between implants.

Unilateral CI use exceeding a sensitive period of 1.5 years drives abnormal mismatches in

activity at the level of the brainstem (Gordon, Salloum et al. 2012) and cortex (Gordon, Wong et al.

2013) which are associated with abnormal asymmetries and integration of bilateral input (Hawley,

Litovsky et al. 2004; Peters, Litovsky et al. 2007; Litovsky 2008; Gordon and Papsin 2009; Van Deun,

Van Wieringen et al. 2009; Van Deun, Van Wieringen et al. 2009; Grieco-Calub and Litovsky 2010;

Salloum, Valero et al. 2010; Chadha, Papsin et al. 2011). Given these findings, in the present Thesis,

we asked whether there are cortical consequences of missing this early sensitive period and driving

maturation of the auditory cortex with unilateral implant stimulation. We tested this with 3

experiments. First, we used well established methods of auditory evoked potential recordings to

measure electric currents generated in the auditory pathways in response to sound to determine

whether auditory activity in the cortex undergoes normally expected maturational changes after 10

years of unilateral CI use. Second, we further developed the TRACS beamformer and used this

objective imaging method to determine which areas of the brain respond to sound in adolescents who

grow up using one CI. Recently, many of these adolescents/young adults who were implanted as

babies and have already had many years of unilateral hearing experience, received a second CI in their

opposite ear in hopes of deriving benefits of bilateral implantation. This provided us with a unique

opportunity to stimulate the unilaterally deaf ear for the first time and locate the cortical sources of

activity generated from the deprived auditory pathways to assess the plastic effects of long-term

53

unilateral stimulation/deprivation in the adolescent brain. Third, we explored how activity in these

areas of the brain is coordinated to respond to sound. We used a mathematical filtering algorithm to

assess the brain regions that respond to sound in a synchronized coordinated manner and determine

how this interaction across brain areas is involved in hearing after long durations of unilateral implant

use. Responses from the newly implanted side were examined to determine whether this ear is

segregated from the cortical hearing network.

54

3. Chapter Three – Central auditory development after long-term

cochlear implant use

This chapter has been published with required journal formatting:

Jiwani, S., Papsin, B.C., Gordon, K.A., 2013. Central auditory development after long-term cochlear

implant use. Clinical Neurophysiology, 124, 1868-80.

3.1 Abstract

Objective: We determined whether long-term cortical auditory development is altered or delayed in

children using cochlear implants (CIs) relative to their normal hearing peers. We hypothesized that

cortical development in children using unilateral CIs follows a normal trajectory with long-term

auditory input when the duration of bilateral auditory deprivation in childhood is limited.

Methods: Electrically-evoked cortical responses were recorded in 79 children who received one CI

within 2.03 ± 1.36 years of bilateral deafness and had up to ~16 years of time-in-sound experience,

and in 58 peers with normal hearing. Amplitude differences between the responses from children

using CIs and with normal hearing were calculated between 0 and 300ms.

Results: Responses from CI users remain different from those of their normal hearing peers. These

differences decreased over time, but were not eliminated even after 10 years of time-in-sound.

Specifically, the P1-N1-P2-N2 complex, typical of a normally mature response, began to emerge by 10

years of time-in-sound experience, but the amplitudes of P2 and N2 became abnormally large.

Conclusion: Mature-like cortical responses emerge in children after long-term unilateral CI use,

however, differences from normal persist.

Significance: Maturation of cortical responses with long-term CI use potentially underlies functional

improvements in hearing. Persistent differences from normal could reflect an increase in attention or

multi-sensory processing during listening.

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3.2 Introduction

Hearing can be restored to children who are deaf by providing cochlear implants (CIs) which

electrically stimulate the auditory pathways. Although the CI promotes short term changes in the

auditory system (Ponton and Eggermont 2001; Sharma, Dorman et al. 2002; Sharma, Dorman et al.

2002; Gordon, Tanaka et al. 2005; Sharma and Dorman 2006; Gordon, Tanaka et al. 2008; Gordon,

Wong et al. 2010), there is little known about whether the children using these devices develop a mature

auditory system after long-term use. Normal maturation could be impeded by several factors including:

1) the abnormal auditory input provided by the implant; 2) stimulation in only one ear; and 3) bilateral

auditory deprivation during potentially sensitive developmental periods in early life. In the present

study, we took an optimistic approach and hypothesized that cortical development, measured by

assessing changes in the cortical evoked potential response, follows a normal trajectory with time-in-

sound over long-term unilateral CI use when the duration of bilateral auditory deprivation in childhood

is limited.

3.3.1 Deafness prior to cochlear implantation alters normal brain development

Prior to cochlear implantation, the immature and deaf auditory brain is vulnerable to take-over

by non-auditory neuronal networks (i.e., cross-modal plasticity) (Lee, Lee et al. 2001; Bavelier and

Neville 2002; Sharma, Dorman et al. 2002; Harrison, Gordon et al. 2005; Gordon, Papsin et al. 2007;

Moore and Shannon 2009; Sharma, Nash et al. 2009). Recent evidence of cross-modal reorganization

in a cat model of congenital deafness indicates that while the primary auditory cortex is spared (Kral,

Schroder et al. 2003), association areas of the auditory system become the targets of other sensory

systems (Lomber, Meredith et al. 2010; Meredith and Lomber 2011). Specifically, the Posterior

Auditory Field and the Dorsal Zone of the association auditory cortex become recruited by the visual

system to perform visual functions (Lomber, Meredith et al. 2010). These changes appear to result

from a direct competition for resources in areas that receive multi-sensory input and likely reflect the

brain’s attempt to compensate for auditory deprivation with enhanced visual processing.

Electrical stimulation of the auditory nerve with a CI could provide sufficient input to the brain

to slow or halt cross-modal changes (Kral, Hartmann et al. 2001; Harrison, Gordon et al. 2005; Papsin

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and Gordon 2007; Gordon, Jiwani et al. 2011). Providing a CI at young ages drives cortical auditory

development within 3 to 6 months of implant use (Gordon, Papsin et al. 2005; Sharma and Dorman

2006). Yet, normal maturation of the auditory cortex requires much longer periods and is known to

continue throughout adolescence until ~20 years of age (Albrecht, Suchodoletz et al. 2000). This

suggests that long durations of hearing might be needed to achieve a mature auditory cortex in children

who are deaf and use CIs. Failure to reach maturity could result from delivering abnormal stimulation

to one ear alone with an implant (Ponton and Eggermont 2001) and any effects of bilateral deafness

in early development (Kral, Hartmann et al. 2001; Bavelier and Neville 2002; Eggermont and Ponton

2003). In the present investigation, we asked whether normal patterns of cortical maturation occur in

children who have used their CIs to hear for many years.

3.3.2 Early auditory cortical development in cochlear implant users follows a

normal-like trajectory

The development of the central auditory pathways over time can be studied using cortical

auditory evoked potential responses. Recent investigations indicate that electrically-evoked auditory

cortical responses of deaf children who have limited durations of bilateral deafness and have good

speech perception outcomes with their implants resemble the large amplitude broad positive peak

response recorded from young children with normal hearing who are under 10 years of age (Ponton

and Eggermont 2001; Sharma, Dorman et al. 2002; Sharma, Dorman et al. 2002; Gordon, Tanaka et

al. 2008). Many groups have suggested that this immature positive peaked response is homologuous

to the normal P1 cortical peak (Ponton, Eggermont et al. 2000; Ponton and Eggermont 2001; Ponton,

Eggermont et al. 2002; Sharma, Dorman et al. 2002; Gilley, Sharma et al. 2006; Sharma, Nash et al.

2009), which is generated by recurrent excitatory inputs from the thalamus to neurons in deep layers

(III to VI) of the auditory cortex (specifically the lateral portion of Heschl’s gyrus) (Liegeois-Chauvel,

Musolino et al. 1994). It may also reflect temporally overlapping auditory output from the reticular

activating system, which is known to integrate auditory and non-auditory multi-sensory input (Kraus,

McGee et al. 1992; Liegeois-Chauvel, Musolino et al. 1994; Ponton, Eggermont et al. 2000; Eggermont

and Ponton 2003).

57

Sharma and colleagues (2002; 2006) reported that when children with congenital deafness

receive a CI by 3.5 years, the positive P1-like peak in the cortical response decreases to age-appropriate

P1 latencies by 6 months post-implantation. They concluded that the central auditory system remains

highly plastic and minimally degenerate for a period of about 3 years following auditory deprivation in

these children (Sharma, Nash et al. 2009). These findings were consistent with reports by Eggermont,

Ponton and colleages (1997; 2003) who also found that the rate of cortical auditory maturation in

congenitally deaf CI users, measured by the latency of the positive peak, is delayed relative to normal

only by the amount of time that the child spent without significant hearing.

3.3.3 Auditory cortical maturation may be altered in cochlear implant users

Previous investigators raised concerns that the superficial layers of the auditory cortex may

never mature in CI users if the implant is not provided before 3.5 years of age (Eggermont and Ponton

2003; Sharma, Gilley et al. 2007), while others suggested that this might not occur even if the period

of auditory deprivation was further limited (Eggermont and Ponton 2003). The superficial layers of

the auditory cortex (III and II), which only mature around 9 to 12 years of age in typically developing

children (Ponton, Eggermont et al. 2000; Moore and Guan 2001), might require auditory input in early

life to develop (Eggermont and Ponton 2003). In normal hearing individuals, the cortical auditory

evoked potential response reflects this maturational process. Of importance, the large positive peaked

response seen early in development is thought to reflect activity in deeper auditory cortical layers (IV,

V and VI) (Kraus, McGee et al. 1992; Ponton and Eggermont 2001; Gordon, Tanaka et al. 2008),

which are known to develop first (Ponton, Eggermont et al. 2000; Moore and Guan 2001). However,

as primary auditory thalamo-cortical and cortico-cortical connections in superficial cortical layers

mature in adolescence, the development of a small negative amplitude peak, labelled N1, causes this

positive peak to bifurcate into two separate adult P1 and P2 components (Ponton, Eggermont et al.

2000; Ponton and Eggermont 2001; Eggermont and Ponton 2003; Wunderlich and Cone-Wesson

2006; Gordon, Tanaka et al. 2008). N1 is believed to be generated by late maturing auditory thalamo-

cortical and cortico-cortical activity in the superficial layers (III and II) of the superior temporal cortex

(Ponton, Eggermont et al. 2000; Ponton and Eggermont 2001; Ponton, Eggermont et al. 2002). The

development of these neural connections have been linked to the emergence of more complex

auditory-specific perceptual skills, such as hearing in noise, understanding degraded speech, sound

58

localization, and gap detection, as well as other complex temporal processing skills (Ponton,

Eggermont et al. 2000).

Eggermont and Ponton (2003) questioned whether children using CIs would ever develop

cortical responses containing this small negativity (Eggermont, Ponton et al. 1997; Ponton, Eggermont

et al. 2000; Ponton and Eggermont 2001; Eggermont and Ponton 2003). If this did not occur, it would

suggest that development of neuronal connections in the superficial layers of the auditory cortex of

children using CIs is persistently delayed or proceeds in an aberrant fashion. Effects of deafness

and/or unilateral CI stimulation could disrupt interhemispheric connections and auditory thalamo-

cortical and cortico-cortical pathways that are normally present by adolescence (Ponton, Eggermont

et al. 2000).

Although it is clear that chronic auditory stimulation with a CI promotes activity in the central

auditory system of children who are deaf from infancy (Kral, Hartmann et al. 2001; Harrison, Gordon

et al. 2005; Gordon, Valero et al. 2007; Papsin and Gordon 2007; Gordon, Jiwani et al. 2011), the long-

term development of the auditory cortex in these children has not been specifically evaluated. In the

present study, we used auditory evoked potential recordings to assess changes in the cortical evoked

response in a cohort of children who had up to 16 years of time-in-sound experience. Responses from

this group were compared with those recorded from more inexperienced CI users and age matched

normal hearing controls. Although normal maturation was not fully achieved, we found evidence of

continued change in cortical activity over long-term CI use.

3.4 Methods

3.4.1 Participants

Table 3.1 provides demographic details for the 79 children using CIs who participated in this

study. Thirty-nine of the children were female and 40 were male. This group of children had (mean

± standard deviation (SD)) 2.03 ± 1.36 years of bilateral deafness and between 0.69 to 15.95 years of

time-in-sound experience at the time of the test. Most of the children (n=56) were pre-lingually deaf,

10 children had a peri-lingual onset of severe-to-profound hearing loss, and 13 lost their hearing post-

lingually. Aetiology of deafness varied. Most were congenital in nature due to unknown causes (n=38);

59

37 of the hearing losses had a genetic aetiology, including 2 with a confirmed diagnosis of Pendred

syndrome, 4 with Ushers, 1 with KID syndrome, 3 with an abnormal cochlea and 1 with a

developmental delay. Two of the children acquired a severe-to-profound hearing loss due to

meningitis and 2 for other causes, including a progressive hearing loss resulting from a Cholesteatoma.

Of all the 79 children who participated in this study, 9 children had 5.68 ± 1.77 years of useable residual

hearing prior to cochlear implantation and combined with duration of CI experience, had, on average,

over 10 years of total time-in-sound experience (i.e., 13.22 ± 1.41 years) at the time of the test. The

other 70 children were deaf from infancy and received their CI by 2.35 ± 1.27 years of age. Of these

children, 17 had used an implant for over 10 years (i.e., 12.59 ± 1.44 years) and 50 had less experience

(i.e., 4.43 ± 2.67 years). All children were implanted with a CI device from Cochlear Inc. with full

insertion. Eight children used a Nucleus CI22 device, 26 used a CI24R(CS) contour implant, 15

children had a CI24R(CA) contour advance, 18 children received a CI24M device, and 12 used a

CI24RE Freedom Contour Advance implant. The type of CI device used by each child is indicated in

Table 1. To compare results with normal hearing responses, acoustically-evoked cortical responses

were recorded from 58 normal hearing controls who were between 7 and 19 years of age (31 female :

27 male). Children in the normal hearing control group were matched for chronological age and

duration of hearing experience (time-in-sound).

As expected, many variables changed together over time. Strong positive correlations were

found in the implant group between total time-in-sound experience and age at test (R=0.97, p<0.01),

duration of CI use (R=0.90, p<0.01), age at cochlear implantation (R=0.68, p<0.01), duration of

residual hearing (R=0.45, p<0.01) and duration of bilateral deafness (R=0.37, p<0.05). Thus, it was

impossible to isolate the duration of total time-in-sound experience from these other variables.

Accordingly, the analyses of the present study focused on experience-dependent changes in the cortical

response (i.e., total time-in-sound experience).

60

Table 3-1: Mean (X) ± standard deviations (SD) of demographic information of the CI users.

61

3.4.2 Evoked potential recordings

Electrically-evoked cortical responses were recorded using the NeuroScan 4.3 system with a

Synamps I amplifier. Responses were recorded from all participants while they sat in a soundproof

booth and watched a silent movie with closed captioning. Responses were recorded from a surface

electrode at a midline cephalic location (Cz) and referenced to each earlobe in a two channel recording.

The frontopolar point (Fpz) was used for the ground electrode. Responses were sampled at a rate of

500Hz and an online band-pass filter from 0.05Hz to 100Hz was applied. Averaged responses were

further filtered off-line when necessary, using a 30Hz low-pass digital filter with a 12dB/octave rolloff.

A minimum of 200 sweeps were recorded and at least 2 visually replicable responses were obtained for

all test conditions. All sweeps containing greater than ± 100µV were rejected from the average.

Biphasic electrical pulse trains of 250 pulses per second (i.e., 9 pulses per train) lasting 36ms

were delivered by a single electrode on the apical end of the electrode array (#20, #18, or #16,

depending on the stimulation mode). Pulse trains were presented at a rate of 1Hz to generate cortical

responses. Given the variability in the types of device used and the different MAPS, the stimuli were

delivered from a single electrode at intensities which were at maximum comfortably loud levels for

each child. To determine current presentation levels, auditory brainstem responses were electrically-

evoked by biphasic electrical pulses at a stimulus repetition rate of 11Hz. Current level was increased

to maximize the amplitude growth of the auditory brainstem response within the range of comfort for

the child. Once these levels were set according to the auditory brainstem response test, the current

levels were decreased by 10 current units for the pulse train stimuli, to account for the increased

perception of loudness with greater number of pulses presented in short periods. Stimulus intensity

of biphasic pulse trains used to record the electrically-evoked cortical responses in CI users ranged

from 180 to 240 current units. The stimulation intensity used for each child in our study is indicated

in Table 1. Auditory evoked cortical responses recorded from normal hearing individuals were

measured using 500Hz tone burst stimuli, lasting 36ms. A Tukey window was applied over the first

and last eighths of each tone, to minimize high frequency onset and offset effects. Stimuli were

presented at a rate of 1Hz through ER3-14A insert earphones to one ear at a time. The behavioural

threshold of hearing for this tone was measured in each of the children using the modified Hughson-

Westlake bracketing method (Carhart and Jerger 1959), and the tone was then presented at an intensity

level of 40dB above the threshold for that ear.

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3.4.3 Analysis of the electrically-evoked cortical responses

Changes in the morphology of the cortical auditory evoked waveform and in the amplitude

and latency of the cortical responses have been used as indices of auditory maturation in typically

developing children (Albrecht, Suchodoletz et al. 2000; Wunderlich, Cone-Wesson et al. 2006) and in

deaf children who use a CI to hear (Gordon, Tanaka et al. 2005; Harrison, Gordon et al. 2005; Sharma,

Dorman et al. 2005; Gordon, Tanaka et al. 2008). Amplitude peaks in the response were visually

identified at latencies corresponding to those identified in normal responses (Gordon, Tanaka et al.

2008). The observer was blinded to child, age at implant, age at test, and duration of CI use. To

compare the differences in the cortical responses of long-term CI users relative to a normal hearing

mature auditory cortical response, a grand mean normal hearing mature cortical waveform was created

using acoustically-evoked auditory responses from 15 typically developing, normal hearing children

who were between 13 to 18 years of age at the time of the test (mean ± SD time-in-sound/age = 15.54

± 2.11 years). Figure 3.1 shows the grand mean normal hearing mature cortical waveform with upper

and lower bound 95% confidence intervals.

Figure 3-1: Normal hearing mature cortical response.

Grand mean normal hearing mature cortical waveform from 15 typically developing, normal hearing

children who were between 12 to 18 years of age at the time of testing. Mean age/time-in-sound is

15.54 ± 2.11 years.

63

The amplitude differences between the individual cortical response waveforms of CI users and

the normal hearing mature waveform was then calculated in a recording window ranging from 0 to

300ms. The Trapezoid rule was used to calculate the amplitude difference between the 2 waveforms:

the grand mean normal hearing mature cortical waveform was subtracted from the cortical response

of each CI user at each 2ms amplitude point between 0 to 300 ms (i.e., 150 amplitude difference

points). The sum of these points was then multiplied by 2 (i.e., distance between each amplitude point)

to provide the total difference from normal amplitude for each child’s response. The amplitude

difference analysis was used to visually compare the morphological development of the cortical

waveform of CI users at different durations of device use, relative to a normal hearing mature response,

without making a priori decisions on the presence/absence of previously defined latency ranges of

amplitude peaks. In turn, this allowed for an objective quantification of any differences from normal

across latencies.

Amplitude differences in the 50 to 150ms and the 150ms to 300ms latency range were assessed

separately as dependent variables using multiple linear regression, with time-in-sound and implant type

as predictor variables. Duration of total time-in-sound was calculated as the duration of CI experience

plus the duration of any period of useable residual hearing prior to implantation. The duration of

useable residual hearing was defined as the number of years that thresholds of 40dB HL or better were

present with or without hearing aids at any two given frequencies. Given the large time-in-sound range

of the children in the CI group (i.e., 0.71 to 15.95 years) and the large age range in the normal hearing

group (i.e., 7 to 19 years), responses from children were separated into interval groups of 0 to 2 years,

2 to 4 years, 4 to 7 years, 7 to 10 years, 10 to 13 years, 13 to 16 years, and 16 to 19 years of time-in-

sound. This grouping by time-in-sound in the CI users and age in the normal hearing group allowed

us to analyze changes in the response as a function of time-in-sound experience. Data from normal

hearing participants and CI users in 3 groups (time-in-sound = 7 to 10 years, 10 to 13 years, and 13 to

16 years) were compared using t-tests with Bonferroni confidence interval adjustments. These analyses

were followed by more traditional peak picking methods to assess whether expected changes in specific

peaks were occurring over time. Differences between responses recorded from the CI users and the

children with normal hearing were evaluated using 2-tailed independent t-tests with Bonferroni

adjustments.

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3.5 Results

3.5.1 Cortical responses continue to mature with auditory experience in normal

hearing children and in users of cochlear implants

Responses from CI users who had up to 16 years of auditory experience are shown in Figure

3.2 on the left column (Figure 3.2A) and responses from normal hearing children who were between

7 to 19 years of age at the time of the test are shown on the right (Figure 3.2B). Responses were

grouped by time-in-sound intervals into ranges of 0 to 2 years, 2 to 4 years, 4 to 7 years, 7 to 10 years,

10 to 13 years, 13 to 16 years, and 16 to 19 years of experience.

As indicated in Figure 3.2, the auditory cortical response recorded from CI users and normal

hearing children who had between 0.69 to 7 years of time-in-sound experience is dominated by a large

positive peak, followed by a large negative peak. This positive peaked response is largest in amplitude

in children who had less than two years of time-in-sound experience (mean ± SD: 13.05 ± 11.62µV),

and decreases as auditory experience extends to 7 years (5.44 ± 5.65µV). Between 7 and 10 years time-

in-sound, a small negative deflection begins to emerge around 100ms, causing the morphology of the

cortical response to change from one positive peaked response into a multi-peaked waveform. By 10

years of time-in-sound, the response in all cases is comprised of P1, N1, P2 and N2 peaks. The P1-N1

complex is not seen in children who had less than 10 years of time-in-sound experience. As shown in

Figure 3.2B on the right, morphological changes of the auditory evoked cortical response in normal

hearing children occur in a similar way and at similar durations of time-in-sound. Children with both

normal hearing and CIs required 10 years of auditory experience to develop responses with the

polyphasic P1-N1-P2-N2 complex, typical of a mature auditory cortical response. Indeed, cortical

waveforms produced by CI users indicated amplitude values similar to those of their normal hearing

peers across the latency range (i.e., 0 to 300ms) for children who had between 7 to 13 years of hearing

experience (p>0.05). However, differences from normal increased in children with more experience

(t(15.6) = 2.4, p<0.05).

65

Figure 3-2: Development of the cortical response over time.

Progressive changes in the auditory evoked cortical responses are shown for A. CI users from 0. 69

to 16 years of time-in-sound (n=79) and B. normal hearing children from 7 to 19 years of age (n=58).

The responses are separated into ranges of 0 to 2, 2 to 4, 4 to 7, 7 to 10, 10 to 13, 13 to 16, and 16 to

19 years of time-in-sound experience. Individual responses are indicated by the thinner waveforms

and the grand mean response for that time-in-sound range is indicated by the thick waveform.

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3.5.2 Cortical development in users of cochlear implants follows a normal

trajectory with time-in-sound with differences emerging in latencies

greater than 150ms

As shown in Figure 3.2, early cortical wave peaks appear to follow a normal maturational time

course with time-in-sound experience, but peaks in the later latency ranges remain different from

normal. Figure 3.3A shows the difference in amplitude (in grey shading) between the grand mean

cortical responses of CI users grouped by specific time-in-sound intervals (dark grey waveforms) and

a grand mean normal hearing mature waveform (black waveform) over a 0 to 300ms latency period.

The mean age at test of the responses from the normal hearing group used to create the mature cortical

waveform was 15.54 years. As seen from Figure 3.3A, the shaded areas of difference from normal

are largest in paediatric CI users who have less than 7 years of time-in-sound experience. However, as

their auditory experience approaches the mean time-in-sound of the normal hearing waveform (~15

years), differences between the CI and the normal cortical responses become minimal. Indeed,

responses from children with over 10 years of time-in-sound consistently contain a small biphasic peak

which occurs at the same latency range as the normal P1 and N1 peaks (i.e., between 50 to 150ms). The

P1-N1 complex in these more mature responses is followed by P2 and N2 peaks in the 150 to 300ms

latency range.

Figure 3.3B displays these amplitude differences between the CI responses and the grand

mean normal hearing cortical waveform in a 3-dimentional plot as a function of latency and against

time-in-sound. The colours are used to identify the magnitude of difference between the responses of

the children using CIs and the grand mean normal hearing mature waveform. The dark red colour

shows greater differences from normal and the dark blue represents the least differences from the

normal response. With time-in-sound experience, the cortical responses of long-term CI users

approach a mature normal hearing response. Of interest, amplitude differences from the normal

mature response in the 50 to 150ms latency range (i.e., P1-N1 latency range) are greatest (areas of dark

red) in children with less than 7 years of time-in-sound, compared to a mature normal hearing response.

However, differences from normal decrease with auditory experience. With over 10 years of time-in-

sound experience, the early cortical peaks in the responses recorded from CI users approach normal-

like latency and amplitude values compared to the normal hearing grand mean cortical waveform

(t(34.7)=0.6, p>0.05), as indicated by the dark blue areas. By contrast, abnormally large peak amplitudes

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emerge with auditory experience in the 150 to 300ms latency range (i.e., P2-N2 latency range) in long-

term users of CIs who have over 10 years of time-in-sound experience (light blue colour) (t(37.8)=3.9,

p<0.01).

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Figure 3-3: Cortical response difference as a function of time after cochlear implantation compared

to the normal hearing mature waveform.

A. Grand mean cortical waveforms of CI users are plotted for specific intervals of time-in-sound

experience. All mean responses are compared to a normal and mature waveform (mean age/time-in-

sound: 15.54 ± 2.11 years, n=15). B. The trajectory of cortical response waveforms of CI users

(n=79) from 1.04 ± 0.42 years to 14.07 ± 0.86 years of time-in-sound experience are plotted on a 3-

dimensional map: x-axis = Latency (ms); y-axis = Amplitude (µV); z-axis = Duration of time-in-sound

(years). Difference between the CI and normal responses is plotted by colour. The largest differences,

shown in dark red, occur at short time-in-sound. The dark blue colour represents minimum

differences.

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3.5.3 Normal-like cortical maturation in the 50 to 150ms latency range is time

and experience dependent

To further assess changes in the cortical responses over time, we analysed early (50 to 150ms)

and later latency (150 to 300ms) ranges of the response separately. In Figure 3.4A., amplitude

differences in the 50 to 150ms latency range (i.e., P1-N1 latency range) between the cortical waveform

of the CI users and the grand mean normal hearing mature waveform are plotted against total time-in-

sound for all 79 CI users. Positive amplitude differences indicate larger amplitudes in CI users and

negative amplitudes indicate larger amplitudes in the group with normal hearing. Linear regression

analyses revealed that cortical responses of CI users approach normal values in the 50 to 150ms time

window with increasing time-in-sound experience (t(1, 77)=-3.7, p<0.01), regardless of implant type (t(2,

76)=-0.9, p>0.05).

Given that the differences from normal in the 50 to 150ms range decrease with time-in-sound,

we identified peak amplitude values for the P1-N1 complex in the 50 to 150ms latency range and

assessed how these change in latency and amplitude with time-in-sound for children with normal

hearing and their peers with CIs. Data summarized in Figure 3.4B illustrates the mean absolute

latencies and amplitudes of the P1 and N1 peaks once this complex emerges (i.e., after 10 years time-

in-sound experience). Cortical responses recorded from 11 children in each group who had between

10 to 13 years time-in-sound, and from 15 CI users and 22 normal hearing adolescents with 13 to 16

years time-in-sound experience, were compared. Independent 2-tailed t-test analyses revealed that

neither the latencies (P1: t(15.8)=-1.0, p>0.05; N1: t(16.8)=-0.7, p>0.05) nor the amplitudes (P1: t(16.6)=-0.1,

p>0.05; N1: t(16.6)=-0.6, p>0.05) of peaks P1 and N1 were significantly different from normal at this

long-term stage of CI use (p>0.05).

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compared to normal hearing peers.

A. Amplitude differences between CI (n=79) and the normal mature grand mean response were

calculated between 50 and 150ms (amplitude x 50 latency measurements) (µV x ms) and plotted against

time-in-sound. B. Mean ± standard deviations of the P1 and N1 absolute latencies and amplitudes of

CI users (light gray squares) and normal hearing individuals (black diamonds) are plotted as a function

of time-in-sound ranging from 10 to 19 years.

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3.5.4 Cortical abnormalities in the 150 to 300ms latency range is experience

dependent

In Figure 3.5A., the amplitude differences of all responses in the 150 to 300ms latency range

(i.e., P2-N2 latency range) are plotted against total time-in-sound for the responses recorded from all

79 CI users in this study. Linear regression analyses indicate that increases in amplitudes emerge in

the CI group, in this time window, with increasing time-in-sound experience (t(1, 77)=3.6, p<0.01). The

type of CI device used did not have an effect on these changes in amplitudes over time (t(2, 76)=-0.4,

p>0.05).

Changes in latency and amplitude of the peaks in this later latency range with time-in-sound

were assessed for 11 CI users and 11 normal hearing children who had between 10 to 13 years time-

in-sound, and for 15 CI users and 22 normal hearing children between 13 to 16 years. Figure 3.5B.

plots the absolute latencies and amplitudes of late latency peaks in responses from children who had

at least 10 years of time-in-sound experience. As shown, the latency of P2 is significantly increased

from normal at 10 to 13 years time-in-sound (when peaks P1 and N1 emerge) (t(6.7)=4.2, p<0.01), but

decreases with more auditory experience and is similar to normal values by 13 to 16 years (t(16.6)=1.2,

p>0.05). By contrast, the amplitude of peak P2 remains abnormally large in CI users even with 13 to

16 years of time-in-sound experience (t(15.9)=2.5, p<0.05).

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compared to normal hearing peers.

A. Amplitude differences between CI (n=79) and the normal mature grand mean response were

calculated between 150 and 300ms (amplitude x 50 latency measurements) (µV x ms) and plotted

against time-in-sound. B. Mean ± standard deviations of the P2 and N2 absolute latencies and

amplitudes of CI users (light gray squares) and normal hearing individuals (black diamonds) are plotted

as a function of time-in-sound ranging from 10 to 19 years.

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3.6 Discussion

In this study, we assessed whether cortical auditory development reaches maturation with long-

term unilateral CI use in children who had fairly short periods of bilateral auditory deprivation prior

to implantation. We found that auditory-evoked cortical waveforms approached normal-like

responses in children with at least 10 years of CI use, suggesting evidence of continuing cortical

development with auditory experience throughout adolescence. Importantly, a small normal-like P1-

N1 complex in the 50 to 150ms latency range, followed by a large and prominent P2-N2 complex

between 150 to 300ms was consistently observed in children who had over 10 years of time-in-sound

experience, but differences from normal persisted over time in latencies encompassing the P2

component.

3.6.1 Cortical activity early in development is similar between cochlear implant

users and their normal hearing peers

Analyses of cortical waveforms shown in Figures 3.2 and 3.3 indicate that early in

development, the cortical responses of CI users are dominated by a large and positive peak. This

positive peaked response (Ponton, Eggermont et al. 2000; Ponton and Eggermont 2001; Ponton,

Eggermont et al. 2002; Sharma, Dorman et al. 2002; Eggermont and Ponton 2003; Sharma and

Dorman 2006; Gordon, Valero et al. 2008; Sharma, Nash et al. 2009; Gordon, Jiwani et al. 2011;

Gordon, Tanaka et al. 2011) emerges as early as one month following CI activation (Sharma and

Dorman 2006) and persists with CI use up to ~10 years (Ponton, Eggermont et al. 2000; Ponton and

Eggermont 2001). These results are similar to previous reports indicating the dominance of this

response following early auditory experience (Ponton, Eggermont et al. 2000; Ponton and Eggermont

2001; Ponton, Eggermont et al. 2002; Sharma, Dorman et al. 2002; Eggermont and Ponton 2003;

Sharma and Dorman 2006; Gordon, Valero et al. 2008; Sharma, Nash et al. 2009; Gordon, Jiwani et

al. 2011; Gordon, Tanaka et al. 2011). This large positive peak is also seen in normal hearing children

early in development (Ponton and Eggermont 2001). It has been suggested that rapid decreases in the

latency of this large positive peaked response occur within the first 3 months following initial

stimulation with a CI in children who receive an implant by 3.5 years of age (Sharma and Dorman

2006; Sharma, Nash et al. 2009), reaching age-appropriate normal values within 6 to 9 months of

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chronic CI use (Sharma, Dorman et al. 2002; Sharma, Dorman et al. 2002; Sharma and Dorman 2006;

Sharma, Nash et al. 2009). This suggests that when a CI is provided within a sensitive period, the

development of the auditory cortex in CI users who are younger than 10 years of age is similar to

normal (Eggermont and Ponton 2003; Sharma and Dorman 2006).

Investigators have suggested that the large amplitude positive peak in the cortical responses of

young children with normal hearing may either reflect excitatory activity in thalamo-cortical projections

to deep layers of the auditory cortex (Liegeois-Chauvel, Musolino et al. 1994), or may reflect a

convergence of temporally overlapping neural sources which generate both the adult peaks P1 and P2

(Ponton and Eggermont 2001). It is possible that this peak reflects immaturity in the auditory cortex,

since peak amplitudes are known to be largest earlier in development, and decrease with age as auditory

cortical sources mature (Ponton and Eggermont 2001). Alternatively, it is also possible that this large

positive peaked response may be synonymous to the adult peak P2. Wunderlich, Cone-Wesson and

Shepherd (2006) suggested that, in normal hearing newborns and young infants, the large amplitude

positive peak is more likely to be a P2 peak arising from deep cortical activity (Ponton and Eggermont

2001) in the non-lemniscal auditory pathways (Crowley and Colrain 2004). Since the generators of

peak P2 have an early maturational time course, it may indeed be that this large positive peaked

response reflects auditory activity driven from the association auditory cortex and the reticular

activating system, rather than from Heschl’s gyrus (i.e., P1 generator), which is known to have a slower

rate of maturation (Liegeois-Chauvel, Musolino et al. 1991; Kraus, McGee et al. 1992; Liegeois-

Chauvel, Musolino et al. 1994; Godey, Schwartz et al. 2001). Multi-channel recordings of electrically-

evoked cortical activity in children would be required to localize the sources of activity generating this

large response early in development. Nevertheless, data from the present study shown in Figure 3.2

indicates that the positive peak in CI users appears at similar latencies and amplitudes at very early

stages of implant use and thus likely has the same neural generators as normal. This is further

supported by our finding that the changes in this response over time are similar to normal.

As shown in the amplitude difference analyses of Figures 3.3A and 3.3B, the positive peak

decreased in amplitude over the first 7 years of time-in-sound in children using CIs, revealing

decreasing differences from the normal hearing mature response with auditory experience. The similar

peak in normally hearing children also decreases in amplitude and latency with age, as the auditory

system matures (Eggermont and Ponton 2003; Sharma and Dorman 2006). We know from normal

hearing data that maximum synaptic density in the auditory cortex is reached by ~3 months of age

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(Huttenlocher and Dabholkar 1997). Thus, the large amplitude positive peaked cortical response

reported from normal hearing infants (Wunderlich, Cone-Wesson et al. 2006) and recorded from CI

users at initial stages of hearing experience may reflect the high synaptic density which is present in

early cortical development (Huttenlocher and Dabholkar 1997; Wunderlich and Cone-Wesson 2006;

Wunderlich, Cone-Wesson et al. 2006; Picton and Taylor 2007). Moreover, because the amplitude of

a peak is known to reflect synaptic density and efficiency (Eggermont 1988; Picton and Taylor 2007),

the reduction in amplitude in the early latency range (50 to 150ms) with time-in-sound (Figures 3.3

and 3.4) could reflect decreasing numbers of activated cells and synapses contributing to the response.

Synaptic pruning begins in late childhood (Huttenlocher and Dabholkar 1997; Ponton,

Eggermont et al. 2000) and is thought to be complete by ~12 years of age in the auditory cortex,

resulting in an abrupt decrease of synaptic density (Huttenlocher and Dabholkar 1997). Thus, it has

been suggested that the decrease in amplitude of the cortical response in children with normal hearing

up to 7 years of age likely reflects this reduction in synaptic density (Wunderlich, Cone-Wesson et al.

2006; Picton and Taylor 2007). Furthermore, neural maturation in childhood, characterized by changes

in the location and orientation of neural substrates in the auditory cortex may also influence the

amplitude of the cortical response (Wunderlich, Cone-Wesson et al. 2006). In addition, other

mechanisms may also affect the decrease in amplitude of cortical wavepeaks in early development.

Increased axon myelination and changes in synaptic mechanisms with development might contribute

to changes in the cortical waveform morphology occurring with time and auditory experience in

normal hearing children (Sharma, Kraus et al. 1997; Albrecht, Suchodoletz et al. 2000). Thus, as

neurotransmission becomes more efficient with auditory development, the observed decreases in

amplitude over the first 7 years of time-in-sound experience could reflect an ongoing process of

synaptogenesis in CI users that is similar to normal. These findings are consistent with previous reports

of decreasing amplitudes of the auditory evoked cortical response reported from normal hearing

children in this same time frame (Albrecht, Suchodoletz et al. 2000; Ponton, Eggermont et al. 2000;

Wunderlich and Cone-Wesson 2006; Wunderlich, Cone-Wesson et al. 2006).

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3.6.2 Long-term cortical development follows a normal-like trajectory with

time-in-sound

The data presented in Figures 3.2 and 3.3A suggest that a developmental milestone is

occurring in the auditory cortex around 10 years of time-in-sound in children using CIs. Indeed, by

10 years, the auditory evoked cortical response recorded in all such children had developed into a

mature polyphasic P1-N1-P2-N2 waveform. This is in line with the time-course of development of the

mature polyphasic P1-N1-P2-N2 cortical waveform in normal hearing adolescents, illustrated in Figure

3.2 and previously reported by other groups as well (Ponton, Eggermont et al. 2000; Ponton and

Eggermont 2001; Wunderlich and Cone-Wesson 2006; Wunderlich, Cone-Wesson et al. 2006). Figure

3.3B shows that differences from the normal hearing mature response are largest in children who have

less than 7 years of time-in-sound experience. However, as peak N1 develops, the cortical response in

the 50 to 150ms latency range approaches the normal hearing mature waveform in all children who

had more than 10 years of hearing experience (areas of dark blue in Figure 3.3B), indicating minimal

differences from normal.

Linear regression analyses shown in Figures 3.4A and 3.4B indicate that the cortical responses

in the early latency range significantly change over time (R=0.39). Children who had limited duration

of bilateral deafness and had longer durations of auditory experience produced cortical waveforms that

approached the normal hearing response in the 50 to 150ms latency range (i.e., P1 and N1 latency

range). The moderate strength of correlation reflects inter-subject variability, which should be

expected, given that auditory development after implantation will depend on multiple factors (Holden,

Skinner et al. 2002; Skinner, Holden et al. 2002; Nicholas and Geers 2007; Geers and Sedey 2011).

The data in Figure 3.4B shows that both the latencies and amplitudes of peaks P1 and N1 reach age

appropriate values in children with more auditory experience. Since the development of activity-

dependent processes in the brainstem tracts do not mature without significant auditory input (Gordon,

Papsin et al. 2003; Gordon, Papsin et al. 2006; Gordon, Papsin et al. 2007; Gordon, Valero et al. 2007;

Gordon, Valero et al. 2008; Gordon, Jiwani et al. 2011), these cortical changes are very likely due to

the exposure to auditory input with CIs. Chronic auditory stimulation provided by a CI over the long-

term may contribute to the establishment and/or strengthening of activity-dependent synaptic

connections between neurons and perhaps increased myelination of nerve fibres throughout the

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central auditory pathways. These mechanisms, known to increase neural synchronization (Gilley,

Sharma et al. 2005), may underlie the emergence of the P1 and N1 peaks in the evoked response.

It has been suggested that, although P1 generators are adult-like by 8 years of age and P2

generators are fully mature by 5 years of age (Albrecht, Suchodoletz et al. 2000; Ponton and Eggermont

2001), it is only at ~10 years of age that axons in superficial layers of the auditory cortex reach maturity

(Ponton, Eggermont et al. 2000; Moore and Guan 2001; Moore and Linthicum 2007). Interestingly,

it is also around this time (i.e., 9 to 12 years) that the cortical responses of normal hearing children and

CI users begin to develop into adult-like peaks (the P1-N1-P2-N2 complex) as shown in Figures 3.2,

3.3, and 3.4. This polyphasic waveform was identifiable only in children who had more than 10 years

of auditory experience and suggests that long-term CI users experience analogous cortical maturational

changes to those of their normal hearing peers at this stage of auditory processing. If the N1 reflects

re-entrant activity in thalamo-cortical and cortico-cortical pathways in the superficial layers of the

auditory cortex (Ponton and Eggermont 2001), then it is possible that these areas in the brain are

maturing in children who have used a CI for over 10 years, despite earlier concerns that this

development might never occur in children using implants (Ponton and Eggermont 2001; Eggermont

and Ponton 2003). We intend to explore this further using multi-channel recordings in future work to

assess the maturation of cortical sources in long-term CI users and their normal hearing peers.

Evidence of development of peak N1, perhaps reflecting maturation in superficial layers of the

cortex in children using CIs is encouraging, because these areas are essential for thalamo-cortical and

cortico-cortical maturation. Thalamo-cortical connections play a crucial role in the transfer of primary

(auditory specific) and non-primary (multi-sensory) auditory input from the medial geniculate body in

the thalamus (Razak, Zumsteg et al. 2009) to the ipsilateral and contralateral auditory cortices (Ponton,

Eggermont et al. 2000; Winer, Diehl et al. 2001; Winer, Miller et al. 2005; Razak, Zumsteg et al. 2009).

Cortico-cortical connections on the other hand, mediate the transfer of information between auditory

cortices in both hemispheres via commissural fibres and between the auditory cortex and other primary

sensory areas (Lee and Winer 2005; Winer, Miller et al. 2005; Klinge, Eippert et al. 2010). Thus, the

appropriate development of these connections in the brain has important implications for: 1) the relay

of auditory information from the outside world to the cortex; 2) communication between the two

hemispheres; and 3) the connectivity between different sensory areas. In addition, it has been

suggested that in normal hearing individuals, the maturation of these thalamo-cortical and cortico-

cortical auditory processes may be related to the development of complex auditory perceptual skills

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which occur during adolescence, such as discriminating speech in the presence of noise and

understanding degraded speech input, among other functional auditory skills (Ponton, Eggermont et

al. 2000; Eggermont and Ponton 2003). Since the emergence of peak N1 coincides with the

maturational time course of these processes, it is very likely that similar underlying developmental

mechanisms are also taking place in long-term CI users who have over 10 years of auditory experience.

In line with the time course of development of these skills, behavioural studies have shown significant

and continued improvement on long-term language comprehension and verbal reasoning skills in early

implanted children who used a CI for over 10 years, compared with their performance on language

tests in early elementary grades (Geers and Sedey 2011). Thus, while auditory development of early

cortical wave peaks is likely dependent on both time-in-sound and age; it is possible that the duration

of auditory experience bears more weight, at least for the development of superficial cortical layers.

The findings of the present study indicate that the N1 peak, and in turn, mature adult-like auditory

cortical responses, do develop with long-term CI stimulation. These changes likely support the

remarkable improvements in auditory function seen over time in children using CIs (Beadle, McKinley

et al. 2005).

3.6.3 Differences from normal in the later cortical peaks may reflect increased

cortical activity from non-auditory modalities

While the mature polyphasic cortical waveform does emerge with chronic long-term CI

experience, differences in later latencies occur over time in children with CIs, relative to their normal

hearing peers. Specifically, responses in the later latency range, between 150 to 300ms, became

significantly larger than normal in children with more than 10 years of auditory experience, as shown

in Figures 3.2 and 3.3. These deviations from normal were confirmed in the regression analysis

(R=0.38) of Figure 3.5A and in the abnormally large amplitude values of the P2 component (p<0.05)

identified in Figure 3.5B. It is possible that the degree of residual hearing prior to implantation may

not have sufficiently promoted development in the neural generators of these later latency peaks,

leaving aberrant or altered development of activity in deep auditory cortical layers (generating peaks P2

and N2). It is also possible that the long-term absence of binaural hearing through CIs in this cohort

impeded the normal maturation of peak P2 generators.

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Increases in the amplitude of peak P2 reflect more demand for attention and arousal while

hearing (Picton and Hillyard 1974; Rif, Hari et al. 1991; García-Larrea, Lukaszewicz et al. 1992; Novak,

Ritter et al. 1992; Kraus and McGee 1993; Ponton and Eggermont 2001; Tremblay, Kraus et al. 2001;

Moller and Rollins 2002; Tremblay and Kraus 2002; Eggermont and Ponton 2003; Alain, Snyder et al.

2007; Tremblay 2007; Tremblay, Shahin et al. 2009); increased recruitment of multi-sensory input,

including vision and touch, during complex decision-making processes (Hocherman, Benson et al.

1976; Hari 1990; Kraus, McGee et al. 1992; Kraus and McGee 1993; Grady, Van Meter et al. 1997;

Webster and Colrain 2000; Moller and Rollins 2002; Crowley and Colrain 2004; Busse, Roberts et al.

2005; Plailly, Howard et al. 2008; Kraus and Chandrasekaran 2010; Rinne 2010); and increased

responsiveness to the external environment during sleep (Weitzman and Kremen 1965; Ornitz, Ritvo

et al. 1967; Kraus, McGee et al. 1989; Kraus, McGee et al. 1992; Kraus and McGee 1993; McGee,

Kraus et al. 1993; Coull 1998; Colrain, Webster et al. 1999; Colrain and Campbell 2007). Enhanced P2

amplitudes observed following auditory training in normal hearing adults (Tremblay, Kraus et al. 2001;

Tremblay and Kraus 2002; Tremblay 2007; Tremblay, Shahin et al. 2009), suggests that focused

auditory learning increases the number of cortical neurons responding to the sound with improved

neural synchrony (Tremblay 2007; Tremblay, Shahin et al. 2009), and may reflect modulatory

influences from mechanisms of selective attention/arousal and other top-down processes (Alain,

Snyder et al. 2007; Tremblay, Shahin et al. 2009). These are the very processes which are known to

influence the amplitudes of peaks N1 and P2 (Picton and Hillyard 1974) and lead to improved auditory

perception (Shinn-Cunningham and Best 2008). Underlying generators could involve association

auditory areas and auditory activity driven from the reticular activating system, which includes frontal

and parietal areas (Hari 1990; Rif, Hari et al. 1991; Kraus and McGee 1993; Posner and Dehaene 1994;

Ponton and Eggermont 2001; Moller and Rollins 2002; Eggermont and Ponton 2003). It has been

suggested that these pathways supplement the primary auditory network for complex processing of

sound (Hocherman, Benson et al. 1976; Grady, Van Meter et al. 1997; Busse, Roberts et al. 2005). It

is therefore possible that the larger than normal amplitude of peak P2 observed in long-term CI users

reflects increased activity in the distributed cortical network involved in selective attention/arousal and

multi-sensory integration during auditory processing.

The larger than normal amplitude of peak P2 observed in the present study could reflect

increased recruitment/interaction between auditory and non-auditory multi-sensory processes (i.e.,

vision and/or touch) by children using CIs. Such children have been shown to use multi-sensory

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information more effectively than their peers with normal hearing to facilitate the development of

complex auditory working memory skills (Brenner & Geers, 2011), spoken language comprehension

and complex auditory processing, such as understanding subtle emotional cues in speech (Hopyan-

Misakyan, Gordon et al. 2009; Hopyan, Gordon et al. 2011). Furthermore, functional neuroimaging

studies have also shown that activation of the visual cortex (Giraud, Price et al. 2001) and the posterior

portions of the auditory association areas (Nishimura, Hashikawa et al. 1999) increase during listening

tasks in long-term CI users, particularly when given auditory and visual input simultaneously

(Nishimura, Hashikawa et al. 1999). Despite receiving auditory information, users of CIs still rely on

contributions from non-auditory modalities when listening and processing speech (Nishimura,

Hashikawa et al. 1999; Finney, Fine et al. 2001; Giraud, Price et al. 2001; Doucet, Bergeron et al. 2006).

Together, these data suggest that CI users must recruit attentional resources and integrate multi-

sensory input to a greater than normal degree. This would help to compensate for: 1) the

reorganization of the developing brain when faced with sensory deprivation prior to cochlear

implantation; 2) the imperfect auditory signal provided by a CI to improve auditory perception; 3)

auditory input in only one ear, compromising binaural hearing and causing possible reorganization in

the pathways that were deprived of auditory input for many years.

3.7 Conclusion

It is hoped that early cochlear implantation will lead to normal maturation of the central

auditory system. In the present study, we assessed cortical activity in children and adolescents who

were deaf and received a unilateral CI during childhood after a limited duration of deafness. The CI

users studied had experienced up to sixteen years of time-in-sound. We found that, over the long-

term, their auditory responses matured into waveforms which were very similar to those of normal

hearing adolescents/young adults. This indicates that at least some degree of auditory development

proceeds normally with CI use. However, differences from the mature normal hearing cortical

response persist, even after sixteen years of auditory experience, suggesting slight alterations to normal

cortical processing. We question whether some of these differences reflect an increased dependence

on attentional resources or recruitment of multi-sensory input for complex auditory processing.

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Nonetheless, the present findings provide encouraging evidence for long-term auditory development

in CIs users who were implanted as children after limited bilateral deafness.

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4. Chapter Four – Early unilateral cochlear implantation promotes

mature cortical asymmetries in adolescents who are deaf

This paper was submitted to Human Brain Mapping using required journal formatting:

Jiwani, S., Papsin, B.C., Gordon, K.A. Eearly unilateral cochlear implantation promotes mature

cortical asymmetries in adolescents who are deaf.

4.1 Abstract

Unilateral cochlear implant (CI) stimulation establishes hearing to children who are deaf, but

compromises bilateral auditory development if a second implant is not provided within 1.5 years. In

the present study we are asking: 1) what are the cortical consequences of missing this early sensitive

period in adolescents who have developed a mature auditory cortex with unilateral implant

stimulation?, 2) what are the effects of unilateral deprivation on pathways from the opposite ear?

Cortical responses were recorded from 64-cephalic electrodes within the first week of bilateral

CI activation in adolescents who had over 10 years of unilateral implant experience and in normal

hearing peers. Cortical activation underlying the evoked peaks was localized to areas of the brain using

beamformer imaging.

Findings indicated stronger activity in the contralateral left hemisphere with stimulation from

the right CI. This could be driven by a reduction in inhibitory processes from the deprived side, and

indicate that cortical abnormalities remain in adolescents despite having developed a mature auditory

cortex with unilateral implant stimulation. Providing a second CI to the opposite and deprived ear

thereafter resulted in abnormal cortical responses with abnormally large and widespread dipole activity

across the cortex, indicating abnormal changes in the un-stimulated pathways. Thus, using a unilateral

CI to hear beyond the period of cortical maturation causes lasting asymmetries in the auditory system

and does little to protect the cortical pathways from effects of auditory deprivation, perhaps reflecting

a closing of a sensitive period for restoring auditory development on the deprived side.

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4.2 Introduction

Cochlear implants (CI) are surgically implanted auditory prostheses which restore hearing to

individuals who are deaf. While CIs allow children to develop remarkable oral speech and language

abilities, their hearing is significantly poorer than normal because the CI provides only a crude

representation of acoustic sounds and eliminates important cochlear processing. Prior to cochlear

implantation, the absence of auditory input in early life leaves the auditory brain vulnerable to cross-

modal recruitment (Finney, Fine et al. 2001; Bavelier and Neville 2002; Bavelier, Dye et al. 2006) by

the visual (Lomber, Meredith et al. 2010) and somatosensory systems (Lomber, Meredith et al. 2010;

Meredith and Lomber 2011). If hearing is not restored during sensitive periods in development, this

reorganization will impair hearing with a CI (Lee, Lee et al. 2001). CIs have thus been provided to

children within limited durations of bilateral deafness with the aim to halt and hopefully reverse any

such effects of deafness on the brain.

Traditionally, CIs have been provided to children in only one ear, which put them at risk for

language delays and educational difficulties (Bess and Tharpe 1984; Bess and Tharpe 1986). While it

is clear that unilateral stimulation with an implant promotes auditory maturation in the brainstem

(Gordon, Papsin et al. 2006; Gordon, Jiwani et al. 2013), midbrain (Gordon, Papsin et al. 2005) and

cortex (Jiwani, Papsin et al. 2013), depriving the opposite pathways of auditory input might leave the

auditory system susceptible to deafness-induced reorganization. In turn, this could distort bilateral

auditory development as well as the ability to restore binaural hearing with a second implant at a later

time, perhaps permanently (Gordon, Jiwani et al. 2011; Gordon, Jiwani et al. 2013). We must therefore

determine whether there is an age at which it is too late to re-establish function in the opposite

pathways with a second implant.

Graham and colleagues suggested that the mid-teenage years could mark the end of a critical

period for implanting the non-implanted side in adolescents who are congenitally deaf and have used

a unilateral CI to hear for most of their lives (Graham, Vickers et al. 2009; Graham and Vickers 2011).

Adolescents who received a CI in the deprived ear after 15 years of age had significantly worse speech

perception abilities compared to their younger bilaterally implanted peers (Peters, Litovsky et al. 2007;

Graham, Vickers et al. 2009; Graham and Vickers 2011). Compromised benefit from spatial separation

of noise (Chadha, Papsin et al. 2011), and reduced sound localization (Van Deun, Van Wieringen et al.

2009; Grieco-Calub and Litovsky 2010) and lateralization (Salloum, Valero et al. 2010) abilities have

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also been reported in children who received a second implant after long delays. Moreover, asymmetries

in auditory function increased as the duration of unilateral implant experience increased (Gordon and

Papsin 2009; Illg, Giourgas et al. 2013). This led to inconsistent use of the second implanted ear

(Fitzgerald, Green et al. 2013) and reduced binaural hearing abilities relative to children who received

bilateral implants within limited delays (Gordon and Papsin 2009; Van Deun, Van Wieringen et al.

2009; Grieco-Calub and Litovsky 2010; Salloum, Valero et al. 2010; Gordon, Jiwani et al. 2011). Poor

performance of older children with their second implant may be attributed to increased dependency

on the first and earlier implanted ear for hearing (Kral, Hubka et al. 2013), decreased motivation or

emotional resistance to change in teenagers (Fitzpatrick and Irannejad 2008), or decreased auditory

plasticity with maturation (Lohmann and Kessels 2014).

The latter issue, the remarkable capacity of the developing brain to change, has been studied

in animal models of unilateral deafness. Abnormally strengthened afferent projections from the

cochlear nucleus of the stimulated ear to the ipsilateral (Moore and Kowalchuk 1988; Kil, Hkageyama

et al. 1995; Kitzes, Kageyama et al. 1995; Nordeen, Killackey et al. 2004) and contralateral brainstem

(Kil, Hkageyama et al. 1995; Kitzes, Kageyama et al. 1995) were observed in neonate animals following

unilateral cochlear ablation. Cortical changes have also occurred as a result of unilateral hearing loss;

connections in the neural circuitry of the primary auditory cortex from the hearing ear increased,

whereas those of the opposite and deprived ear were weakened (Popescu and Polley 2010; Kral, Hubka

et al. 2013). These changes were not found when the loss was bilateral (Moore 1990) or induced later

in life (Nordeen, Killackey et al. 1983; Moore and Kowalchuk 1988; Nordeen, Killackey et al. 2004;

Popescu and Polley 2010; Kral, Hubka et al. 2013). Similar asymmetries were found in children using

unilateral CIs when the period of unilateral stimulation/deprivation exceeded 1.5 years. Faster

response latencies in the brainstem (Gordon, Salloum et al. 2012) reflected a strengthening of pathways

from the more experienced ear; and abnormally strong activity driven by the first CI to both auditory

cortices (Gordon, Wong et al. 2013; Kral, Hubka et al. 2013) indicated a strengthening of inputs in the

immature auditory pathways from the unilaterally implanted right ear. This has been explained by a

disruption in the normal organization of inhibitory-excitatory activity when input to both ears are

unbalanced (Mossop, Wilson et al. 2000; Nordeen, Killackey et al. 2004; Popescu and Polley 2010),

resulting in a loss of inhibitory processes (Vale, Juíz et al. 2004; Kotak, Fujisawa et al. 2005; Takesian,

Kotak et al. 2009) that would have normally occurred with bilateral hearing (Grothe, Pecka et al. 2010).

Because the cortical changes observed in the children using unilateral CIs occurred over approximately

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the same time-course of CI-driven brainstem maturation (~1.5 year) (Gordon, Papsin et al. 2006), an

important human developmental period for bilateral input may have been missed (Gordon, Wong et

al. 2013).

Adolescence marks the maturation of the auditory cortex (Eggermont 1988; Ponton,

Eggermont et al. 2000; Moore and Linthicum 2007; Jiwani, Papsin et al. 2013) which could signal the

end of another important developmental period. Much of the brain is maturing during this time.

There is a slowing of white matter increase and a sharp decline in gray matter during adolescence

(Lebel and Beaulieu 2011) that likely reflects synaptic elimination (Giedd, Blumenthal et al. 1999;

Sowell, Thompson et al. 2001; Blakemore 2012), as existing connections in the mature brain are refined

(Blakemore and Choudhury 2006; Lohmann and Kessels 2014) and as each cortical hemisphere

becomes specialized (Davidson 1984; Zatorre and Belin 2001; Le Grand, Mondloch et al. 2003; Toga

and Thompson 2003; Rivera, Reiss et al. 2005; Gotts, Jo et al. 2013). In the auditory brain, the left

cortex becomes tuned to temporal processing, whereas association regions of the right auditory cortex

become biased to spectral variations of sound (Zatorre and Belin 2001; Schönwiesner, Rübsamen et

al. 2005; Jamison, Watkins et al. 2006).

Maturation driven by CI stimulation, particularly when only from one ear, could be very

different from normal. Whilst long-term speech and language outcomes in children with a single CI

show abilities which approach age-appropriate levels (Geers, Tobey et al. 2008; Geers and Sedey 2011;

Geers and Sedey 2011), they still face challenges as they mature including increased effort/attention

needed to hear (Lee, Giraud et al. 2007; Hopyan-Misakyan, Gordon et al. 2009; Pisoni, Conway et al.

2010; Sandmann, Dillier et al. 2012; Gordon, Jiwani et al. 2013; Kronenberger, Colson et al. 2014).

Having provided CIs to children for over two decades, we are now in a position to ask how their

auditory system has matured with the input provided from this unique device. Many such adolescents

have recently been seeking a second implant for their long-term deprived ear in the hopes of deriving

benefits of binaural hearing, decreasing listening effort and improving communication. This provided

a unique opportunity to stimulate the long-term deprived pathways for the first time and study the

plastic effects of long-term unilateral implant stimulation/deprivation in the adolescent brain. Given

the long durations of deprivation in the non-implanted ear and their older ages, we expect unique

cortical effects in this group of new bilateral implant users.

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In the present study, we explored the underlying consequences of driving auditory maturation

in the brainstem and cortex with CI stimulation from only one ear. We asked: 1) how does missing an

early sensitive period for bilateral input (i.e., brainstem) and driving cortical maturation from one ear

compromise the normal development of the auditory cortex in adolescents who have used a unilateral

CI to hear for most of their lives?, and, 2) what are the effects of unilateral deprivation on pathways

from the opposite ear? Results indicate that allowing the auditory cortex to mature with over a decade

of unilateral CI use drives lasting asymmetries in the auditory system and does not protect the opposite

pathways from deafness-induced cortical changes. While the stimulated right ear strengthens activity

to the contralateral left hemisphere over the long-term, the deprived pathways from the left ear recruit

abnormally large cortical regions in the brain. Establishing binaural hearing may thus be challenging

after unilaterally-driven maturation of the auditory cortex.

4.3 Materials and Methods

4.3.1 Participants

Thirty-four adolescents who received one CI in their right ear by 3.2 ± 1.3 years of age after a

limited period of bilateral auditory deprivation (1.8 ± 1.3 years) participated in this study. They had

12.4 ± 1.7 years of unilateral CI experience at the time of the test. All were successful implant users

and did not ever receive auditory stimulation in their opposite ear. Twenty-one of these adolescents

later received a second implant in their opposite-left ear after 12.0 ± 2.1 years of unilateral deprivation

on that side. Age at implantation on this second implanted side was 15.9 ± 2.0 years. Responses were

recorded from the 21 bilateral CI recipients on the first day of activation of the second implant to

study the long-term cortical effects of single-sided deafness on the deprived pathways in the mature

auditory system. This provided us with a unique opportunity to stimulate the long-term deprived ear

for the first time and study the plastic effects of long-term unilateral implant stimulation/deprivation.

Etiology of deafness varied. Eight adolescents were diagnosed with a genetic anomaly; 2 had a 35delG

mutation on the GJB-2 gene; 3 lost their hearing after a meningitis infection; 2 were diagnosed with a

Mondini malformation (1 with hypoplasia of the vestibulocochlear nerve and 1 with KID syndrome)

and 3 had enlarged vestibular aqueducts. The other 16 adolescents had a congenital hearing loss of

unknown etiology. All adolescents were implanted with a Cochlear Nucleus device from Cochlear

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Corporation Limited (4 N22 implants, 20 CI24M implants, 10 CI24R(CS) devices) in the right-

experienced ear. In the newly implanted side, 16 received a CI24RE(CA) implant and 6 were implanted

with a CI513. Of all 34 adolescents tested, 24 were boys and 10 were girls. All but 2 adolescents were

right handed. The control group was composed of sixteen adolescents (6 boys : 10 girls) who had

normal hearing in both ears. Adolescents in this group were 15.9 ± 6.4 years of age at the time of the

test and were matched for chronological age and duration of hearing experience.

4.3.2 Recording cortical responses

Cortical responses were evoked by each ear/implant separately using 64-cephalic electrodes

and referenced to the right earlobe. In the CI group, responses were generated using biphasic electrical

pulse trains of 250 pulses per second, lasting 36ms and delivered by a single electrode (#20) at the apex

of the electrode array. These electrical pulse trains were presented at a rate of 1Hz. Similar current

levels were presented from each CI at comfortably loud levels. These levels were determined as in

previous studies (Gordon, Wong et al. 2013) by recording auditory brainstem responses at increasing

intensities, as shown in the example in Figure 4.1. Electrically-evoked brainstem responses recorded

from the experienced and newly implanted sides separately are shown in response to electrical pulses

presented at 11Hz. Current levels were increased within a comfortable range of intensities for the

participant. The maximum levels at which wave eV amplitudes on each side were equal were used to

evoke cortical responses. Levels were reduced by 10 Clinical Units on each side so that stimulation

would be provided at a slightly reduced part of the dynamic range.

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Cortical responses evoked in CI users were compared with the same responses recorded from

the 16 adolescents with normal hearing. Responses in normal hearing peers were evoked by 500Hz

tone-bursts. This stimulus was chosen because this frequency was allocated to the same apical

electrode (#20) of the CI device used to evoke responses in all CI participants. The same stimulus

duration (36ms) and rate of presentation (1Hz) was used as in the CI users. The tone was enveloped

Figure 4-1: Balanced stimulus levels between the experienced and newly implanted ears determined

by matching peak eV amplitude of the brainstem response.

A. Electrically evoked auditory brainstem responses recorded from one adolescent. Right ear had

13.35 years of CI experience. Left ear had 6 days of stimulation. Current levels on the experienced

side were increased to maximize the amplitude of the brainstem response within a comfortable

listening range. Current levels delivered to the naïve-left CI were increased until the wave eV amplitude

of the responses matched the maximum of the wave eV response from the experienced side. B. Peak-

to-peak amplitude of wave eV for responses recorded on the experienced-right and naïve-left sides for

different stimulus intensity levels. Matched wave eV responses are marked by the dashed line. The

corresponding current levels – 10 Clinical Units were used to stimulate each CI separately and record

the cortical evoked response.

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with a Tukey window over the first and last eights to minimize effects of high frequency onset and

offset. Tone-bursts were delivered at 40dB above behavioural threshold and presented to the right

and left ears separately using ER3-14A insert earphones. Responses for all participants were recorded

using the NeuroScan-4.3 system with a Synamps-II amplifier. They were sampled at a rate of 1000Hz

and an online band-pass filter between 0.15 to 100Hz was applied. A minimum of 400 sweeps with at

least two visually replicable cortical responses were obtained. Epochs which were greater than ±100µV

between the 100 to 800ms latencies were rejected.

4.3.3 Localization of cortical evoked peaks

The Time Restricted, Artefact and Coherence Source suppression (TRACS) linearly

constrained minimum variance beamformer (Wong and Gordon 2009) was used to localize activity

underlying the evoked peaks in the cortex in response to stimulation from the experienced and naïve

CIs, and right and left ears in normal hearing peers. Suppression of the electrical artefact from the CI

device (Wong and Gordon 2009) and region suppression to eliminate coherent source interference

were applied (Dalal, Sekihara et al. 2006). See Supporting Information for additional details.

Covariance was estimated over latency windows encompassing each peak of the cortical response for

each individual (Van Veen, Van Drongelen et al. 1997). A pseudo-Z statistic was used to normalize

the signal-to-noise ratio of each 3 x 3 x 3 mm voxel. Once sources were localized using this lead

normalization process, the strength of source activity, measured in dipole moments (nAm), was

computed for the peaks of the cortical waveform. A one-tailed omnibus-noise T-test (Petersson,

Nichols et al. 1999) was used to calculate a statistical threshold pseudo-Z value (p≤0.0005) reflecting

baseline brain activity. Only voxels with pseudo-Z activity greater than this omnibus value were

accepted and used in the analyses.

Dipole activity was visualized topographically on age-appropriate head model templates

derived from the Montreal Neurological Institute (MNI) magnetic resonance imaging (MRI) library

for each adolescent in 63,646 voxels in brain space. Dipole strength was visualized as colours from

dark blue, reflecting weaker dipole activity, to dark red, indicating stronger dipoles. Mean beamformer

brain images were created to assess areas of cortical activity which were consistently evoked by sound

for each ear/implant. Two-sided uncorrected paired permutation tests were used to compare voxel-

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by-voxel dipole activity in 2048 permutations (Blair and Karniski 1993; Chau, McIntosh et al. 2004) to

assess differences between the left and right hemispheres. Significant absolute differences (p<0.005)

were plotted on topographic brain maps for each cortical wavepeak. Un-paired permutation analyses

to assess differences in activity for each voxel-pair between ears and between each group was calculated

to measure aural preference and group differences for each cortical wavepeak. Significant absolute

differences at p<0.01 were considered significant for these analyses. The voxels reflecting the

strongest dipoles in the left and right auditory cortices were then extracted for each cortical wavepeak

in each individual. The location of the auditory cortex were identified within MNI coordinates (X =

<-55, Y = >-35 to <-5, Z = >-10 to <20) mm in the left hemisphere and (X = >55, Y = >-35 to <-

5, Z = >-10 to <20) mm in the right hemisphere in both the normal hearing and the CI group,

consistent with other reports (Wong and Gordon 2009; Gordon, Wong et al. 2010; Gordon, Wong et

al. 2013). Dipole locations are shown on glass brain images. Repeated measures ANOVA with

Bonferroni corrections were used to identify differences in peak dipole moment and latencies between

activity evoked in each auditory cortex and in each group. Percent cortical lateralization and aural

preference were calculated from the extracted peak dipoles using the following formulas:

% Cortical Lateralization =

(right hemisphere dipole – left hemisphere dipole) /

(right hemisphere dipole + left hemisphere dipole) x 100.

% Aural Preference =

(dipole from contralateral stimulus – dipole from ipsilateral stimulus) /

(dipole from contralateral stimulus + dipole from ipsilateral stimulus) x 100.

4.3.4 Speech perception tests to assess outcomes with CIs

Functional outcomes with CIs were assessed using the age-appropriate Phonemic Balanced

Kindergarten (PBK) monosyllabic words open-set speech perception test. This test assesses speech

recognition abilities using a list of twenty-five words. Words were presented at 0-degree azimuth in a

double-walled sound-proof booth, through a GSI-61 Grason-Stadler audiometer, using monitored-

live voice at 65dB sound pressure level. Words were presented in quiet to the first and second implants

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separately after 8.0 ± 2.1 months (5.8 to 15.0 months) of bilateral CI use and scored as a percentage

of words that were repeated correctly (percent accuracy). Pearson correlations were used to assess

associations between speech perception scores, dipole moment and cortical lateralization.

4.4 Results

4.4.1 Tone-bursts preferentially stimulate the right auditory cortex in

adolescents with normal hearing

Cortical responses recorded at a midline-cephalic location (Cz) and mean global field power

with corresponding head topographies of potential distribution are shown in Figures 4.2A and 4.2B

for the normal hearing group. Adolescents with normal hearing produced cortical responses with

peaks P1, N1 and P2, characteristic of the mature response (Albrecht, Suchodoletz et al. 2000; Ponton,

Eggermont et al. 2000; Wunderlich, Cone-Wesson et al. 2006), when either the right (n=13) or left

ears (n=12) were stimulated by 500Hz tone-bursts. Mean latencies and amplitudes for all responses

appear in Table 4.1 in the Supplementary Information section. Responses were similarly distributed

over the scalp between the right and left ears. However, dipole moments underlying the mature

cortical peaks were stronger in the right hemisphere. This is shown by the dark red hotspots in the

right hemisphere mean topographic plots of Figure 4.2C and by the larger right (red bars) than left

cortex (blue bars) peak dipole magnitude in Figure 4.2E. Dipoles in auditory cortex showed effects

of side of stimulation (F(1,10)=5.976, p=0.035), hemisphere (F(1,10)=8.018, p=0.015) and an interaction

of these factors (F(1,10)=10.308, p=0.009) but no differences between the different cortical peaks

(F(2,20)=8.018, p>0.05). Post-Hoc t-tests with Bonferonni corrections revealed similar left hemisphere

activation when the right and left ears were stimulated separately (t(76)=-0.03, p>0.05), but confirm that

dipoles were significantly stronger in the right hemisphere for left ear stimulation (t(66.9)=-2.43, p=0.02).

Aural preference in each hemisphere, shown in Figure 4.3, was consistent with these results. Aural

preference in the left cortex was not evident in the mature auditory system (i.e., left auditory cortex

responded to both ears similarly), but a contralateral dominance remained present in the right auditory

cortex for the left ear (P1: t(10)=-4.5, p=0.001). This means that as mature cortical responses emerge,

the right hemisphere preferentially responds to tone-bursts, particularly when they are presented to

the left ear.

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Figure 4-2: Cortical dipole activity evoked by auditory stimulation of the right and left ears of normal

hearing adolescents.

A. Auditory evoked cortical responses were stimulated from the right (n=13) and left (n=12) ears of

adolescents with normal hearing, aged 15.9 ± 6.4 years. Individual responses from a midline cephalic

electrode (Cz) (thin grey lines), and grand mean responses (thick black lines) show 3 peaks (P1, N1, P2),

characteristic of mature responses. B. Mean global field power is plotted for mean response data

from each ear. Topographic maps indicate similarly distributed scalp potentials (red = positive

potentials, blue = negative potentials) for the mature peaks in both ears. C. Mean peak dipole activity

evoked by each ear for each cortical wavepeak (P1, N1, P2) is plotted in each of 63,646 voxels in brain

space on age-appropriate topographic head models derived from the Montreal Neurological Institute

(MNI) MRI Library (MNI Axial orientation). Stronger activity, shown by hotspots of dark red, occurs

in the right hemisphere, particularly for left ear stimulation. D. Peaks dipoles underlying each cortical

wavepeak in the left (blue) and right (red) auditory cortices were chosen within the hotspots shown in

C. for each child. Peak dipole locations are shown on glass brain images. Axis are MNI coordinates

in millimeters. E. Mean (± 1 standard error (SE)) dipole moment strength is plotted for the left (blue

bars) and right (red bars) auditory cortices for all cortical peaks. Consistent with the topographic plots

in C., peak dipole activity is stronger in the right than left auditory cortex for stimulation of both ears,

particularly for left ear stimulation. F. Mean (± 1 SE) peak dipole latency are similar between the left

(blue) and right (red) auditory cortices and are in line with cortical wavepeak latencies shown in A. and

B.

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Figure 4-3: Aural preference evoked by auditory stimulation of the right and left ears of normal

hearing adolescents.

A. Aural preference in each cortical hemisphere was assessed across 63,646 peak dipoles using

permutation testing in adolescents with normal hearing by comparing cortical activation with right

versus left ear stimulation. Significant absolute dipole moment differences (p<0.01) for right – left ear

stimulation are plotted for each cortical wavepeak on topographic brain plots. Voxels with dark red

colours indicate greater intra-hemispheric dipole differences between stimulation of each ear, and

those with dark blue colours reflect smaller dipole differences. P1 and N1 show large aural difference

for tone-burst stimuli, particularly in the right cortical hemisphere and frontal areas. B. Mean (± 1

SE) percent aural preference, [(dipole moment evoked from contralateral stimulus – dipole moment

evoked from ipsilateral stimulus) / (dipole moment evoked from contralateral stimulus + dipole

moment evoked from ipsilateral stimulus) x 100], from peak dipoles (from Figure 4.2D) are shown

for the mature cortical wavepeaks. Stimulation of the right and left ear evokes different activation in

the cortex. A contralateral aural preference in the right auditory cortex (red bars) was present for all

peaks (P1, N1, P2). Aural preference in the left auditory cortex (blue bars) was only present for P1.

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4.4.2 Long periods of unilateral CI use drive abnormal patterns of auditory

activity

Auditory stimulation with a CI for over 10 years appears to promote normal-like maturation

of cortical responses. As shown in Figure 4.4A, the cortical waveform developed into a polyphasic

response with similar latencies to the normal hearing group (P1: t(10)=−0.88, p>0.05; N1: t(10.18)=−1.3,

p>0.05; P2: t(10.77)=1.43, p>0.05) and similar peak-to-peak amplitudes for the P1-N1 complex

(t(6.87)=1.75, p>0.05) and dipole moment magnitudes (Figures 4.4C and 4.4E), and latencies of

extracted peak dipoles in Figure 4.4F were also in line with those of the normal hearing group.

Nonetheless, differences from normal remained. The amplitude of peak P2 was significantly larger in

CI users (t(14.51)=2.49, p<0.05) and current distribution across the scalp, shown in Figure 4.4B, was

unusually similar for all three peaks of the mature response regardless of whether the wavepeak

recorded at Cz was of a positive or negative polarity. Furthermore, even though cortical activity evoked

by the experienced CI was generated predominantly in areas of the temporal cortex, auditory input in

these adolescents activated the left and right auditory cortices differently than their normal hearing

peers. Dipole activity underlying the mature cortical response was stronger in the left than right

auditory cortex as shown by the red hotspots in the topographic brain images of Figure 4.4C and

larger blue than red bars in Figure 4.4E reflecting magnitude of extracted peak dipoles from Figure

4.4D (F(2,24)=10.978, p<0.001; post hoc: P1: t(26)=2.4, p<0.05, P2: t(26)=3.9, p<0.01). This reflects

cortical activation in an opposite direction to the rightward hemispheric bias that was observed in

normal hearing peers in Figure 4.2 and indicates a contralateral dominance of the auditory pathways

in the left auditory cortex with long-term unilateral stimulation of the right-experienced implant. This

confirms that unlike their normal hearing peers, unilateral CI users did not develop right hemisphere

specialization to tone-bursts despite developing cortical responses with expected mature wavepeaks.

Activity evoked by stimulation of the naïve pathways on the first day of activation of that left

side was significantly different from the experienced side. As shown in Figures 4.4G and 4.4H, the

morphology of these cortical waveforms was atypical and different from the response evoked by the

experienced ear. These were characterized by a large negative amplitude peak, labelled N(ci), followed

by a large positive peak (P(ci)). This abnormal response was consistently evoked by the deprived

pathways in all CI users with long-term unilateral deafness. While the latency of these peaks, shown

in Figure 4.4L, were similar to that of N1 and P2 of the experienced side (Figure 4.4F) (N(ci)/N1:

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t(11)=1.85, p>0.05; P(ci)/P2: t(11)=2.71, p>0.05), the absolute amplitudes (N(ci)/N1: t(11)=3.45, p<0.01;

P(ci)/P2: t(11)=3.31, p<0.01), peak-to-peak amplitudes (N(ci)-P(ci)/N1-P2: t(11)=-3.37, p<0.01), and global

field power (±5µV) were significantly larger than responses from the experienced and normal hearing

ears (F(3,70)=5.4, p<0.05). Underlying dipole activity shown by topographic plots in Figure 4.4I and

peak dipole strength in Figure 4.4K extracted from Figure 4.4J indicated further differences. Dipole

activity was more widespread and symmetric across both auditory cortices (N(ci): t(20)=-0.56, p>0.05;

P(ci): t(20)=-1.6, p>0.05), and dipole moments for both peaks were abnormally large in both hemisphere

(F(3,36)=5.481, p=0.03) compared to the experienced side and both the right and left normal hearing

ears.

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Figure 4-4: Cortical dipole activity evoked by auditory stimulation of the experienced-right and naïve-

left ears of CI users.

Auditory evoked cortical responses were stimulated from the experienced-right (n=32) and naïve-left

(n=21) ears of adolescents with CIs, aged 15.9 ± 2.0 years. Cortical activity evoked by stimulation of

the right ear after 12.4 ± 1.7 years of unilateral CI experience is shown in A. – F. Left ear had 12.0 ±

2.1 years of unilateral deprivation. Responses recorded within the first week of CI activation on that

side are shown in G. – L. Individual responses from a midline cephalic electrode (Cz) (thin grey lines),

and grand mean responses (thick black lines) show 3 peaks (P1, N1, P2), characteristic of mature

responses, evoked by stimulation of the experienced-right CI in A., but an abnormal biphasic peaked

response (N(ci), P(ci)) of abnormally large amplitudes was evoked by the naïve-left side (n=21), shown

in G. Mean global field power is plotted for mean response data from each CI (B. indicates responses

from the experienced side and H. shows activity evoked by the naïve side). Topographic maps

indicate unusually similarly distributed scalp potentials (red = positive potentials, blue = negative

potentials) for the 3 peaks of the mature response on the experience side. These are different between

both peaks on the naïve-left side. Global field power is abnormally large on this side (±5µV) compared

to the experienced side (±2µV) and either ear of normal hearing peers (±1µV). C. Mean peak dipole

activity evoked by the experienced CI for each cortical wavepeak is plotted in each of 63,646 voxels in

brain space on age-appropriate topographic head models derived from the MNI MRI Library (MNI

Axial orientation). A strong contralateral bias in the left hemisphere, shown by hotspots of dark red,

occurs with stimulation of the experienced-right CI. By contrast, dipole activity evoked by stimulation

of the naïve-left ear in I. is symmetrically distributed in both hemispheres and is stronger compared

to right ear dipoles for both peaks of the response. D. & J. Peak dipoles underlying each cortical

wavepeak in the left (blue) and right (red) auditory cortices were chosen within the hotspots shown in

C. and I. for each child. Peak dipole locations are shown on glass brain images. Axis are MNI

coordinates in millimeters. E. Mean (± 1 SE) dipole moment strength is plotted for the left (blue

bars) and right (red bars) auditory cortices for all cortical peaks. Consistent with the topographic plots

in C., peak dipole activity is significantly stronger in the left than right auditory cortex for the mature

peaks P1 (p<0.05) and P2 (p<0.01) on the experienced side. K. The same responses are plotted for

the naïve side and shows dipole activity consistent with the data in I. F. & L. Mean (± 1 SE) peak

dipole latency are similar between the left (blue) and right (red) auditory cortices and are in line with

cortical wavepeak latencies shown in A. and B. for the experienced side and in G. and H. for the

naïve side.

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Permutation analyses were used to identify significant differences in activity between left and

right auditory cortices in the normal hearing and CI groups. Figures 4.5A-D revealed significant

differences in activation between left and right temporo-frontal and temporo-parietal regions in both

groups with unique patterns in the CI users relative to their normal hearing peers. In the normal

auditory system, the emergence of mature cortical responses was expected to underlie the development

of hemispheric specialization (Zatorre and Belin 2001; Jamison, Watkins et al. 2006). We hypothesized

that this would be observed as a shift in lateralization toward the right auditory cortex in response to

tonal stimulation. As shown in Figure 4.5A, minimal differences in activity between the cortical

hemispheres were evident when tones bursts were presented to normal right ears using this analysis.

Significant differences were clearer in the auditory cortices as well as temporo-frontal and temporo-

parietal regions for normal left ear stimulation as shown in Figure 4.5B. These differences were larger

in the right than left cortical hemisphere. In the CI group, the left temporo-parietal junction was more

strongly activated than the right for all peaks, and the right temporo-frontal region was more strongly

activated than the left in the latency range of P2. As shown in Figure 4.5D, stimulation from the

newly implanted ear resulted in a greater activation of right than left parietal-temporal-occipital

association areas and left than right temporo-frontal cortex. Peak dipoles from the left and right

auditory cortex were compared. Normalized lateralization values shown in Figure 4.5E indicated that

while tonal stimuli lateralized to the right auditory cortex regardless of ear of stimulation in adolescents

with normal hearing, the opposite is true of adolescents with long term right CI use.

Despite developing mature-like cortical responses with over a decade of CI experience,

significantly strong left hemisphere lateralization was found for all peaks recorded in CI users (P1:

t(10)=-2.460, p=0.034, N1: t(14) =-2.260, p=0.04, P2: t(15) =-6.912, p<0.001). This pattern was significantly

different from the responses of either ear in normal hearing peers (F(4,92)=3.286, p=0.015, post-hoc:

right stimulation: P1: p=0.03, P2: p=0.003; left stimulation: P1: p=0.002, N1: p=0.001, P2: p<0.001).

Dipole activity evoked by stimulation in the newly implanted ear in both hemispheres was more

symmetrical as shown by a reduction in lateralization for peak N(ci) and P(ci) (N(ci): t(15) =-0.726, p=0.479

P(ci)=2.238: t(12), p=0.816). This was significantly different from the right lateralized responses

stimulated by tones in normal left ears (F(1,7)=6.674, p=0.036, post-hoc: N1: p=0.03, P2: p=0.006),

indicating that the cortex responds to input delivered by the naïve pathways very differently.

Symmetrical activation of both hemispheres indicated diffuse activation of the cortex and increased

cortical activity in response to sound when those pathways were stimulated for the first time.

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4.4.3 Additional cortical areas are recruited by cochlear implant stimulation

relative to normal

We hypothesized that long-term unilateral CI use would drive abnormal underlying cortical

activity in the stimulated pathways compared to normal and leave the opposite deprived pathways

vulnerable to significant change. To assess this, we compared responses between CI and normal

hearing groups using permutation analyses. As shown in Figure 4.6A, significantly larger dipoles were

identified in the frontal cortex underlying peak P1 and in the right precuneus region for peak P2 for the

Figure 4-5: Cortical lateralization evoked by stimulation of the right/experienced and left/naïve

ear/implant in normal hearing adolescents and CI users.

Cortical lateralization for each peak of the cortical waveform was assessed across 63,646 peak dipoles

using permutation testing to compare activation of the left and right hemispheres. Significant absolute

differences in dipole moments for right – left hemisphere (p<0.005) are plotted on topographic plots

for stimulation of the right ear in A. and the left ear in B. for adolescents with normal hearing; and

the right-experienced CI in C. and naïve-left side in D. in the implant cohort. Auditory activity

lateralized towards the right hemisphere in normal hearing individuals, particularly in response to left

ear stimulation, as shown by the dark red hotspots indicating greater inter-hemispheric dipole

differences. A significant shift in lateralization towards the contralateral left auditory cortex was

observed in CI users with stimulation of the experienced-right side. Cortical asymmetries towards the

auditory cortices in either hemisphere were not clear when stimulated from the naïve side.

Lateralization of secondary sources in the left temporo-parietal junction and right temporo-frontal

cortex was present for the experienced-right side, with stronger activity underlying P2. This activity

was reversed on the naïve-left side and occurred with increased dipole strength in the right parietal-

temporal-occipital association areas and left temporo-frontal cortex. E. Mean (± 1 SE) percent

cortical lateralization of peak dipoles is consistent with these results. Cortical lateralization from peak

dipoles was calculated using the formula: [(right hemisphere peak dipole moment – left hemisphere

peak dipole moment) / (right hemisphere peak dipole moment + left hemisphere peak dipole moment)

x 100]. Red bars indicate dipoles evoked from stimulation of the right ear/experienced CI and blue

bars indicate activity from the left ear/naïve CI.

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experienced CI side compared to responses from the right ear in the normal hearing group, indicating

that CI users recruit additional cortical areas to process sound. At the same time, depriving auditory

input on the opposite side for over a decade led to significantly different activation in those pathways

relative to responses from the normal hearing left ear. Dipole activity in the naïve-left ear shown in

Figure 4.6B was significantly larger across most of the cortex, particularly for peak N(ci), compared to

normal left ear evoked activity. This might indicate aberrant cortical organization as a result of long-

term deafness, in line with our hypothesis.

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4.4.4 Abnormal activity evoked by the naïve side predicts poor speech

perception outcomes

We asked whether there was a relationship between cortical activity in CI users and their speech

perception once they had used their bilateral CIs for at least 6 months. As shown in Figure 4.7A,

speech perception performance with the experienced CI was high, with a mean ± 1 standard-error

score of 77.54 ± 2.88%. By contrast, this was significantly worse (14 ± 4.92%) when adolescents

listened with their newly implanted ear alone (t(17)=5.70, p<0.01). All but two adolescents achieved

less than 50% accuracy. An analysis of speech perception and dipole activity between both ears, shown

in Figure 4.7B, indicated a significant correlation between speech perception outcomes and left

hemisphere lateralization for peak P2 (R=-0.55, p=0.02). We hypothesized that this relationship

reflects a supportive role of increased activity in the contralateral pathways towards the left cortex for

speech perception, rather than reduced activity in the right auditory cortex. In support, a significant

positive correlation between dipole strength and speech perception scores was found in the left

auditory cortex (P1: R=0.48, p=0.05, N1: R=0.51, p=0.03, P2: R=0.53, p=0.02) but not the right (P1:

R=-0.14, p=0.62, N1: R=0.43, p=0.06, P2: R=0.03, p=0.92) for the experienced-right CI. No

significant correlations with speech outcomes were found for cortical activity evoked by the naïve CI.

Figure 4-6: Group differences in cortical dipole activity between normal hearing adolescents and CI

users.

Permutation analyses were used to compare dipole activation between the group of CI users and the

group of normal hearing peers. Significant absolute dipole differences between the two groups

(p<0.01) are shown on topographic brain plots for experienced-right CI – normal hearing right ear

stimulation in A., and naïve-left CI – normal hearing left ear stimulation in B. Dipole magnitudes

underlying the mature cortical peaks were generally similar between adolescents with normal hearing

and experienced CI users, but CI stimulation of the experienced side activated cortical regions in the

left frontal cortex for peak P1 and the precuneous regions for P2 which were not present in normal

hearing peers, as shown by the dark red hotspots in A. By contrast, the naïve ear evoked abnormally

large and diffuse cortical activity across the brain, with significantly stronger dipole activity compared

to the left ear of the normal hearing cohort.

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4.5 Discussion

Data from the present study suggest that hemispheric specialization emerges with normal

maturation of the auditory cortex. In response to tone-bursts, adolescents with normal hearing showed

Figure 4-7: Speech perception performance on the experienced-right and naïve-left sides in CI users.

A. Speech perception outcomes measured from the experienced side (n=28) (red) and naïve ear

(n=18) (blue) of CI users was assessed using the Phonemic Balanced Kindergarten (PBK) speech test

after 6 to 18 months of bilateral CI experience. Individual responses are indicated by the round

symbols for the experienced-right ear and diamonds for the naïve-left ear, with mean performance

shown by the bar graph. Performance on the experienced side was significantly better than the naïve

side (p<0.01). B. Analyses of cortical lateralization and performance on the PBK speech test indicated

significant correlation between left hemisphere lateralization for peak P2 (p<0.05) and better speech

scores on the experienced CI side. No significant correlations were found for dipole activity evoked

by stimulation of the naïve side and speech perception.

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mature cortical responses, which lateralized to the right auditory hemisphere. Despite developing

normal-like cortical peaks, adolescents who had over a decade of unilateral CI experience developed

cortical responses which, in contrast to the normal hearing group, lateralized to the contralateral left

auditory cortex with stimulation of the right-experienced ear and bilateral cortical activity in response

to stimulation from the naïve-left ear. Increased response in the left auditory cortex reflects

strengthening from unilaterally stimulated pathways and may support speech perception in CI users.

Very poor performance in the newly implanted ear could reflect undefined and perhaps compromised

auditory processing. In support, additional cortical areas were stimulated in adolescents using CIs

relative to their normal hearing peers, particularly when evoked by the newly implanted ear, suggesting

alternate processing of auditory input. These findings indicate that long-term stimulation of the

auditory system with a unilateral CI promotes an asymmetric mature auditory cortex while, at the same

time, leaving pathways from the opposite ear unprotected from abnormal effects of deafness. Because

sensitive periods in development typically end once a period of maturation is reached (Lenroot and

Giedd 2006; Blakemore 2012; Lohmann and Kessels 2014), further changes from the newly implanted

side may be challenging to promote in these adolescents.

4.5.1 Hemispheric specialization requires normal bilateral hearing

Normal cortical activity was measured in adolescents with normal hearing in response to a non-

speech 500Hz tone to mimic the stimuli that CI users received through an apical electrode of their

device. Data in Figure 4.2 indicated a normally mature response to this tone-burst with more activity

in the right than left auditory cortex. Lateralization to the right hemisphere occurred for both

presentation to left and right ears as shown in Figure 4.5. This appears to have emerged in

development, as immature cortical responses to the same stimuli in younger children with normal

hearing showed contralateral lateralization of similar degrees for both left and right ear stimulation

(Gordon, Wong et al. 2013). Lateralization of immature responses to the contralateral cortex in the

normal hearing group was consistent with the anatomy of afferent auditory projections. The majority

of auditory fibers crosses to the contralateral side at the level of the brainstem and ascend to the

ipsilateral auditory cortex (Glendenning, Brusno‐Bechtold et al. 1981; Nordeen, Killackey et al. 1983;

Ponton, Vasama et al. 2001). Although it is possible for stimulation from one ear to reach the ipsilateral

cortex, the contralateral pathway will have the more direct route (Ponton, Vasama et al. 2001). Perhaps

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it is for this reason that animals show an aural preference for the contralateral ear in each auditory

cortex (Kral 2013; Kral, Heid et al. 2013; Kral, Hubka et al. 2013).

The adult human auditory brain is more specialized; activity in the left auditory cortex is tuned

to temporal processing, whereas regions of the right auditory cortex respond to spectral processing

(Zatorre and Belin 2001; Zatorre, Belin et al. 2002; Schönwiesner, Rübsamen et al. 2005; Jamison,

Watkins et al. 2006). Much of this processing in the right hemisphere occurs in secondary association

areas (Schönwiesner, Rübsamen et al. 2005). Neurons in belt and parabelt regions of the superior

temporal gyrus, which are later to develop (Moore and Guan 2001; Moore and Linthicum 2007), are

involved in spectral analyses of complex sounds at early stages of processing (Rauschecker and Tian

2004; Schönwiesner, Rübsamen et al. 2005) and are more sensitive to spectral stimuli (Zatorre, Belin

et al. 2002; Schönwiesner, Rübsamen et al. 2005; Jamison, Watkins et al. 2006). Interactions with

frontal cortical regions have also been reported for processing patterns of tones, particularly when

demands on working memory are elicited by the task (Zatorre, Belin et al. 2002). Activation of

secondary sources in the right frontal and parietal regions underlying peaks N1 and P2, shown in Figure

4.5, indicate consistent findings in our cohort of adolescents with normal hearing. These cortical peaks

reflect responsiveness in association auditory regions (Ponton, Eggermont et al. 2000; Ponton,

Eggermont et al. 2002; Wunderlich and Cone-Wesson 2006; Wunderlich, Cone-Wesson et al. 2006)

which are involved in 1) complex auditory discrimination such as perceiving speech in the presence of

noise and understanding degraded speech (Eggermont and Ponton 2003), 2) increased

attention/arousal during listening (Picton and Hillyard 1974; Rif, Hari et al. 1991; Tremblay, Kraus et

al. 2001; Tremblay and Kraus 2002; Alain, Snyder et al. 2007; Tremblay 2007; Tremblay, Shahin et al.

2009), and 3) multi-sensory integration between auditory inputs with vision and touch (Grady, Van

Meter et al. 1997; Webster and Colrain 2000; Moller and Rollins 2002; Crowley and Colrain 2004;

Busse, Roberts et al. 2005; Rinne 2010). Thus, dipole activation underlying the wavepeaks across

secondary cortical regions in adolescents with normal hearing marks the establishment of appropriate

specialization once the auditory brain matures.

The brain undergoes significant structural and functional changes, which are more rapid in

earlier development and mostly complete by late adolescence (Giedd, Snell et al. 1996; Giedd,

Blumenthal et al. 1999; Blakemore and Choudhury 2006; Lenroot and Giedd 2006; Lebel and Beaulieu

2011; Blakemore 2012; Lohmann and Kessels 2014). Asymmetric function in the auditory cortices for

temporal and spectral processing of sound has been attributed to the development of structural

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differences in each hemisphere. There are wider and more spaced cell columns coupled with heavier

axon myelination and increased inter-connectivity in left auditory regions compared to the right,

corresponding to rapid transmission and more precise temporal resolution in the left hemisphere

(Penhune, Zatorre et al. 1996; Zatorre and Belin 2001; Zatorre, Belin et al. 2002; Toga and Thompson

2003). Such inter-hemispheric structural specialization in the auditory system is mediated by auditory

experience (Penhune, Zatorre et al. 1996) and normal maturational changes occuring during

adolescence (Moore and Linthicum 2007; Kadis, Pang et al. 2011), in line with the maturational time-

course of the auditory evoked cortical response (Ponton, Eggermont et al. 2000; Ponton, Eggermont

et al. 2002; Eggermont and Ponton 2003; Moore and Linthicum 2007; Jiwani, Papsin et al. 2013).

Some of the same processes likely occurred in adolescents using unilateral CIs, given that

cortical peaks characteristic of mature responses were recorded in this group. The emergence of these

mature-like peaks is consistent with previous reports (Jiwani, Papsin et al. 2013) and suggests that the

neural generators, thalamo-cortical and cortical-cortical connections linked to the development of

superficial cortical layers (Ponton and Eggermont 2001), are maturing in adolescents who have used a

unilateral CI for most of their lives. The development of mature responses coupled with good speech

perception outcomes when using the implant in that ear (Figure 4.7) provides a general impression

that at least some degree of auditory development proceeds normally with long-term CI stimulation.

On the other hand, dipole activity in Figure 4.4 and lateralization measures in Figure 4.5 indicate

significantly stronger dipoles in the contralateral left auditory brain in response to stimulation of the

experienced-right implant. Thus, adolescents with right CIs did not develop the normal right brain

hemispheric bias associated with non-speech stimuli, despite having developed mature normal-like

cortical waveforms.

4.5.2 Long periods of unilateral CI use strengthens pathways from the

stimulated ear

There are several reasons why adolescents using CIs may not have developed specialized

auditory cortices similar to their normal hearing peers. They had been bilaterally deaf from early in life

(typically from birth) and listened, often unilaterally, to a representation of sound missing much of its

fine temporal information. The lack of temporal fine structure makes pitch discrimination difficult

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(Drennan and Rubinstein 2008; Zeng, Rebscher et al. 2008). The asymmetric dipole activity shown in

Figures 4.5 and 4.7 could thus be explained by 1) persistent immaturity in the ascending pathways, 2)

disrupted excitatory-inhibitory balance arising from long periods of deprivation in the opposite ear

and/or 3) increased sensitivity of the left hemisphere for CI input, perhaps to support speech

processing (Zatorre and Belin 2001; Zatorre, Belin et al. 2002; Schönwiesner, Rübsamen et al. 2005;

Kadis, Pang et al. 2011; Chilosi, Comparini et al. 2014). This could occur to compensate for the

distorted access to acoustic input through the CI and/or the lack of binaural hearing.

It is possible that specialization has not yet emerged in these pathways, with contralateral

afferent projections still dominating auditory input as in earlier development (Gordon, Jiwani et al.

2013; Gordon, Wong et al. 2013). Effects of unilateral auditory deprivation/stimulation appear to

occur early and persist into maturation. In younger children with CIs, abnormal strengthening of

activity in the contralateral pathways from the experienced-right ear to the brainstem (Gordon, Salloum

et al. 2012) and cortex (Gordon, Wong et al. 2013) was found when unilateral implant use exceeded

1.5 years. The data in Figures 4.4 and 4.5 are consistent with these findings, indicating that increased

activity in the left auditory cortex from the right implanted ear continues into maturation with longer

periods of unilateral CI use. There was also strengthening of pathways to the ipsilateral cortex from

the unilaterally right stimulated ear in the immature cortex, as measured by a reversal of stimulus

preference from the contralateral ear to the ipsilateral first implanted ear (Gordon, Wong et al. 2013).

This could not be assessed in the present study because of the highly abnormal responses with very

large underlying dipoles evoked in the newly implanted side.

Asymmetric strengthening of the contralateral pathways from the stimulated ear might also be

explained by increased excitability of auditory neurons from this side. The normal organization of

inhibitory and excitatory activity breaks down when input to both ears are unbalanced. A significant

unilateral hearing loss during early stages of development not only leads to a loss of neurons in the

cochlear nucleus of the affected side (Hashisaki and Rubel 1989; Nordeen, Killackey et al. 2004), but

also results in reduced synaptic inhibition and enhanced excitatory glutamatergic conductance in the

superior olive (Kotak and Sanes 1996), the inferior colliculus (Kitzes 1984; Moore and Kitzes 2004;

Nordeen, Killackey et al. 2004; Vale, Juíz et al. 2004; Takesian, Kotak et al. 2009; Popescu and Polley

2010) and the primary auditory cortex of the stimulated pathways (Kotak, Fujisawa et al. 2005; Moore,

Devlin et al. 2005; Popescu and Polley 2010; Kral, Heid et al. 2013; Kral, Hubka et al. 2013).

Importantly, effects are found only when the loss is present in early life (Nordeen, Killackey et al. 1983;

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Reale, Brugge et al. 1987; Moore and Kowalchuk 1988; Nordeen, Killackey et al. 2004) and when it is

unilateral (Moore 1990). Such deafness-induced disruptions to the delicate balance of excitatory-

inhibitory inputs influence and shape the development of binaural hearing in the brainstem (Grothe,

Pecka et al. 2010) and neuronal circuits in the auditory cortex (Turrigiano and Nelson 2004; King

2010). The coupling of excitatory-inhibitory synaptic inputs in the auditory system is influenced by

experience during development (King 2010). Maturation of inhibitory tuning occurs more slowly than

that of excitation (Dorrn, Yuan et al. 2010) and inhibitory synapses are more vulnerable to deafness-

induced perturbation (Sanes and Kotak 2011). Thus, the abnormal strengthening of pathways from

the unilaterally stimulated CI ear could reflect a disrupted balance of excitatory-inhibitory transmission

during early development.

An additional explanation for the abnormally increased dipoles in the left auditory cortex of

CI users is the possibility that this reflects compensation for inadequate input from the unilateral CI.

The left auditory cortex normally codes temporal information including speech. Although no speech

sounds were provided to evoke the cortical responses in this study, speech perception scores on the

PBK test in the experienced ear increased with stronger dipoles in the left auditory cortex, as shown

in Figure 4.7B. This is consistent with a previous report showing better grammar and expressive

language scores in children with right CIs who lateralized auditory input in the contralateral left

hemisphere (Chilosi, Comparini et al. 2014). In support, strong left cortical activity in individuals with

normal hearing has been associated with better language skills (Kadis, Pang et al. 2011), more precise

auditory processing (Zatorre and Belin 2001; Zatorre, Belin et al. 2002; Schönwiesner, Rübsamen et

al. 2005) and increased reading and spelling skills (Abrams, Nicol et al. 2006). Enhanced activity in the

left cortex of adolescents using CIs could thus mark plastic changes in the brain to compensate for the

abnormal electrical input provided by the implant device and/or stimulation of the auditory pathways

from only one side. Indeed, it is clear that individuals compensate for CI listening by using increased

multi-sensory information (Giraud, Price et al. 2001; Doucet, Bergeron et al. 2006; Giraud and Lee

2007; Lee, Giraud et al. 2007; Sandmann, Dillier et al. 2012) and increased effort/attention (Hopyan-

Misakyan, Gordon et al. 2009; Pisoni, Conway et al. 2010; Gordon, Jiwani et al. 2013; Kronenberger,

Colson et al. 2014). Increased cortical processing to support CI listening in good users has been shown

by increased activation of the left dorsolateral pre-frontal, frontal and parietal networks, including the

precuneus regions, which are involved with higher cognitive functions (Giraud, Price et al. 2001;

Giraud and Lee 2007), and larger amplitudes of the P2 peak of the electrophysiological response

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(Jiwani, Papsin et al. 2013). In the present study, adolescents with CIs had abnormally increased activity

in the frontal cortex and precuneus regions, shown in Figure 4.6, even in a passive response evoked

by non-speech stimulation from the ear they had listened to for most of their lives. This suggests a

profound reorganization of the cortical network to support CI listening.

4.5.3 Activity evoked by stimulation of the newly implanted ear is abnormal

It is difficult to separate the effects of stimulation from one ear from the simultaneous effects

of deprivation in the other ear in adolescents using unilateral CIs. We suggest, however, that leaving

the opposite pathways deprived of input beyond the period of brainstem (Gordon, Papsin et al. 2006;

Gordon, Jiwani et al. 2013) and cortical (Jiwani, Papsin et al. 2013) maturation further disrupts

organization of activity in the auditory pathways. As shown in Figure 4.4, cortical responses at initial

stimulation of that side were atypical and dominated by an abnormally large biphasic waveform, despite

equal amplitudes of brainstem responses on each side. It may reflect cortical immaturity, as a similar

response has been observed in normal hearing pre-term infants (Wunderlich and Cone-Wesson 2006)

and children with little auditory input due to GJB-2 deafness (Gordon, Tanaka et al. 2011). It could

also reflect abnormal cortical activity, as the same response was recorded from children with congenital

deafness implanted late (Sharma, Dorman et al. 2002) and in children who had poor speech perception

with their implants (Gordon, Tanaka et al. 2008).

Cortical activity underlying the abnormal response in the newly implanted ear, shown in Figure

4.4, occurred with abnormally large dipole moments compared to the activity evoked by the opposite

experience side and the normal hearing group. Moreover, activity was more widespread as shown in

Figure 4.6, with a loss of cortical lateralization as plotted in Figure 4.5. Reduced cortical lateralization

has been associated with poor auditory processing skills, decreased academic performance and

increased difficulty with reading and spelling (Abrams, Nicol et al. 2006). Poor speech perception

outcomes when adolescents were listening with the new implant after ~8 months of experience, shown

in Figure 4.7, is consistent with these reports, suggesting altered cortical processing in the deprived

pathways.

The long period of deprivation in this ear could have left it vulnerable to many structural and

functional changes. Significant reorganization of subcortical projections (Kitzes, Kageyama et al. 1995;

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Mossop, Wilson et al. 2000; Moore and Kitzes 2004; Moore and Kowalchuk 2004; Nordeen, Killackey

et al. 2004; Vale, Juíz et al. 2004) and cortical activation patterns have been reported with unilateral

auditory deprivation in early life, both in animals (Popescu and Polley 2010; Kral, Heid et al. 2013;

Kral, Hubka et al. 2013) and congenitally deaf children receiving sequential CIs (Gordon, Jiwani et al.

2013; Gordon, Wong et al. 2013). This reorganization drove increased allocation of resources (Kral,

Hubka et al. 2013) and hemispheric preference towards the hearing ear (Gordon, Wong et al. 2013;

Kral, Hubka et al. 2013) while reducing efficiency and responsiveness of the deprived side to activate

the cortex but not eliminating it (Popescu and Polley 2010; Kral, Heid et al. 2013). Similar cortical

consequences occur in the visual system, with monocular deprivation. Findings of reduced visual

acuity from a deprived eye has been attributed to uneven competition between the two pathways

(Hubel and Wiesel 1970; Hubel, Wiesel et al. 1977; Le Vay, Wiesel et al. 1980; Blakemore 1988; Lewis

and Maurer 2005), resulting in jittered representation of visual input in the cortex (Jeffrey, Wang et al.

2004). The widespread dipole activity observed from the naïve CI could thus reflect undefined cortical

activity across both hemispheres, and suggests that similar aberrant processes may underlie auditory

cortical activity in these pathways. This might reflect an immaturity or dis-integration of auditory areas

in the cortex (Kral and Sharma 2012), and would explain the inferior auditory outcome observed from

this side.

Kral and colleagues indicated that unilateral deprivation in early life drives a separation of the

experienced and naïve pathways, which places the deprived ear at a disadvantage for competition of

cortical resources (Kral, Heid et al. 2013). Our results of generally abnormal and undefined cortical

organization in response to novel auditory input evoked by the naïve CI compared to the experienced

side support this and highlight the deleterious effects of unilateral deprivation on the brain.

4.6 Conclusion

Maturation of the auditory brain is an experience-dependent process which underlies

hemispheric specialization in adolescents with normal hearing. Unfortunately, cortical organization in

the auditory pathways differs from normal in both ears in adolescents who have used a unilateral CI

to hear for most of their lives. Our findings indicate that driving maturation of the auditory cortex

with only one implant for over a decade leads to lasting asymmetries in the auditory system and leaves

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the deprived pathways unprotected from effects of unilateral auditory deprivation. Because sensitive

periods typically end when maturation is reached, maturation of the cortex from the experienced CI

may mark the closing of an important developmental period in the adolescent brain for promoting

auditory development in the deprived pathways.

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4.7 Supplementary Information on Methods

The Time-Restricted, Artefact and Coherent Source suppression (TRACS) beamformer (Wong

and Gordon 2009) imaging method was used to localize cortical activation underlying the evoked peaks

in the cortex of adolescents. This method was developed by our laboratory in linearly constrained

minimum variance beamformer analysis, and was designed specifically to suppress the electrical

artefact from the cochlear implant (CI) device and assess auditory activity in CI users (Wong and

Gordon 2009). Unfortunately, other imaging methods which offer better spatial resolution than

electroencephalography (EEG) (i.e., functional magnetic resonance imaging (fMRI), magneto-

encephalography (MEG)) are incompatible with the CI magnet in the receiver stimulator component

of the subcutaneous CI (Loizou 1999).

The beamformer is an adaptive spatial filter which uses age-appropriate head model templates

and lead potential matrices to estimate activity at each voxel in the brain (Van Veen, Van Drongelen

et al. 1997). Using these filters, the beamformer correlates brain electrical activity at a given source to

the electric potential distribution measured by sensors at the surface of the scalp while suppressing

activity originating at different locations (Van Veen, Van Drongelen et al. 1997). In this way, the

beamformer provides an estimate of neural power for each voxel (3 x 3 x 3mm) in the cortex (Van

Veen, Van Drongelen et al. 1997; Fuchs 2007) across 63,646 voxels in brain space. These

reconstructed sources provide information about the strength of activity at identified locations and

their respective latencies in response to auditory stimulation in both CI users and normal hearing peers.

A 3-layer boundary element mesh was constructed using age-appropriate head model templates

derived from the Montreal Neurological Institute (MNI) MRI library. This was used to represent age-

appropriate head geometry and tissue conductivities of the brain, meninges, skull and scalp to account

for spatial smearing of electric potentials at the surface of the head. Source activity in the left

hemisphere was assessed using region suppression of activity in the right hemisphere, and vice versa,

as bilaterally correlated activity is known to pose a particular problem for source localization in auditory

cortices (Dalal, Sekihara et al. 2006). In adolescents using CIs, a time restricted artefact suppression

algorithm was applied to suppress the implant-generated electrical artefact, corresponding to the 4

largest singular vector values over the -80 to 10ms latency range. This ensures that singular vectors

representing up to 97% of the CI artefact are suppressed (Wong and Gordon 2009). The artefact is

generated as the CI device processes sounds and transmits input from the external processor to the

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internally implanted component/magnet. The CI artefact lasts for at least the duration of the stimulus

and likely reflects residual electrical energy created by the radio frequency transmission of the signal to

the receiver (Gilley, Sharma et al. 2006; Martin 2007; Debener, Hine et al. 2008; Friesen and Picton

2010). Without the suppression algorithm, source localization of cortical peaks become obscured and

distorted (Gilley, Sharma et al. 2006; Friesen and Picton 2010).

Peaks in the cortical response were visually identified at latencies corresponding to those

previously reported from normal hearing peers and CI users (Gordon, Tanaka et al. 2008; Jiwani,

Papsin et al. 2013). Peak latencies and amplitudes were marked for responses evoked by stimulation

of the right and left ears in the normal hearing group and the experienced-right and naïve-left sides in

the CI group (i.e., P1, N1 and P2 for normal hearing responses and experienced CI stimulation; and N(ci)

and P(ci) for responses evoked by stimulation of the naïve CI). Mean ± standard deviations (SD) are

shown in Supplementary Table 4.1 for each group.

P1

(Mean ± SD)

N1 / N(ci)

(Mean ± SD)

P2 / P(ci)

(Mean ± SD)

Latency (ms)

Normal Hearing Right

Normal Hearing Left

Experienced-Right CI

Naïve Left CI

78.87 ± 9.20

77.63 ± 4.46

79.59 ± 6.22

--

108.83 ± 9.53

111.64 ± 7.16

105.43 ± 9.57

114.10 ± 8.34

164.22 ± 17.94

163.87 ± 19.19

162.20 ± 18.24

184.58 ± 19.01

Amplitude (µV)

Normal Hearing Right

Normal Hearing Left

Experienced-Right CI

Naïve Left CI

0.92 ± 1.46

1.06 ± 1.41

0.63 ± 2.92

--

-1.56 ± 1.72

-2.27 ± 1.95

-1.92 ± 3.18

-12.27 ± 5.94

2.83 ± 1.96

2.61 ± 1.73

5.30 ± 3.61

8.77 ± 5.86

Supplementary Table 4.1: Latencies and amplitudes of cortical response peaks

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The estimate of the covariance matrix for beamforming analysis was calculated over a latency

window >20ms encompassing each peak of the cortical response for each participant. A pseudo-Z

statistic was used to normalize the signal-to-noise ratio of each voxel to avoid an over-weighing of

source localization toward the center of the head (Vrba and Robinson 2001). The pseudo-Z value was

obtained by dividing the mean of the sample signal by the standard deviation of the sample noise.

Once sources were localized using this lead normalization process, the dipole moment of that source,

measured in nAm, was computed and were plotted on topographic maps. Supplementary Figure

4.8 is an example of a topographic image from one adolescent with long-term CI experience and shows

the activity underlying the mature peak P2 in 63,646 brain voxels. Source locations of the strongest

dipoles in the red hotspots are marked in Supplementary Figure 4.8 by the green cross hairs in the

left and right hemispheres separately. The waveforms to the left of the head maps show the

corresponding virtual channel of the voxel, reflecting the strongest peak dipole underlying the peak of

the cortical waveform. In this example, the strongest dipole activity occurs at ~150ms following

stimulus onset and is generated by areas of the left and right temporal lobes.

A statistical threshold of baseline brain activity was computed using a one-tailed omnibus noise

T-test (Petersson, Nichols et al. 1999). This was done to eliminate false detection of spurious sources.

To compute this, a minimum tolerance pseudo-Z statistic was calculated by creating a plus-minus

averaged dipole activity across the whole brain; the polarity of all odd-numbered epochs was inverted

and averaged with all even-numbered epochs. The beamformer analysis was then performed on this

resulting noise-only dataset. This analysis produced a global threshold pseudo-Z value reflecting

baseline brain activity which was significantly different from the evoked brain activity (p ≤ 0.0005).

All voxels with pseudo-Z activity that was equal to or less than this omnibus value were considered to

be baseline brain activity and not evoked by the auditory stimulus. Cortical activity was assessed and

visualized topographically in this way on age-appropriate head templates for each participant in 63,646

brain voxels, with only activity greater than the baseline omnibus threshold plotted.

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Supplementary Figure 4-8: Example from one child with 15.95 years of CI experience in the right

ear indicates activity underlying the mature peak P2.

The virtual channel waveforms and topographic locations corresponding to the voxel with the

strongest activity (red hotspots) is shown for the left and right hemispheres separately. Source

locations are marked by the green cross hairs. As shown, the strongest dipole underlying peak P2

occurs in areas of the left and right auditory cortices at 150ms, in line with the latency of the cortical

wave P2.

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5. Chapter Five – Temporally coordinated activity in the brain is

promoted by long-term cochlear implant use in children

This paper was submitted to Cerebral Cortex using required journal formatting:

Jiwani, S., Doesburg, S. M., Papsin, B.C., Gordon, K.A. Effects of long-term unilateral cochlear

implant use on cortical synchrony in adolescents.

5.1 Abstract

Unilateral cochlear implant (CI) use promotes maturational changes in the auditory system but

causes abnormally increased activity in the contralateral cortex if a second implant is not provided

within 1.5 years. This abnormal development might be attributed to a loss of inhibitory processes

from the deprived side which would have normally been present with bilateral hearing. At the same

time, leaving the opposite pathways deprived of auditory input beyond both the early period of

brainstem maturation and the later one of cortical maturation also disrupts activity in these pathways

and leaves this ear with relatively poorer auditory function. In the present study, we investigated the

effects of driving maturation of the auditory cortex with over a decade of unilateral implant use on the

neural networks that support CI listening in these adolescents. We hypothesized that unilaterally-

driven maturation of the auditory brain would: 1) promote abnormally increased coordinated activity

in brain areas that respond to sound, perhaps reflecting increased attention for auditory processing,

but 2) auditory activity in the deprived pathways would be abnormally desynchronized, perhaps

reflecting segregation of these pathways from the cortical hearing network.

Cortical responses were recorded from 64-cephalic electrodes in 34 adolescents who had over

a decade of unilateral CI experience in the right ear. Twenty-one of these adolescents received a second

implant in their left ear, allowing us to assess the effects of unilateral stimulation on pathways from

the opposite deprived ear. Responses were elicited by electrical pulses delivered from the right and

left CIs separately and compared to a group of 16 normal hearing peers. Neural synchrony was

calculated between electrodes in the theta, alpha, beta and gamma frequency-bands to assess

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temporally coordinated responses to sound across brain regions. Time series of amplitude and phase-

locking values were calculated at 1Hz intervals between 4 and 60Hz for 171 pairs of 19 electrodes.

Our results indicated that stimulation of an experienced-right CI elicited abnormally increased

phase synchronization across the latency range in the theta and beta frequency bands with bursts of

activity in the gamma frequencies. This pattern of cortical synchronization suggests increased

recruitment of attention and higher-order perceptual processes to support CI listening, despite the

seemingly passive auditory task. By contrast, activity was globally desynchronized in response to initial

stimulation of the naïve-left ear. Findings indicate that unilaterally-driven cortical maturation causes

lasting asymmetries in the auditory pathways and altered functional neural networks. Mature auditory

responses could mark the closure of a sensitive period for establishing hearing on the deprived side.

5.2 Introduction

A cochlear implant (CI) is a surgically implanted auditory prosthesis, which stimulates the

auditory nerve with electrical pulses to allow children who are deaf to hear and develop oral

communication. Prior to cochlear implantation, the period of bilateral deafness leaves association

areas of the developing auditory brain vulnerable to recruitment by the visual (Lomber, Meredith et al.

2010) and somatosensory systems (Meredith and Lomber 2011). These cross-modal changes are

associated with enhanced function of the intact senses (Finney, Fine et al. 2001; Bavelier and Neville

2002; Bavelier, Dye et al. 2006) and reflect the brain’s remarkable capacity for plasticity during

development. Such changes may be impossible to reverse if hearing is not restored within sensitive

periods in development (Lee, Lee et al. 2001). Unilateral CIs have been provided to children in early

life to limit such deafness-induced reorganization (Lee, Lee et al. 2001) and promote auditory

development (Sharma, Dorman et al. 2002; Gordon, Papsin et al. 2005; Gordon, Papsin et al. 2006;

Jiwani, Papsin et al. 2013). Unilateral implant stimulation promotes maturational changes to the

auditory pathways (Gordon, Jiwani et al. 2013; Jiwani, Papsin et al. 2013), but drives abnormal

asymmetries in the brainstem (Gordon, Salloum et al. 2012) and cortex (Gordon, Wong et al. 2013;

Jiwani, Papsin et al. Submitted), which persist if a second implant is not provided within a sensitive

period of 1.5 years (Gordon, Wong et al. 2013). We have recently found that long-term unilateral

auditory stimulation/deprivation drove abnormally strengthened activity from the hearing ear to the

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contralateral left auditory cortex (Gordon, Wong et al. 2013; Jiwani, Papsin et al. Submitted) and an

abnormal reversal of aural preference in the ipsilateral cortex (Gordon, Wong et al. 2013; Kral, Hubka

et al. 2013). These asymmetries might be explained by increased excitability of auditory neurons from

this side resulting from a loss of inhibitory processes in pathways from the opposite ear (Vale, Juíz et

al. 2004; Kotak, Fujisawa et al. 2005; Takesian, Kotak et al. 2009; Popescu and Polley 2010; Kral, Heid

et al. 2013; Kral, Hubka et al. 2013) that would have normally occurred with bilateral hearing (Grothe

2003; Grothe, Pecka et al. 2010). At the same time, leaving the opposite pathways deprived of auditory

input beyond the period of cortical maturation (Jiwani, Papsin et al. 2013) also led to significantly

abnormal activity in these pathways (Jiwani, Papsin et al. Submitted), suggesting that aberrant patterns

of activity develop in the absence of auditory input.

Long-term unilateral stimulation/deprivation thus seems to drive a profound reorganization

in the central auditory system. Yet some children amaze us by achieving excellent listening and oral

communication abilities (Geers, Tobey et al. 2008; Geers and Sedey 2011; Geers and Sedey 2011). We

suggest that these children are using compensatory strategies to facilitate listening and auditory

development with the reduced cues delivered by a CI in only one ear. We are already finding that

children with unilateral implants use multi-sensory information more effectively than their peers with

normal hearing to understand subtle emotional cues in speech (Hopyan-Misakyan, Gordon et al. 2009)

but do so with longer reaction times (Hopyan et al., Submitted; Steel et al., Submitted). This might

indicate more effort (Hughes and Galvin 2013; Pals, Sarampalis et al. 2013) and thus reduced efficiency

for auditory processing. More effortful listening in turn, could mean that unilateral CI users expend

more mental resources than their normal hearing peers to aid CI listening (Cleary, Pisoni et al. 2001;

Pisoni, Conway et al. 2010; Pisoni, Kronenberger et al. 2011; Geers, Pisoni et al. 2012; Hughes and

Galvin 2013; Kronenberger, Colson et al. 2014). In support, children who perform well with their

implants activate areas of the dorsolateral prefrontal cortex that are involved in higher cognitive

functions such as attention and working memory (Jeong Lee, Kang et al. 2005; Lee, Giraud et al. 2007),

and the precuneus region, which participates in visual imagery and episodic memory (Giraud, Price et

al. 2001; Jeong Lee, Kang et al. 2005). Activation of these areas indicate altered allocation of cortical

resources for CI listening (Kral and Sharma 2012; Kral 2013; Kral, Heid et al. 2013) and may underlie

differences in cognitive and perceptual processes that individuals with long-term unilateral CI

experience use compared to normal hearing peers.

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We can now assess the task-dependent recruitment of distributed neural networks, which have

been associated with perceptual, motor and cognitive processing, including the engagement of higher

order cognitive processes such as selective attention and working memory in auditory processing,

through the measurement of inter-regional oscillatory synchronization (Lachaux, Rodriguez et al. 1999;

Varela, Lachaux et al. 2001; Fries 2005; Uhlhaas, Pipa et al. 2009; Uhlhaas, Roux et al. 2010). Cognitive

and perceptual functions in the brain are shaped by coordinated interactions/communication,

mediated by the synchronization of neural oscillations, across populations of neurons that are

distributed within and across brain regions (Uhlhaas, Roux et al. 2010). This coordinated activity

mediates the development and maturation of dynamic connections that are fundamental for functional

integration and processing of distributed information across large-scale networks (Varela, Lachaux et

al. 2001; Velazquez, Erra et al. 2009). In brief, neuronal communication is constrained by anatomical

connections between neurons (Fries 2005). A stimulated neuron synapses with all other neurons to

which it is anatomically connected. Activated neural groups then oscillate and those neurons that

oscillate in synchrony exchange bursts of action potentials, which are received by the input pyramidal

neurons during their depolarized phase, when they are most excitable (Fries 2005). Synchronization

between such assemblies of neurons thus allows them to exchange information effectively (Nunez

2000; Doesburg and Ward 2009). This neural encoding, which can be measured from inter-electrode

oscillatory synchronization in electroencephalography (EEG) and magnetoencephalography (MEG),

underlies neuronal communication and represent cognitive dynamics throughout the brain including

mechanisms of attention, memory, learning, anticipation, decision-making and consciousness (Ward

2003; Palva and Palva 2012).

Spectral power (i.e., amplitude) and phase locking of activity in different frequency bands are

measures of local and long-range neural synchronization respectively, which have been implicated in

information processing (Müller, Gruber et al. 2009). Increased long-range neural synchrony in the

gamma and theta frequencies, together with a reduction in local alpha activity has been linked to

increased cognitive processing during tasks of selective attention (Jensen, Kaiser et al. 2007; Doesburg,

Roggeveen et al. 2008; Green, Doesburg et al. 2011), auditory attention control (Doesburg, Green et

al. 2012), short-term and working memory (Doesburg, Herdman et al. 2010; Palva, Monto et al. 2010),

and multisensory integration (Doesburg, Emberson et al. 2008). Increased gamma-band

synchronization has been suggested to reflect local processing of cortical input, but feature binding

and information processing mechanisms are mediated by long-range synchronization in the theta and

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alpha bands (Von Stein and Sarnthein 2000). Appropriate coupling of these frequencies are thus

crucial for maintenance of cortical organization in neural networks and support cognition/perception

and information processing. However, deviations from normal patterns of neural synchronization

have been associated with clinical impairments (Uhlhaas and Singer 2006) including epilepsy (Brugge,

Volkov et al. 2003; Matsumoto, Nair et al. 2004; Uhlhaas and Singer 2006), schizophrenia (Uhlhaas

and Singer 2006; Uhlhaas and Singer 2010; Uhlhaas and Singer 2011), Alzheimer’s disease (Uhlhaas

and Singer 2006), Parkinson’s disease (Schnitzler and Gross 2005; Uhlhaas and Singer 2006; Stoffers,

Bosboom et al. 2007), autism (Uhlhaas and Singer 2006; Vidal, Nicolson et al. 2006; Hughes 2007;

Wilson, Rojas et al. 2007; O’Connor 2012; Khan, Gramfort et al. 2013), attention deficit (Konrad and

Eickhoff 2010), and cognitive difficulties prevalent in children born very preterm (Doesburg, Ribary

et al. 2011; Doesburg, Chau et al. 2013; Doesburg, Moiseev et al. 2013). These conditions have been

associated with a general reduction in both local and long-range oscillatory synchronization.

Desynchronization of cortical activity might reflect functional disconnection between brain regions.

This might also be related to cortical slowing, which is characterized as a higher ratio of synchrony in

slow EEG activity (i.e., theta, alpha) relative to fast oscillations (i.e., higher gamma frequency)

(Monastra, Lubar et al. 1999; Monastra, Lubar et al. 2001; Englot, Yang et al. 2010). Cortical slowing

has been associated with impaired perception and has also been reported in many clinical populations

including attention deficits (Monastra, Lubar et al. 1999; Monastra, Lubar et al. 2001), epilepsy (Englot,

Yang et al. 2010), Alzheimer’s (Petit, Montplaisir et al. 1992) and Parkinson’s disease (Stoffers,

Bosboom et al. 2007) among others. These abnormalities underlie functional impairments in

cognition/perception (Stoffers, Bosboom et al. 2007; Konrad and Eickhoff 2010; Uhlhaas and Singer

2010; Uhlhaas and Singer 2011) and atypical cortical maturation (Konrad and Eickhoff 2010;

Doesburg, Ribary et al. 2011; Doesburg, Moiseev et al. 2013).

The role of synchrony in the impaired auditory system has not yet been defined however.

Given that the auditory pathways change during the period of bilateral and unilateral deafness and that

CIs do not restore normal hearing, we hypothesized that cortical network connectivity is altered in

adolescents who are deaf and have developed a mature auditory system with long-term unilateral CI

stimulation. In the present study, we asked how cortical networks underlying auditory processing are

affected by long-term unilateral CI use in adolescents who were congenitally deaf in both ears and

received a CI in only their right ear as babies. Children with over a decade of hearing experience with

this unique device have developed a mature auditory cortex as a result (Jiwani, Papsin et al. 2013).

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They have subsequently received a second implant in their opposite deprived left ear, allowing us to

assess whether the long-term absence of auditory input in these naïve pathways compromises the

neural networks that support hearing in these adolescents. In the present study, we aimed to 1) map

the cortical areas that are working together to support CI listening and 2) define how the cortical

hearing network compensates for reorganization of the brain caused by long periods of unilateral

stimulation/deprivation.

5.3 Methods

5.3.1 Participants and evoked potentials recordings

Electrically-elicited cortical responses were recorded from thirty-four adolescents who received

a unilateral CI in their right ear at young ages (3.2 ± 1.3 years) and within limited durations of bilateral

deafness (1.8 ± 1.3 years). These adolescents had over a decade (12.0 ± 2.1 years) of experience with

their unilateral CI at the time of the test. Twenty-one of them then received a second implant in the

opposite-left ear at 15.9 ± 1.7 years of age, after 11.5 ± 1.7 years of unilateral deprivation on this side.

Responses were recorded from the bilaterally implanted adolescents within the first week of activation

of the new side. All participants used a CI device from Cochlear Limited in both ears. Etiology of

deafness varied. Ten adolescents had deafness associated with a genetic mutation, two had a Mondini

malformation, three had an enlarged vestibular aqueduct, and three lost their hearing after a meningitis

infection. Etiology of deafness was of unknown nature in the other sixteen adolescents. Table 1

provides the mean ± standard deviation (SD) demographic information.

Cortical responses were recorded from 64-cephalic electrodes and referenced to the right

earlobe. Responses were evoked using a 36ms pulse train of 250 pulses per second at a rate of 1Hz

and delivered to a single electrode at the apical end of the electrode array (#20). Stimulus intensity

levels for each ear were determined by recording auditory brainstem responses. Current levels were

increased to maximize the amplitude growth of the response within comfort levels for the child.

Stimulus levels were then balanced between both ears, as in previous reports (Salloum, Valero et al.

2010; Gordon, Wong et al. 2013; Jiwani, Papsin et al. Submitted), by matching the amplitudes of peak

eV when the experienced-right and naïve-left implants were stimulated separately.

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The same responses were recorded from the right and left ears of sixteen normal hearing

adolescents who were 15.9 ± 6.4 years of age and matched for age and time-in-sound experience at

the time of the test. A 500Hz tone-burst with a 2-1-2 cycle (rise-plateau-fall) lasting 36ms was used to

stimulate the auditory system in these normal hearing peers. Tones were presented at 40dB sensation

level. This tone was chosen to mimic the stimulus delivered to the CI users, because 500Hz is the

frequency which has been assigned to electrode 20 in their internal array. Tone bursts were presented

at a rate of 1Hz and enveloped in a tapered cosine window, called a Tukey window, to minimize effects

of spectral leakage over the first and last eights of each tone. A minimum of 400 sweeps with two

visual replications of the cortical evoked waveforms were recorded. All sweeps with activity ±100µV

were rejected from the average. Responses were sampled at a rate of 1000Hz. An online band-pass

filter between 0.05 to 100Hz was applied with a 12dB/octave rolloff.

Table 5-1: Demographic Information

Normal Hearing

(mean ± SD) (years)

CI Users

(mean ± SD) (years)

Age of first implant - 3.2 ± 1.3

Age of second implant - 15.9 ± 2.0

Age at Test 15.9 ± 6.4 15.9 ± 1.7

Duration of Bilateral deafness - 1.8 ± 1.3

Duration of Unilateral hearing - 12.0 ± 2.1

Duration of Unilateral deafness - 11.5 ± 1.7

Duration of Bilateral Hearing 15.9 ± 6.4 0

Time-in-Sound 15.9 ± 6.4 12.4 ± 1.7

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5.3.2 Phase synchronization analysis

CI-evoked cortical waveforms are contaminated by a large artefact from the CI device which

can obscure the response and render analyses of cortical activity impossible (Miller, Abbas et al. 2000;

Gilley, Sharma et al. 2006; Martin 2007; Friesen and Picton 2010; Castañeda-Villa and James 2011).

This artefact was removed from the recording with independent component analyses (Gilley, Sharma

et al. 2006; McMenamin, Shackman et al. 2010; Castañeda-Villa and James 2011; Viola, De Vos et al.

2012; Fatima, Quraan et al. 2013; Mc Laughlin, Lopez Valdes et al. 2013) using the extended-runica

Infomax ICA decomposition function in the EEGLab Matlab toolbox (Delorme and Makeig 2004).

Independent components representing the CI artifact were identified visually and removed from the

epoched recordings. Additional details on this method are provided in the Supplementary Materials

section. A scalp current density (SCD) analysis was then performed on the data using a MATLAB

script that implements a spherical spline operator algorithm (Perrin, Pernier et al. 1989) to reduce

effects of spurious synchronization caused from volume conduction as SCD more strongly

corresponds to superficial generators near the recording electrode, and accurately estimates the true

synchrony in the response. This is because SCD measures are much less influenced by the location of

the reference electrode. Additional details on this process are also provided in the Supplementary

Materials section.

Inter-electrode phase-locking values (PLV) were calculated at each time point for each 1Hz

frequency from 4Hz to 60Hz (passband = f ± 0.05f, where f represents the filter frequency) of the

SCD data across all 171 electrode pairs for 19 electrodes uniformly distributed on the scalp. The time-

frequency amplitude responses was also analyzed for the same 19-electrode montage This subset of

electrodes was selected from the 64-channel montage to avoid spurious synchronization originating

from common sources, which can often occur when measuring synchronization between nearby

electrodes. This was measured both for the individual data and for the group data to allow us to assess

temporally coordinated responses to sound across brain regions. PLV analysis takes the EEG

waveform and calculates the instantaneous phase of the signal for each trial, at each frequency and for

every latency point using a Hilbert transform, which also produces time series of instantaneous

amplitude values representing the signal envelope (similar to power). Inter-electrode PLVs were then

calculated by measuring the consistency of the phase angle between two electrodes, at a given

frequency and time point, across trials (Le Van Quyen, Foucher et al. 2001; Bruns 2004; Le Van Quyen

and Bragin 2007).

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The advantage of using the Hilbert transform is that it can be used to calculate the phase over

relatively short epochs (Doesburg and Ward 2009). A disadvantage of this method however, is that it

introduces distortions to the beginning and end of the analyzed epochs, with stronger effects in the

lower frequencies. To account for these edge effects, epochs were extended in both directions relative

to stimulus onset from 1250ms before stimulus onset to 2000ms after stimulus. This allowed latencies

outside of the relevant time-window to be affected by the Hilbert transform analyses while protecting

the activity in relevant latencies from contamination. Amplitude and PLV analyses were normalized

relative to a 250ms pre-stimulus baseline window to eliminate synchronization of activity unrelated to

the auditory input. Normalization of PLVs was accomplished by subtracting the mean baseline PLV

from the PLV for every data point and dividing the difference by the standard deviation of baseline

PLV (Doesburg and Ward 2009). Baseline-corrected inter-electrode auditory-elicited synchronization

was then plotted on time-frequency plots for stimulation of the right and left ears in normal hearing

adolescents, and the experienced and naïve ears in CI users.

A surrogate distribution of neural synchrony, as measured by PLVs, was then calculated to

assess the statistical reliability in synchronization and desynchronization (Le Van Quyen, Foucher et

al. 2001; Le Van Quyen and Bragin 2007). This was done by comparing the changes in synchrony to

a null distribution derived from the data. To do this, epochs were randomly shuffled 200 times and

normalized PLVs were re-computed for each frequency and at every latency-point for the scrambled

data, thereby representing a null distribution of synchronization. Only changes in PLV exceeding the

97.5th percentile or below the 2.5th percentile were considered to reflect significant increases or

decreases in synchrony at p<0.05. Significant activity was plotted on topographic brain maps for the

analyzed frequencies at 25ms latency intervals, from 25ms to 800ms following stimulus onset (only

activity between 50 and 300ms is shown, as these were considered most relevant to the present

discussion). A difference analysis of the amplitude and PLVs, and a corresponding surrogate

distribution of phase-locking values, was then calculated to compare neural synchrony for right ear

stimulation between the normal hearing data and the experienced ear in the CI users, and left ear

stimulation between normal hearing adolescents and the CI naïve ear. This was done by subtracting

the activity evoked by CI stimulation from the normal hearing data.

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5.4 Results

5.4.1 Less cortical synchrony is evoked from tone-bursts in normal right than

left ears

Cortical activity elicited by sound was assessed to map the underlying neural network that

supports hearing in typically developing adolescents. As shown from the 64-channel grand mean

average-referenced cortical response (i.e., butterfly plot) in Figures 5.1A and 5.1E, normal hearing

adolescents developed polyphasic cortical waveforms with peaks P1, N1 and P2 consistent with a mature

auditory cortex (Albrecht, Suchodoletz et al. 2000; Ponton, Eggermont et al. 2000; Ponton, Eggermont

et al. 2002; Wunderlich, Cone-Wesson et al. 2006). The distribution of topographic potentials is similar

between both ears; however, as shown by the frequency coherence plots, underlying temporally

coordinated activity in the brain differs for stimulation of the right (Figures 5.1B, 5.1C and 5.1D)

versus left ear (Figures 5.1F, 5.1G and 5.1H) in response to a tone-burst stimulus.

The amplitude time-frequency plot in Figure 5.1B indicates that bursts of increased gamma-

band amplitude centered at ~40Hz were observed, which were prominent over frontal regions (Figure

5.1D), following tones presented to the right ear. This coincided with an amplitude decrease in the

theta and alpha frequencies over parietal electrodes in both hemispheres, corresponding to local

changes in synchronized activity (Doesburg, Emberson et al. 2008; Doesburg, Roggeveen et al. 2008).

By contrast, this activity was reversed for the left ear. Gamma-band activity was reduced relative to

baseline (Figure 5.1F) and compared to the right ear, and occurred in concert with an amplitude

increase in theta and alpha activity across the temporo-parietal regions (Figure 5.1H). The pattern of

long-range oscillatory synchronization shown in Figures 5.1C and 5.1D for the right ear and Figures

5.1G and 5.1H for the left ear, reflective of coordinated activity between distant brain regions rather

than local changes in activity, indicated different long-range neural synchronization between

stimulation of both ears in our cohort of normal hearing adolescents. This is in line with the observed

differences in local EEG amplitude between both ears (Figures 5.1B and 5.1F). Auditory stimulation

of the right and left ears elicited bursts of long-range gamma oscillations, with the strongest

synchronization peaking between 50 and 60Hz. Most of this activity occurred in the latencies

underlying the cortical response and was identified primarily at electrodes over temporal and parietal

areas in both hemispheres and frontal regions in the right cortex. Right frontal activity was more

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pronounced for left ear stimulation (Figure 5.1G). Of note, the left ear also elicited 30Hz-low

frequency gamma bursts between electrodes at left and right temporal cortex and frontal regions, as

shown in Figures 5.1F and 5.1G, indicating greater left ear-evoked activity in the brain compared to

the right ear. This is supported by observations of increased theta coupling in the left ear in Figure

5.1F, which has been suggested to regulate long-range communication within and across brain regions

and organize task-relevant information in the brain (Doesburg, Green et al. 2012).

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Figure 5-1: Cortical oscillatory synchronization evoked by auditory stimulation of the right and left

ears of normal hearing adolescents.

Auditory cortical responses were recorded from the right and left ears separately in 13 normal hearing

adolescents aged 15.9 ± 6.4 years. Cortical activity elicited by stimulation of the right ear is shown in

A – D. Left ear evoked activity is shown in E – H. Grand mean average-referenced waveforms (i.e.,

butterfly plot) of the 64-channel cortical responses with the waveform recorded at a midline cephalic

electrode (Cz) highlighted in red for right ear stimulation (n=13) is shown in A. and in blue for left ear

stimulation (n=12) shown in E. Mean global field power (GFP) head topographies for each peak of

the cortical waveform are shown above the response for both ears (red = positive potentials, blue=

negative potentials, green = baseline). Normalized group mean amplitude activity, reflecting of local

changes in synchrony are shown in B. and F. for the right and left ears respectively for 4 to 60 Hz.

The right ear shows bursts of gamma band activity (red) with reduced low frequency amplitude (blue).

This activity is reversed in the left ear, where local changes in synchrony are more predominant in

oscillations in the theta, alpha and beta bands and reduced for gamma. C. & D. Normalized group

mean changes in long-range synchrony are plotted relative to baseline for frequencies from 4 to 60Hz

for latencies ranging from -200 to 800ms for the right ear in C. Topographic representation of this

activity is shown in D. for theta (4Hz), alpha (10Hz), low gamma (30Hz) and high gamma (60Hz)

frequencies for each 25ms latency interval from 50 to 300ms following stimulus onset. The black lines

indicate statistically significant increases in phase-locking activity between electrode pairs (>97.5th

percentile of the surrogate distribution), and the while lines show statistically significant decreased

activity (<2.5th percentile). These are superimposed over local changes in amplitude which are

represented by the colour gradients on the topographic brain plots. This activity is plotted for the left

ear in G. & H. Both ears show increased synchrony in the theta, beta and gamma frequency bands

but this activity is greater in the left ear, indicating that the left ear evokes greater cortical activity than

the right.

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5.4.2 Right cochlear implants promote atypical cortical synchrony and leave

deprived pathways abnormally desynchronized

Long-term unilateral CI use appears to promote typical development of cortical responses. As

shown in Figure 5.2A, adolescents who had over a decade of CI stimulation in the right ear developed

cortical waveforms which were comprised of the mature peaks P1, N1 and P2. The latency (P1:

t(10)=−0.88, p>0.05; N1: t(10.18)=−1.3, p>0.05; P2: t(10.77)=1.43, p>0.05) and peak-to-peak amplitude (P1-

N1: t(6.87)=1.75, p>0.05) of cortical wavepeaks were generally similar between both groups, except that

peak P2 was significantly larger (t(14.51)=2.49, p<0.05) and global field power scalp amplitudes was

stronger (±2µV) in the CI users compared to either ear of the normal hearing group. On the newly

implanted side, initial stimulation of the naïve pathways shown in Figure 5.2E evoked cortical

responses, which had a significantly different morphology than the responses recorded from normal

(Figures 5.1A and 5.1E) and the experienced side (Figure 5.2A). Here, the morphology of the

waveform was characterized by a large negative amplitude biphasic response, N(ci), followed by a large

positive peak, P(ci). We have described this response in a previous report and suggested that it might

index abnormal or immature underlying activity in the brain (Jiwani, Papsin et al. Submitted). Peak-

to-peak amplitude of this response was significantly larger than any of the mature wavepeaks recorded

from the normal hearing group (F(3,70)=5.4, p<0.05) and the experienced ear (t(11)=-3.37, p<0.01), with

a stronger mean global field power amplitude (±5µV).

Analyses of changes in amplitude, phase-locking values and inter-electrode synchrony further

highlighted differences in cortical processing of sound evoked by CI stimulation compared to normal

hearing adolescents. Neural synchronization elicited by the experienced-right CI after long-term

unilateral experience was increased compared to normal hearing peers in both ears, shown in Figures

5.2B, 5.2C and 5.2D, whereas this activity was significantly and globally reduced on the naïve side

(Figures 5.2F, 5.2G and 5.2H). A general reduction in amplitude of the signal across the different

frequency bands was observed with CI stimulation in both the experienced (Figure 5.2B) and naïve

ears (Figure 5.2F) in latencies greater than 150 to 200ms. Of interest, on the experienced side only,

this activity was preceded by an increase in theta, beta and gamma-band amplitude over left temporal

and frontal electrodes in a narrow latency range underlying the cortical response. Long-range

synchronized activity was also greater on the experienced side compared to the naïve ear and normal

hearing peers, as shown in Figures 5.2C and 5.2D. Auditory stimulation of the experienced-right

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implant evoked a pattern of theta activity that was maintained across a greater latency range (100 to

700ms) and spread across a larger network compared to typically developing normal hearing controls.

A sustained increase in theta activity over left temporal and left parietal regions to frontal electrodes

in both hemispheres was observed. These connections became more distributed across brain regions

(in electrodes over the temporal, parietal and frontal regions) and linked to the right parietal and right

visual cortices in later latencies (Figure 5.2D). These effects are clearly visible in a direct comparison

of long-range synchronization in long-term CI users and normal hearing peers shown in Figures 5.3A

and 5.3B. Theta activity was accompanied by sustained bursts of gamma-band synchronization

between left temporal, parietal and occipital regions to other electrodes, suggestive of increased

perceptual processing and perhaps increased alertness/attention in response to sound (Doesburg,

Green et al. 2012). Of interest, however, gamma activity exceeding 35Hz was reduced in the CI group

compared to normal, as shown in Figures 5.3A and 5.3B, and occurred with a greater-than-normal

ratio of alpha-band synchronization in later latencies (underlying complex perceptual processing)

(Figure 5.3A) across a distributed cortical network (Figure 5.3B), indicative of cortical slowing in

response to sound.

By contrast, long-range synchronization evoked by the naïve-left ear after over a decade of

unilateral deprivation on that side indicated generally desynchronized activity. Theta, beta and gamma-

band oscillations shown in Figure 5.2G were reduced across the cortex relative to baseline and

compared to the experienced side and normal hearing peers. A pattern of robust and sustained long-

range alpha synchrony was observed over widespread electrode locations in posterior, medial, temporal

and frontal regions (Figure 5.2H). A difference analysis of long-range synchronization with normal

hearing left ear stimulation in Figures 5.3C and 5.3D was consistent with these patterns of

oscillations, and indicated reduced cortical connectivity in all but the alpha-band frequencies at initial

stimulation of the naïve-left CI. This is in contrast to the synchronization observed from normal

hearing adolescents and the opposite experienced-right CI side, where theta and gamma activity,

believed to reflect perception and attention (Jensen, Kaiser et al. 2007; Doesburg, Emberson et al.

2008; Doesburg, Roggeveen et al. 2008; Green, Doesburg et al. 2011; Doesburg, Green et al. 2012),

was increased. General patterns of local (Figure 5.2F) and long-range desynchronization (Figures

5.2G, 5.2H, 5.3C and 5.3D) elicited by the newly implanted ear indicate abnormal network

connectivity in the brain after long-term unilateral auditory deprivation.

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Figure 5-2: Cortical oscillatory synchronization evoked by auditory stimulation of the experienced-

right and naïve-left ears in CI users.

Auditory cortical responses were recorded from the experienced-right ear (n=34) and at initial

activation of the naïve-left (n=21) implant separately in adolescents who received a unilateral right CI

within limited durations of bilateral deafness, and received a second one on the naïve-left side after

over a decade of unilateral deprivation. Cortical activity elicited by stimulation of the experienced-

right after 12.0 ± 2.1 years of unilateral CI use is shown in A. – D. Left-naive ear elicited activity is

shown in E. – H. A. Grand mean average-referenced waveforms of the 64-channel cortical responses

evoked by the experienced-right CI show 3 peaks, P1, N1, P2, characteristic of a mature response, but

this responses evoked at initial stimulation of the naïve-left side shown in E. has an abnormal

morphology with a biphasic peaked waveform (N(ci), P(ci)) of abnormally large amplitudes. Mean

global field power (GFP) head topographies for each peak of the cortical waveform are shown above

the response for both ears (red = positive potentials, blue= negative potentials, green = baseline).

Normalized group mean amplitude activity reflective of local changes in synchrony is shown in B. and

F. for the experienced-right and naïve-left ears respectively for 4 to 60 Hz. An increase in alpha, beta

and gamma amplitude occurs in a narrow latency range underlying the cortical waveform on the

experienced side, shown by the red. Amplitude activity is generally reduced thereafter for both ears,

shown in blue. C. & D. Normalized group mean changes in long-range synchrony are plotted relative

to baseline for frequencies from 4 to 60Hz for latencies ranging from -200 to 800ms for the

experienced right ear in C. Topographic representation of this activity is shown in D. for theta (4Hz),

alpha (10Hz), low gamma (30Hz) and high gamma (60Hz) frequencies for 25ms latency interval from

50 to 300ms following stimulus onset. The black lines indicate statistically significant increases in

phase-locking activity between electrode pairs (>97.5th percentile of the surrogate distribution), and

the while lines show statistically significant decreased activity (<2.5th percentile). These are

superimposed over local changes in amplitude which are represented by the colour gradients on the

topographic brain plots. Neural synchrony is increased across the frequency bands for the

experienced-right ear. Increased synchrony is particularly evident for theta and gamma activity

indicating increased cortical processing to sound. Long-range neural synchrony for the naïve-left ear

is plotted in G. & H. As shown, an increase in neural synchronization occurs for the alpha frequency

bands. This occurs with a general widespread de-synchronization of activity in the other frequency

bands.

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Figure 5-3: Difference in cortical oscillatory synchronization evoked by auditory stimulation of the

right/experienced and left/naive ears/implant of normal hearing adolescents and CI users.

A. Difference PLV time-frequency plots between normal hearing peers and CI users for each ear (red

= > synchronization in CI users, blue = > synchronization in normal hearing peers). B. Topographic

maps showing significantly differences in long range phase synchronization between normal hearing

peers and experienced CI users for theta, alpha, and gamma frequencies from 50 to 300ms (black lines

= increased phase-locking in CI users, white lines = increase phase-locking in normal hearing).

Gamma frequencies are reduced in the implant users, particularly at higher frequencies, but long-term

CI stimulation evokes greater than normal theta-band activity across a widespread network. This might

serve to maintain attention across distant brain regions for auditory processing. Altered inter-regional

synchronization elicited by the naïve-left side at initial stimulation of the newly implanted side

compared to normal hearing left ear activity is shown in C. and D. The dominance of blue in C. and

white lines in D. indicates that activity is significantly reduced and de-synchronized on the naïve-left

side compared to normal.

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5.5 Discussion

5.5.1 A specialized cortical hearing network normally matures by adolescence

Results indicated that patterns of neural synchronization depend on the ear of stimulation in

normal hearing adolescents. Gamma and theta synchrony in the temporo-parietal regions of both

hemispheres as well as the right frontal cortex were increased for left compared with right ear

stimulation as shown in Figure 5.1. This suggests increased network connectivity in response to a

500Hz tone-burst in line with findings of specialization to this stimulus in the mature brain of normal

hearing adolescents. Regardless of ear of presentation, the same cohort showed strong right

hemisphere activity (Jiwani, Papsin et al. Submitted) consistent with previous reports (Hine and

Debener 2007; Schönwiesner, Krumbholz et al. 2007). The previous findings together with strong

theta and gamma activation in the right cortex from left ear stimulation, observed in this study, might

underlie mechanisms of hemispheric specialization in response to tonal stimuli (Kimura 1973;

Penhune, Zatorre et al. 1996; Zatorre and Belin 2001; Zatorre, Belin et al. 2002; Schönwiesner,

Rübsamen et al. 2005; Jamison, Watkins et al. 2006; Schönwiesner, Krumbholz et al. 2007). Of note,

cortical asymmetries between both hemispheres were not present in younger peers with an immature

auditory cortex (Gordon, Wong et al. 2013). A relative specialization in the right auditory hemisphere

for spectral processing and a temporal processing bias in the left auditory cortex (Zatorre and Belin

2001; Zatorre, Belin et al. 2002), which is mediated by inter-hemispheric structural differences

(Penhune, Zatorre et al. 1996), thus appears to develop with experience and age (Penhune, Zatorre et

al. 1996; Kadis, Pang et al. 2011).

It has been argued that the different specialization of the left and right hemispheres in the brain

arose as an evolutionary strategy to increase processing efficiency (Rogers 2000; Dharmaretnam and

Rogers 2005; Vallortigara 2006; MacNeilage, Rogers et al. 2009). Cortical specialization reduces

redundant processing in one hemisphere and allows the other side of the brain to perform additional

functions, thereby increasing neural capacity in the cortex (Vallortigara 2006). Normal hemispheric

specialization also increases the brain’s ability to perform parallel processing in the two hemispheres

and attend to two tasks simultaneously (Dharmaretnam and Rogers 2005). Larger amplitude activity

in the right cortex evoked by stimulation of both ears shown in Figures 5.1B and 5.1F and stronger

long-range network connectivity of the gamma-band network across temporal, parietal and right

frontal regions with left ear stimulation in Figures 5.1G and 5.1H, could thus underlie the functional

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organization of cortical specialization to a 500Hz tone-burst. Indeed, increased network

synchronization (Barry, Clarke et al. 2004) and spectral power (Clarke, Barry et al. 2001) in theta, beta

and gamma frequencies such as that observed in Figure 5.1 have been shown to mark maturity and

efficiency in brain networks (Marosi, Harmony et al. 1992; Marosi, Harmony et al. 1997; Uhlhaas, Roux

et al. 2010). The pattern of cortical synchronization observed from our group of normal hearing peers

is in line with reports indicating that spectral processing occurs in the belt and parabelt regions of the

right auditory hemisphere (Zatorre, Belin et al. 2002; Rauschecker and Tian 2004; Schönwiesner,

Rübsamen et al. 2005) and interact with frontal regions for memory encoding and retrieval (Zatorre

and Samson 1991; Zatorre, Evans et al. 1994; Zatorre, Belin et al. 2002).

In addition to cortical specialization, functional correlates of theory of mind and mentalizing

become established during adolescence, as the brain matures (Blakemore 2012). Development of these

cognitive processes coincides with the maturation of the pre-frontal cortex (Moriguchi, Ohnishi et al.

2007) and are related to improvements in executive function (Anderson, Anderson et al. 2001) and

learning (Johnson 2011) that occur with age. These cognitive processes involve cortical activation of

a network of regions similar to that observed in Figure 5.1 (Blakemore and Choudhury 2006; Burnett,

Bird et al. 2009; Burnett and Blakemore 2009; Blakemore 2012), with activity being particularly

stronger in anterior cortical regions (i.e., medial prefontal cortex and inferior frontal gyrus) during

earlier adolescence and moving to posterior and dorsal regions in adulthood (Moriguchi, Ohnishi et

al. 2007; Blakemore 2012). The dynamic patterns of oscillations observed in Figure 5.1 from our

cohort of adolescents with normal hearing might thus reflect underlying processes of mentalizing,

which occur during passive listening tasks (Brown, Martinez et al. 2004; Wilson, Saygin et al. 2004;

Buckner, Andrews‐Hanna et al. 2008). This is supported by our findings of increased theta and beta

modulated changes of the gamma-band network which have been reported to underlie mechanisms of

response anticipation, attention preparation and/or perceptual readiness (Doesburg, Roggeveen et al.

2008; Uhlhaas, Pipa et al. 2009). This very pattern of activity likely governs complex auditory skills

(Ponton, Eggermont et al. 2000) and cognitive/perceptual processes of multi-sensory

attention/interaction (Posner and Dehaene 1994; Busse, Roberts et al. 2005; Fan, McCandliss et al.

2005; Awh, Vogel et al. 2006) which only become adult-like during adolescence (Ponton, Eggermont

et al. 2000; Eggermont and Ponton 2003). This development is coincident with the maturational time-

course of the auditory brain (Albrecht, Suchodoletz et al. 2000; Ponton, Eggermont et al. 2000; Ponton

and Eggermont 2001; Ponton, Eggermont et al. 2002; Wunderlich and Cone-Wesson 2006;

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Wunderlich, Cone-Wesson et al. 2006; Jiwani, Papsin et al. 2013) and hemispheric specialization

(Davidson 1984; Penhune, Zatorre et al. 1996; Rogers 2000; Zatorre and Belin 2001; Zatorre, Belin et

al. 2002; Rivera, Reiss et al. 2005; Jamison, Watkins et al. 2006; Zatorre, Chen et al. 2007; Johnson

2011). The dynamic pattern of synchronization observed from our cohort of adolescents with normal

hearing thus suggests appropriate development of cortico-cortical connections.

Similar perceptual processes were likely activated by sound in CI users as well, since they

developed a mature auditory cortex (as indicated by mature cortical wavepeaks, P1, N1, P2) (Figure

5.2A), which was underlied by patterns of gamma synchronization which also appeared to be

modulated by theta and beta oscillations, as shown in Figure 5.2C. However, abnormalities relative

to normal hearing peers remain. Atypical organization of the auditory network in CI users is indicated

by the abnormally large peak P2 amplitude, as previously reported (Jiwani, Papsin et al. 2013), unusually

strong contralateral lateralization to the left auditory cortex (Jiwani, Papsin et al. Submitted), and

greater-than-normal coordinated synchronization in the brain (Figures 5.2 and 5.3).

5.5.2 Increased connectivity in long-term unilateral CI users reflects greater

processing demands

As shown in Figures 5.2 and 5.3, cortical responses evoked by stimulation of the experienced-

right CI were underlied by increased gamma synchronization over the left temporal, left parietal and

frontal regions in both hemispheres which appeared to be modulated by greater-than-normal theta and

beta oscillations. Increased gamma-band synchronization is linked to selective attention, short and

long-term memory encoding/retrieval and multisensory integration (Jensen, Kaiser et al. 2007;

Uhlhaas, Pipa et al. 2009; Uhlhaas, Roux et al. 2010). This activity increases in inferior frontal, posterior

parietal and anterior temporal cortical regions (association auditory areas) during both passive and

attentive listening tasks (Kaiser 2000, Kaiser 2002, Kaiser 2002, Kaiser 2004; Kaiser and Lutzenberger,

2005). These mechanisms are mediated by an attention control network which is represented by

stronger theta activity over the superior temporal lobe (Green, Doesburg et al. 2011). The pattern of

synchronization observed in the present study might thus indicate an enhanced role for attention in

adolescents who have used a CI to hear for most of their lives compared to typically developing

adolescents, even in a passive listening task evoked by non-speech stimuli. This is further supported

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by observations of decreased local alpha amplitude in Figure 5.2B and increased long-range alpha-

band synchronization in the latency range of peak P2 (Figure 5.2C and 5.2D), which reflect

maintenance of attention (Cooper, Croft et al. 2003; Ward 2003; Palva and Palva 2007; Doesburg,

Roggeveen et al. 2008; Palva and Palva 2011), in CI users.

Individuals with long-term CI experience have been shown to recruit cortical areas linked to

attention (Posner and Dehaene 1994; Pugh, Shaywitz et al. 1996; Grady, Van Meter et al. 1997;

Benedict, Lockwood et al. 1998; Fujiwara, Nagamine et al. 1998; Jäncke, Mirzazade et al. 1999; Fan,

McCandliss et al. 2002; Fan, McCandliss et al. 2005; Okamoto, Stracke et al. 2007). These areas may

be used differently than their peers with normal hearing to facilitate listening and auditory processing

(Jeong Lee, Kang et al. 2005; Lee, Giraud et al. 2007). Activation of the left fronto-parietal network

(including dorsolateral prefrontal and inferior parietal cortices) has been associated with better speech

perception outcomes in CI users (Lee, Giraud et al. 2007). This indicates that recruitment of cognitive

mechanisms related to attention and working memory increase communication successes after

cochlear implantation (Cleary, Pisoni et al. 2001; Jeong Lee, Kang et al. 2005; Giraud and Lee 2007;

Lee, Giraud et al. 2007; Pisoni, Conway et al. 2010; Pisoni, Kronenberger et al. 2011; Geers, Pisoni et

al. 2012; Kronenberger, Colson et al. 2014). Increased attention may contribute to the significant

improvements on speech and language comprehension and production (Geers, Nicholas et al. 2003;

Geers, Tobey et al. 2008; Geers and Sedey 2011) and improvements on measures of verbal memory

capacity (Cleary, Pisoni et al. 2001; Pisoni, Kronenberger et al. 2011; Geers, Pisoni et al. 2012) reported

from CI users over the long-term. In line with these reports, our present findings suggest that

adolescents using CIs to hear capitalize on general cognitive strategies to process sounds. It is possible

that CI hearing drives increased cognitive load on the stimulated side (Kral, Heid et al. 2013), perhaps

reflecting maladaptive (Sandmann, Dillier et al. 2012) or compensatory (Kral and Sharma 2012;

Sharma, Campbell et al. 2014) cortical plasticity after long-term unilateral CI stimulation/deprivation.

Connectivity of the theta and gamma-band network with occipital cortical regions (Figure 5.2) further

suggests that CI users also supplement hearing with vision. The addition of visual input likely serves

to facilitate listening to the degraded auditory cues delivered by a CI (Rubinstein 2004; Drennan and

Rubinstein 2008) and to compensate for auditory limitations associated with bilateral deafness prior to

implantation (Finney, Fine et al. 2001; Lee, Lee et al. 2001; Bavelier and Neville 2002; Bavelier, Dye et

al. 2006; Lomber, Meredith et al. 2010; Meredith and Lomber 2011) and unilateral deprivation

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afterward (Popescu and Polley 2010; Gordon, Jiwani et al. 2013; Gordon, Wong et al. 2013; Kral, Heid

et al. 2013; Kral, Hubka et al. 2013; Jiwani, Papsin et al. Submitted).

More attentive listening with increased reliance on vision to process auditory input could mean

increased effort and perhaps reduced efficiency for CI listening. Reduced gamma-band synchrony in

frequencies above 35Hz recorded from stimulation of the experienced side in adolescents using CIs

compared to normal shown in Figure 5.3, suggests a slowing of cortical processing to sound with CI

stimulation. This is consistent with findings of increased reaction time in response to speech sounds

(Steel, Papsin et al. Submitted) indicating increased listening effort in adolescents with CIs compared

to peers with bilateral implants (Hughes and Galvin 2013) and with normal hearing (Hughes and

Galvin 2013; Pals, Sarampalis et al. 2013). Indeed, adolescents using CIs have listened to a degraded

auditory input missing much of its fine temporal cues from only a single CI for most of their lives.

Distorted auditory input and/or decreased speech intelligibility exerts increased mental

processing/effort and uncertainty (Zekveld, Kramer et al. 2010; Zekveld, Kramer et al. 2011;

Koelewijn, Zekveld et al. 2012), which could mean slower auditory processing and in turn reduced

efficiency for CI listening. Increased effort and attention of the auditory brain for processing sounds

may be attributed to a reduction in inhibitory input from the opposite pathways which were left

deprived of input for over a decade (Vale, Juíz et al. 2004; Takesian, Kotak et al. 2009; Sanes and Kotak

2011). Indeed, investigators have shown that leaving the auditory system unilaterally deprived during

early stages of development drives a strengthening of activity in favor of the stimulated ear from

brainstem (Moore and Kowalchuk 1988; Moore 1990; Kil, Hkageyama et al. 1995; Kitzes, Kageyama

et al. 1995; Nordeen, Killackey et al. 2004) to cortex (Gordon, Wong et al. 2013; Kral, Heid et al. 2013;

Kral, Hubka et al. 2013) and a weakening of ascending connections in the deprived pathways (Popescu

and Polley 2010; Kral, Heid et al. 2013).

5.5.3 Desynchronized activity evoked by the naïve-left CI suggests

disorganization in the deprived pathways

Long-term unilateral stimulation of a right-experienced CI means that pathways of the

opposite-left ear were left deprived of auditory input. We hypothesized that this would lead to a

profound reorganization in the unstimulated pathways with abnormal desynchronized cortical

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oscillations, reflecting immature and inefficient cortical networks. In line with our hypothesis, cortical

responses evoked by initial stimulation of the newly implanted side after over a decade of deprivation

revealed abnormal underlying activity in the brain (Figure 5.2E). Waveform morphology was

characterized by a biphasic response with abnormally large amplitude. We have described this

response previously and showed that abnormally strong and widespread dipole activity underlie both

cortical peaks N(ci) and P(ci) (Jiwani, Papsin et al. Submitted). This atypical response reflects altered

cortical activity in the deprived pathways (Sharma, Dorman et al. 2002; Gordon, Tanaka et al. 2008)

and might index cortical immaturity (Wunderlich, Cone-Wesson et al. 2006; Gordon, Tanaka et al.

2011). In support, coordinated oscillations underlying this response in Figure 5.2 also indicated

abnormal cortical activity. Spectral power (Figures 5.2F) and phase-locking values (Figure 5.2G)

were desynchronized in the theta, beta and gamma frequencies. The reduced temporal coherence

observed from the deprived side could indicate a lack of familiarity or meaninglessness with the

presented stimulus, as such global decreases in neural synchrony are associated with perception of

meaninglessness (Rodriguez, George et al. 1999). Local desynchronization of neuronal assemblies

might also reflect global inhibition (Cooper, Croft et al. 2003; Ward 2003) and/or functional dis-

connectivity between brain regions during stimulus processing (Wilson, Rojas et al. 2007). Of interest,

reductions in gamma amplitudes (Casanova, Buxhoeveden et al. 2002; Casanova, Buxhoeveden et al.

2003; Wilson, Rojas et al. 2007; Khan, Gramfort et al. 2013) and global long-range phase-locking

connectivity patterns (Hughes 2007; Khan, Gramfort et al. 2013) similar to the oscillations observed

following stimulation of the naïve side (Figure 5.2), are consistent with that of other clinical

populations (Uhlhaas and Singer 2006), including autism (Hughes 2007; Wilson, Rojas et al. 2007;

Tessier and Broadie 2009; Khan, Gramfort et al. 2013). It is possible that abnormal structural and

functional changes (Kitzes, Kageyama et al. 1995; Mossop, Wilson et al. 2000; Moore and Kitzes 2004;

Moore and Kowalchuk 2004; Nordeen, Killackey et al. 2004; Vale, Juíz et al. 2004; Popescu and Polley

2010; Kral, Heid et al. 2013; Kral, Hubka et al. 2013) occurring in the naïve pathways as a result of

long periods of unilateral deprivation drove abnormal network connectivity in those pathways. This

would explain earlier findings of poorer speech perception outcomes on this side even after 8 to 12

months of hearing experience with the second CI (Jiwani, Papsin et al. Submitted).

Alternatively, this pattern of oscillations could reflect immaturity in the deprived pathways.

Synchronization of oscillatory activity undergo significant changes and refinement towards more

precise oscillations during adolescence (Uhlhaas, Roux et al. 2010) which are related to development

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of anatomical and physiological processes (Giedd, Blumenthal et al. 1999; Paus 2005; Uhlhaas, Roux

et al. 2009) as well as maturation of cognitive and perceptual functions (Varela, Lachaux et al. 2001;

Ward 2003; Uhlhaas, Roux et al. 2009; Blakemore 2012). Both local and long-range neural synchrony

in the theta-band (which are significantly reduced during childhood) increase until early adolescence

over fronto-central regions during auditory processing (Müller, Gruber et al. 2009), and in the beta and

gamma-bands over occipital (Werkle-Bergner, Shing et al. 2009) and parietal electrodes (Uhlhaas, Roux

et al. 2009) during visual processing. By contrast, this activity remains abnormally desynchronized in

earlier stages of immaturity of the preterm brain. A slowing of cortical oscillations (Doesburg, Ribary

et al. 2011; Doesburg, Chau et al. 2013; Doesburg, Moiseev et al. 2013) and weaker resting-state

network connectivity (Damaraju, Phillips et al. 2010) has been reported in children born under <32

weeks gestational age compared to children born at term. This indicates altered thalamo-cortical and

cortical dynamics in the preterm brain. The generally reduced oscillatory activity evoked by stimulation

of the naïve CI compared to the experienced ear (Figure 5.2) and normal hearing peers (Figure 5.3)

could thus be characteristic of earlier stages of cortical immaturity. This would explain the atypical

negative peaked cortical waveform similar to that shown in Figure 5.2E recorded from normal hearing

preterm babies under 35 weeks gestation (Wunderlich, Cone-Wesson et al. 2006) and children with

limited auditory input due to GJB-2 deafness (Gordon, Tanaka et al. 2011).

Cortical immaturity has been associated with oscillatory slowing (i.e., a shift in activity towards

slower frequencies) and in turn, poorer cognitive outcomes in preterm children (Doesburg, Moiseev

et al. 2013) and individuals suffering from Parkinson’s disease (Stoffers, Bosboom et al. 2007). In the

present study, global frequency desynchronization with increased long-range alpha synchrony

(Figures 5.2E-H and 3B) similarly indicates a widespread slowing of activity in the brain, perhaps

reflecting a general weakening for auditory processing in the deprived pathways. This is in agreement

with data from animal models of unilateral deafness (Popescu and Polley 2010; Kral, Heid et al. 2013;

Kral, Hubka et al. 2013) and studies of monocular deprivation in the visual system (Hubel and Wiesel

1970; Hubel, Wiesel et al. 1977; Le Vay, Wiesel et al. 1980; Blakemore 1988; Jeffrey, Wang et al. 2004;

Lewis and Maurer 2005). These studies indicate that lack of input competition between two pathways

drives functional changes in the balance of inhibitory-excitatory circuits (Vale, Juíz et al. 2004; Kotak,

Fujisawa et al. 2005; Takesian, Kotak et al. 2009; Sanes and Kotak 2011) which lead to weakened

activity in the deprived side (Popescu and Polley 2010; Kral, Heid et al. 2013). Significantly poorer

auditory performance (Gordon and Papsin 2009; Illg, Giourgas et al. 2013; Jiwani, Papsin et al.

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Submitted) and inconsistent use of the CI on this later implanted side (Fitzgerald, Green et al. 2013)

compared to the experienced ear may thus be attributed to deleterious and/or immature development

of auditory pathways in the deprived ear. Given that the capacity for auditory plasticity decreases with

age (Lohmann and Kessels 2014) and sensitive periods in development typically close when maturation

is reached (Blakemore 2012; Lohmann and Kessels 2014), promoting development from this long-

term deprived side during adolescence may thus be challenging.

5.6 Conclusion

Cortical synchronization of neural activity between brain regions is crucial for maintaining

organization of information in cortical circuits and underlies a variety cognitive/perceptual brain

functions. As shown in the present study, normal development of oscillatory activity in the brain

reflects maturation of cortical specialization in adolescents with normal hearing. However, the cortical

auditory network is altered in adolescents who have used a unilateral CI to hear for most of their lives.

Our findings indicate for the first time that driving maturation of the auditory cortex from only one

ear with a CI alters neural dynamics in the auditory brain. Increased cortical synchronization evoked

by stimulation of the experienced-right CI reflects abnormally increased cognitive processing to sound,

perhaps reflecting increased recruitment of attention resources for CI listening. At the same time, this

maturation leaves the opposite deprived pathways with aberrant globally desynchronized connectivity.

This allows the unstimulated pathways to become segregated from the cortical hearing network,

thereby highlighting the deleterious effects of long-term unilateral deprivation.

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5.7 Supplementary Information for Methods

5.7.1 Independent component analysis to reject cochlear implant artifact

Recording cortical evoked responses in cochlear implant (CI) users poses a particular problem

because the implant device itself produces a large electrical artifact that is recorded by scalp electrodes.

For the most part, this artifact is generated by the radio frequency transmission of the signal from the

processor to the receiver. It is large in amplitude, time-locked to the stimulus and will last for at least

the duration of the stimulus. The artifact thus interferes with the response and can completely obscure

the cortical waveform, in turn making any further analyses impossible. It is characterized by a biphasic

low-frequency pedestal of large amplitude which begins shortly after stimulus presentation and is

followed by a high frequency ringing (Gilley, Sharma et al. 2006). Devices which use monopolar

stimulation (i.e., CI24M, CI24R(CS), CI24RE(CA) and CI513) produce larger amplitude artifacts,

because the electric current from activated electrodes is spread over a larger distance to the return

ground electrode. This causes more distributed/dispersed electrical splattering/activity over the scalp,

compared to CIs that use bipolar stimulation, where each active electrode is paired with its own closely

situated ground electrode (Gilley, Sharma et al. 2006).

Several techniques have been proposed to suppress (Gilley, Sharma et al. 2006; Debener, Hine

et al. 2008; Wong and Gordon 2009; Friesen and Picton 2010; Viola, Thorne et al. 2011; Viola, De

Vos et al. 2012) or remove the electrical artifact from the CI response. One suggested method in single

channel recordings has been to place the reference electrode at a location on the scalp that would yield

the same artifact as the recording electrode, yet, be sufficiently far away from that electrode to ensure

that the recorded potential is neutral from the cortical evoked response (Gilley, Sharma et al. 2006).

This technique is based on the assumption that the CI artifact would be suppressed or cancelled out if

the artifact remains stable and if the reference electrode is placed at a location that would optimize the

differential recording and minimize its contribution to the recording. Another commonly used method

to remove the CI artifact is the subtraction technique. With this method, cortical responses are

recorded in different conditions or with different inter-stimulus intervals, and are then subtracted from

each other (Miller, Abbas et al. 2000; Friesen and Picton 2010). This method assumes that the artifact

remains the same in different recording conditions, even if the neural response is different (Friesen

and Picton 2010). The subtraction method would thus eliminate the artifact, and leave only the

difference waveform as a measure of the cortical response. However, this method requires that

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additional conditions and additional averages of the cortical response be recorded, as the subtraction

technique introduces residual noise in the difference waveform (Friesen and Picton 2010) and may

distort the evoked response when the nerve is in only a partially refractory state (Miller, Abbas et al.

2000).

Most recently, investigators have used an independent component analysis (ICA) method to

separate artifacts from the neural response (Debener, Hine et al. 2008; Castaneda-Villa, Manuel

Cornejo-Cruz et al. 2010; McMenamin, Shackman et al. 2010; Castañeda-Villa and James 2011; Viola,

Thorne et al. 2011; Viola, De Vos et al. 2012; Fatima, Quraan et al. 2013). Scalp-recorded EEG signals

are a collection of signals from mixed sources which reflect both cortical activity and non-cortical

sources. ICA transforms this data by applying spatial filters over the scalp, using statistical techniques,

which decomposes a multivariate/mixed signal into its individual statistically independent components

(Hyvärinen and Oja 1997; Lee, Girolami et al. 1999; Delorme and Makeig 2004; Naik and Kumar

2011). ICA separation is based on two primary assumptions: 1) the sources of signal and artifact are

independent from each other, even though the mixed signals are not, and 2) source activity has a non-

gaussian distribution (Delorme and Makeig 2004). For the CI artifacts, both of these conditions are

met (Gilley, Sharma et al. 2006). In this way, ICA decomposition is able to spatially filter and identify

independent components produced by distinct sources from those of the cortical evoked activity.

In the present study, 64-channel cortical evoked responses were decomposed into 64

independent components using the extended-runica Infomax ICA decomposition function in the

EEGLab Matlab toolbox (Delorme and Makeig 2004). Independent components were identified

visually, and those representing the CI artifact were removed from the epoched recordings.

Supplementary Figure 5.4A shows an example of the component properties for four independent

components representing the CI artifact, and other common EEG artifacts, such as eye blinks and

60Hz noise, and brain related activity reflecting the cortical evoked response. Topographic distribution

of potentials is shown on the left with the individual trials and averaged activity on the right for each

component. As shown in Supplementary Figure 5.4B, the CI artifact, which occurs between -80

and 40ms, dominates the cortical evoked waveform and completely obscured/contaminated the

underlying distribution of frequency oscillations, as measured by the amplitude and phase-locking

synchrony plots, making this analysis impossible. After the components with the CI artifact were

removed using ICA decomposition, the cortical response and underlying frequency oscillation activity

could be seen, as shown in Supplementary Figure 5.4C.

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5.7.2 Scalp current density to reduce spurious synchronization cause from

volume conduction

In EEG, since cortical evoked responses are recorded from surface sensors, far away from

their generators which are located deep within the scalp, the electric field becomes

distorted/distributed/smeared as it travels from current sources through tissues of varying

conductivities (i.e., brain, cerebral spinal fluid, skull bone and scalp) (van den Broek, Reinders et al.

1998). This imposes a problem of volume conduction, where the information recorded at two adjacent

electrode sites may reflect the integrated activity of shared neural populations (i.e., two electrodes

reflecting activity from the same neural sources/populations) (Lachaux, Rodriguez et al. 1999). This

is particularly exacerbated if the two electrodes are located at less than 3-4 cm from each other (Nunez,

Srinivasan et al. 1997). In turn, this creates spurious activity which can be ‘falsely’ misinterpreted as

synchronously oscillating activity. To reduce such effects of spurious synchronization (caused from

volume conduction) and estimate more accurately the true synchrony in the response, scalp current

density (SCD) was calculated, using a MATLAB script which implements a spherical spline operator

Supplementary Figure 5-4: Independent component analysis to remove contamination of CI artefact

on the cortical response.

A. Independent components representing the CI artifact, eye blinks, 60Hz electrical noise and the

cortical evoked response are shown. The scalp morphology of each component is shown by head

plots on the left. The voltage potential of the components in each trial and averaged across trials is

shown to the right of each head. B. 64-channel cortical evoked response is shown on the left with

corresponding amplitude (top) and phase-locking value (bottom) analyses of synchronization for

frequencies from 4 to 60Hz as a function of latency. The CI artefact dominates cortical activity in B.

as shown by the large red spot, rendering further cortical analyses impossible. C. Removal of CI

artifact contamination from the response using independent component analyses allows analyses of

cortical activity to be performed. The peaks of the cortical response in the left panel are clear and

dynamics in synchrony can be seen (red = increased synchrony, blue = decreased synchrony, green =

baseline)

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algorithm (Perrin, Pernier et al. 1989). This is a reference-free measure of potential distribution over

the scalp, which reduces the overlap of current recorded from surface sensor electrodes. This method

has previously been used for similar analyses (Doesburg, Kitajo et al. 2005; Doesburg, Emberson et

al. 2008; Doesburg, Roggeveen et al. 2008). The scalp-distribution information that SCD yields is

independent of the location of the reference electrode used during EEG recordings, represents more

concentric current activity, and emphasizes dipoles with shallower generators (Pernier et al., 1988). In

addition, long-range neural synchrony was analyzed for 19 pairs of electrodes which were distributed

uniformly across the scalp (i.e., Fp1, Fp2, F7, F3, Fz, F4, F8, T7, C3, Cz, C4, T8, P7, P3, Pz, P4, P8,

O1, O2) and separated by ≥ 4cm, which further reduces the effects of volume conduction.

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6. Chapter Six – General discussion

The aim of restoring auditory sensation through cochlear implants (CIs) is to drive

development of the auditory system, promote acquisition of receptive and expressive spoken language,

encourage integration of children who are deaf into mainstream educational, occupational and social

settings, and increase quality of life and emotional well-being. To achieve these goals, CIs have been

provided to children in early development to limit deafness-induced reorganization of the auditory

brain. They have also been increasingly provided in both ears with the intent to establish binaural

hearing and reduce the risks of auditory deprivation in the un-implanted ear. This is particularly

important for children, because they typically learn and play/interact in groups where they need to

attend to several sources, and are often in environments where noise, reverberation and distance pose

particular challenges for hearing and listening. Unfortunately, in the earlier days of cochlear

implantation, these devices were provided to children in only one ear. While this promoted

development of auditory pathways from the hearing ear, unilateral implant stimulation left the opposite

and deprived pathways unprotected from effects of deafness. At the time, the reasons for providing

children with only one implant (outlined in section 2.11) were all justified and reasonable.

However, the work from Bess, Tharpe and colleagues uncovered many difficulties that these

children were experiencing with hearing from only one side. Unilateral hearing in children has been

associated with language delays, educational/learning difficulties and lower intelligent quotient scores

(Bess and Tharpe 1984; Bess and Tharpe 1986; Culbertson and Gilbert 1986; Bess, Dodd-Murphy et

al. 1998). They also have greater challenges forming social relationships and integrating in peer groups.

Children with unilateral hearing also tend to have more withdrawn behaviours and generally poorer

emotional health compared to their bilaterally hearing peers (Culbertson and Gilbert 1986). In addition

to these difficulties, the atypical auditory input delivered by a unilateral CI in children who are

bilaterally deaf might further alter development of the auditory system over the long-term (Eggermont

and Ponton 2003). In turn, this would impose further difficulties for children and adolescents to hear

in mainstream listening environments, may affect their ability to make friends and secure employment,

and might have negative consequences for their overall psychosocial development (Hyde and Punch

2011; Hyde, Punch et al. 2011; Punch and Hyde 2011; Punch and Hyde 2011).

In the present Thesis we aimed to address concerns regarding auditory cortical maturation over

the long-term in unilateral CI users (Chapters Three, Four and Five). We also wondered about the

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plastic effects of long-term unilateral hearing on the opposite pathways (Chapters Four and Five). Has

long-term unilateral cochlear implantation promoted development/maturation in the stimulated

auditory pathways? If so, has this occurred at the expense of pathways from the opposite side? The

auditory pathways ascending from both ears are not completely independent from each other (Gordon

et al. In Preparation; Jiwani et al., 2010 Abstract) and recent findings suggested that a sensitive period

of 1.5 years exists for binaural input in the auditory system (Gordon, Wong et al. 2013). Keeping this

in mind, we also wanted to explore whether hearing could be established to the opposite deprived

pathways with a second CI after this sensitive period had been missed and the auditory cortex reached

maturation with unilateral CI stimulation. To answer these general questions, in the present Thesis,

we asked 5 specific questions:

1) Does the cortical evoked potential response follows a normal trajectory with time-in-sound

over long-term unilateral CI use when the duration of bilateral auditory deprivation in

childhood is limited?

2) How does missing an early sensitive period for bilateral input (i.e., brainstem) and driving

cortical maturation from one ear compromise the normal development of the auditory cortex

in adolescents who have used a unilateral CI to hear for most of their lives?

3) What are the effects of long-term unilateral deprivation on pathways from the opposite ear?

4) How is the cortical network underlying auditory processing organized in adolescents who

were congenitally deaf in both ears and used a unilateral CI to hear for most of their lives?

5) Has long-term unilateral deprivation caused segregation of the unstimulated pathways from

the auditory network?

Our specific hypotheses for each question were: 1) auditory development in children using

unilateral CIs will follow a normal trajectory with long-term auditory input when the duration of

bilateral deafness in childhood is limited; 2) areas of the brain which normally respond to sound will

be activated by auditory input in children who grow up using one CI; by contrast, 3) activity from the

deprived ear will abnormally recruit more diffuse cortical activity in the brain; 4) long durations of

unilateral CI use will promote co-ordinated cortical activity (neural networks) between brain areas that

are normally activated by sound, but 5) the deprived pathways will be segregated from this network.

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6.1 Normal maturation of the auditory system requires hearing in both ears to

be normal

As described in Chapter Two, normal hearing requires that all elements of the auditory

pathways have intact structure and function from early in life. Essential developmental steps in the

auditory system occur in utero (Pujol, Lavigne-rebillard et al. 1991; Graven and Browne 2008) and

during the first months to years after birth (Pujol and Hilding 1973; Pujol, Lavigne-rebillard et al. 1991;

Moore and Guan 2001; Eggermont and Moore 2012). However, activity-dependent maturational

changes in the auditory system continue well into adolescence (Albrecht, Suchodoletz et al. 2000;

Wunderlich and Cone-Wesson 2006; Wunderlich, Cone-Wesson et al. 2006). Importantly, distinct

developmental time-courses exist for different generators in the auditory system (Albrecht,

Suchodoletz et al. 2000). While maturation of the auditory brainstem pathways is mostly complete by

2 years of age, cortical maturation continues until approximately 20 years. Deep cortical layers and

association auditory regions mature first, but activity in superficial layers of the auditory cortex only

start to become adult-like after 9 years of age (Albrecht, Suchodoletz et al. 2000; Ponton, Eggermont

et al. 2000; Moore and Guan 2001; Ponton, Eggermont et al. 2002). Investigators have suggested that

while deeper cortical layers may mature in the absence of auditory input, maturation of superficial

layers require sound stimulation during critical periods in development (Eggermont and Ponton 2003).

Normal patterns of maturation and refinement in the auditory cortex are underlied by

development of excitatory and inhibitory synaptic transmissions, which are mediated by activity-

dependent mechanisms. Excitatory receptor cells promotes maturation of synaptic strength and

precise synaptic connections, while inbitory glycinergic transmissions allow specific synaptic

projections to become refined in many neuronal systems (Sanes and Takács 1993; Kotak and Sanes

1996). These mechanisms subserve the development of dentritic arbors (Cline 2001), axonal

myelination and support synaptogenesis (Huttenlocher and Dabholkar 1997; Cline 2001) – all of which

promote plastic changes in the brain during sensitive periods in development to fine tune the auditory

system, allow life-long learning and adaptation to the environment (Rauschecker 1999; Abbott and

Nelson 2000; Song, Miller et al. 2000; Eggermont 2008).

We tracked the development of the cortical response over time in normal hearing children and

adolescents in Chapter Three. As shown in Figure 3.2, the cortical waveform recorded from the

immature auditory system of children who were younger than 10 years of age was dominated by a large

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positive amplitude peak. As auditory cortical pathways matured into adolescence, this response

developed into an adult-polyphasic waveform with peaks P1, N1 and P2, characteristic of a mature

auditory cortex. These findings were consistent with reports from other groups showing a similar

trajectory of auditory development in normal hearing individuals from childhood to adulthood

(Ponton, Don et al. 1996; Ponton, Eggermont et al. 2000; Ponton and Eggermont 2001; Ponton,

Eggermont et al. 2002; Wunderlich and Cone-Wesson 2006; Wunderlich, Cone-Wesson et al. 2006).

Presence of these cortical peaks reveals much about the development of underlying cortical

structure and function. The auditory cortex is known to receive excitatory afferent projections from

both the thalamus into deep and middle layers and input from other auditory cortical regions into

superficial layers II (Kral and Eggermont 2007). Cortical evoked response peaks recorded from

cephalic electrodes on the head reflect changes in extra-cellular potentials (i.e., the voltage charge

outside of the pyramidal cell membrane) in superficial cortical layers of the brain. Positive peaks

indicate that the extra-cellular voltage in superficial layers II is more positive. This occurs when

pyramidal cells in deep or middle cortical layers are activated by excitatory inputs. This causes the

dendritic membrane to depolarize (i.e., intracellular voltage becomes less negative than its resting

potential as an influx of Na+ flows into the dendrite via ion channels in the post-synaptic membrane)

and the extracellular current in these layers to become more negative in order to balance the current

change across the membrane. However, to balance the intracellular potential change from the

depolarized membrane in middle cortical layers, a return current flow at the other end of the dendrite

in superficial layers causes the charge in this intracellular space to become more negative and

subsequently the extracellular charge close to the scalp, more positive. This is recorded by scalp-

surface electrodes as a positive deflection (i.e., P1, P2, P(ci)) in the cortical response (Eggermont 2007;

Eggermont 2008). On the other hand, negative deflections such as N1 and presumably N(ci), reflect the

negative extra-cellular post-synaptic potential in superficial layers which results from depolarization of

dendritic cells when they are activated by excitatory cortico-cortical input (Eggermont 2007;

Eggermont 2008).

Late emergence of peak N1 suggests that axon neurofilaments in superficial cortical layers only

mature after ~9 years of age, at which time their conduction velocity and ability to synchronize

increases (Moore and Guan 2001). Of interest, development of this response coincides with

improvement in many complex and sophisticated auditory processing skills during adolescence such

as understanding degraded and masked speech and perceiving speech in the presence of noise

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(Eggermont and Ponton 2003). Investigators have suggested that N1 may “reflect the conscious

detection of any discrete change in any subjective dimension of the auditory environment” (p. 281,

Hyde 1997) and may in addition reflect attention switching (Näätänen and Picton, 1987). Normal

maturation of this response might similarly represent hemispheric specialization in the cortex. Indeed,

a relative specialization of the left auditory cortex for processing rapidly changing sounds such as

speech, and of the right auditory regions for processing slower input such as tones and melodies exists

in the brain (Penhune, Zatorre et al. 1996; Zatorre and Belin 2001; Zatorre, Belin et al. 2002;

Schönwiesner, Rübsamen et al. 2005; Jamison, Watkins et al. 2006; Schönwiesner, Krumbholz et al.

2007). This cortical specialization is underlied by structural differences between the two hemispheres

(Penhune, Zatorre et al. 1996; Zatorre, Belin et al. 2002), which develop with auditory experience

(Penhune, Zatorre et al. 1996) and normal maturational changes that occur during adolescence (Moore

and Linthicum 2007; Kadis, Pang et al. 2011).

In Chapters Four and Five we investigated the activity underlying the mature cortical response

to map the areas of the brain that respond to sound and the cortical hearing network that is evoked by

a 500Hz tone-burst stimulus in normal hearing adolescents. This specific frequency was chosen to

mimic the stimulus that was delivered to users of CIs, as their responses were compared to that of the

normal hearing group. Localization of auditory activity measured in Chapter Four and neural

synchrony analyses in Chapter Five suggests that specialization of the cortical hemispheres emerged

with maturation of the cortical response in our cohort of normal hearing adolescents. As shown in

Figures 4.1, 4.5A, 4.5B and 4.5E dipole activity in response to a 500Hz tone was stronger in the right

than left auditory cortex for stimulation of both ears. This lateralization was particularly stronger for

stimulation of the left ear. Analyses of aural preference in Figure 4.3 confirm these results, further

indicating that the right auditory cortex preferentially responds to left ear stimulation. Of interest,

neural synchrony analyses in Figure 5.1 of Chapter Five also revealed differences in neural oscillations

when the right and left ears were stimulated separately. Increased coupling of theta and gamma-band

activity in the right hemisphere evoked by stimulation of the left ear compared to the right indicate

increased processing of cortical input and active feature binding analyses across long-range distance in

the brain between frontal, temporal and parietal regions. This suggests that in response to a tone-

burst, network connectivity in the cortex from the left ear is increased relative to the right ear. These

results are consistent with findings from other groups who similarly showed stronger auditory activity

in the right brain, with a greater degree of lateralization for left than right ear stimulation in response

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to tones and white noise in normal hearing adults (Hine and Debener 2007). The present results

indicate that both the left and right auditory cortices are involved in processing spectral simuli, but

that the right hemisphere seems to serve a particularly important role for pitch processing in normal

hearing individuals.

This asymmetry likely emerged in maturation, as younger children with normal hearing who

had not yet developed mature cortical responses showed a more symmetrical contralateral lateralization

for stimulation of each ear in response to the same tone-burst stimulus (Gordon, Wong et al. 2013).

Lateralization of auditory activity in the brain is in line with the anatomy of ascending projections in

the auditory pathways. In the immature brain, the contralateral pathways have the more direct route

to the cortex because they contain fewer synapses and a greater number of afferent fibers compared

to the ipsilateral pathways (Glendenning, Brusno‐Bechtold et al. 1981; Nordeen, Killackey et al. 1983;

Ponton, Vasama et al. 2001). As the brain matures, structural asymmetries in white matter volume and

cellular organization of the left and right auditory cortex develop. The volume of white matter in the

left Heschl’s Gyrus and left Posterior Temporal lobe is larger compared to the right. Grey matter

volume between both hemispheres is similar, however. Pyramidal cells in layer III of the primary

auditory cortex are also larger on the left side and occur with wider and more widely spaced cell

columns. These cell columns receive thalamo-cortical input from a larger number of afferent fibers

that are heavily myelinated and have heavily branched axons relative to the complementary structure

in the right hemisphere (Penhune, Zatorre et al. 1996; Zatorre, Belin et al. 2002). These

interhemispheric structural differences refine connections in the brain and allow them to serve a

supportive role for specialized auditory processing of complex information contained in speech and

music. The larger number of heavily myelinated cells in the left hemisphere with thicker axonal

branching facilitates transmission and encoding of rapidly changing temporal events, such as speech

sounds (Penhune, Zatorre et al. 1996; Zatorre, Belin et al. 2002). The relatively smaller and slower cell

structure in the right cortex on the other hand seems to be more sensitive to tonal patterns and is

optimal for processing spectral content, such as music and melodies. Unfortunately, only a tone-burst

stimulus was used in ours and many other studies (Zatorre and Belin 2001; Langers, van Dijk et al.

2005; Schönwiesner, Rübsamen et al. 2005; Hine and Debener 2007; Schönwiesner, Krumbholz et al.

2007) investigating differences in cortical lateralization in the normal hearing adolescent/adult brain.

We suggest that future studies should investigate whether using 1) a fast broadband click stimulus and

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2) a speech stimulus, might affect the direction of hemispheric lateralization after cortical maturation

is reached.

Specialization of the cortex allows for a division of labor between the two hemispheres which

becomes optimized with experience (Gotts, Jo et al. 2013). This allows the brain to reduce

redundancies, avoid competition, increase neural capacity and process input more efficiently and more

effectively (Rogers 2000; Toga and Thompson 2003; Dharmaretnam and Rogers 2005; Vallortigara

2006; MacNeilage, Rogers et al. 2009; Gotts, Jo et al. 2013). The degree of lateralization of brain

structure and function has been associated with improved cognitive abilities and functional task

performance (Abrams, Nicol et al. 2006; Gotts, Jo et al. 2013). Of interest, maturation of the pre-

frontal cortex, which is involved with complex cognitive and perceptual functions related to learning,

attention processing, decision making, problem solving, mentalizing, memory consolidation, etc… also

occurs around this time (Anderson, Anderson et al. 2001; Johnson 2001; Moriguchi, Ohnishi et al.

2007; Johnson 2011; Blakemore 2012). This likely contributes to the improvements in cognitive

behaviours and perceptual functions which are underpinned by brain maturation. Mechanisms of

plasticity decrease with increase age (Lohmann and Kessels 2014). Investigators have suggested that

once maturation is reached, the threshold for plasticity decreases, perhaps to protect the mature brain

from large-scale reorganization and allow fine-tuning of cortical connections (Lenroot and Giedd 2006;

Blakemore 2012; Lohmann and Kessels 2014). Adolescence thus highlights an important time in

development, which is characterized by much refinement and specialization in the cortex and could

mark the closing of an important period in brain plasticity.

6.2 Unilateral implant stimulation promotes cortical maturation but leaves the

brain with abnormal organization

Adolescents who were deaf in both ears from early life and used a CI to hear for over a decade

developed a similar cortical response to that of normal peers with polyphasic peaks P1, N1, P2 as shown

in Figures 3.2 and 3.3, characteristic of a mature auditory cortex. The cortical response has been

shown to decrease rapidly at initial stages of development in children who received a CI within limited

periods of bilateral deafness and reached age-appropriate peak latency and amplitude over 3 to 6

months of implant use (Sharma, Dorman et al. 2002). After this initial period, these responses changed

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at a rate that is similar to normal (Eggermont, Ponton et al. 1997; Eggermont and Ponton 2003).

Eggermont and Ponton indicated that the latency of the cortical response was delayed in CI users

relative to age-matched normal hearing responses by an amount of time that was equivalent to the

period of deafness (Ponton and Eggermont 2001). This suggests that the duration of exposure to

sound (referred to as time-in-sound and calculated as chronological age – duration of bilateral deafness)

rather than chronological age, influences the rate of cortical maturation in children. These investigators

raised concerns that bilateral deprivation prior to cochlear implantation might alter the maturation of

thalamo-cortical and cortico-cortical loops in superficial layers, which develop around 9 to 12 years of

age and underlie the emergence of peak N1 in the cortical response. These pathways mediate the

transfer of primary auditory and multi-sensory input from the thalamus to various regions of the

ipsilateral and contralateral auditory cortices (Winer, Diehl et al. 2001; Winer, Miller et al. 2005; Razak,

Zumsteg et al. 2009), and the transmission of information from the auditory cortex to primary and

secondary sensory areas in both hemispheres (Read, Winer et al. 2002; Lee and Winer 2005; Klinge,

Eippert et al. 2010). Altered development of these pathways would hinder auditory processing and

may result in further struggles during listening for CI users.

The data from Chapter Three indicates that the developmental trajectory of the electrically

evoked cortical waveform (Figures 3.2 and 3.3) is similar between CI users and normal hearing

individual. Appropriate development of mature normal-like peaks P1, N1 and P2 in adolescents who

had over 10 years of time-in-sound experience suggests that long-term CI stimulation establishes

appropriate 1) relay of auditory input from the ear to the cortex, via the thalamus; 2) communication

between the two cortical hemispheres; and/or 3) connectivity between different sensory areas. The

data in Figure 3.4 suggests that this development is experience-dependent, with the cortical response

becoming more normal-like with time-in-sound experience. However, as shown in Figures 3.3 and

3.5, the waveform has at least one abnormality; the amplitude of peak P2 in CI users is larger than in

normal hearing peers. These results are consistent with previous studies indicating larger peak P2

amplitudes in a group of adults who were fitted with unilateral hearing aids (Bertoli, Probst et al. 2011)

and others who had a bilateral mild to moderate sensorineural hearing loss (Campbell and Sharma

2013), suggesting that hearing loss alters activity in the brain. Enhancements in the P2 amplitude,

particularly in the left hemisphere, have also been reported in normal hearing adults following focused

auditory training tasks (Tremblay and Kraus 2002; Tremblay 2007; Tremblay, Shahin et al. 2009) and

likely reflect increased listening effort and/or attention during listening. We suggest that the larger-

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than-normal amplitude of peak P2 from our cohort of CI users might represent re-allocation of cortical

resources or recruitment of additional cortical areas to process sounds to support hearing from only

one side to the atypical electrical input delivered by the CI and/or compensatory cortical plasticity

resulting from early onset deafness. The importance of this recent finding is that it suggests that

deviations from normal cortical processing remain in these young people despite long-term unilateral

implant use.

Cortical localization measures and neural synchrony analyses in Chapters Four and Five further

indicate that the activity underlying the cortical response is abnormally organized in experienced CI

users compared to normal hearing peers. As shown in Figures 4.4 and 4.5, stimulation of the right

CI after over a decade of experience indicated strong lateralization towards the contralateral left

auditory cortex. This is opposite to the right hemisphere bias that was observed from adolescents with

normal hearing, shown in Figures 4.2 and 4.5. Consistent with these findings, neural synchronization

analyses indicating greater-than-normal coordinated synchronization in the theta, beta and gamma

bands from areas of the left temporo-parietal regions to the frontal cortex in Figure 5.2, further

suggests altered organization of the auditory network compared to normal hearing peers. The strong

asymmetric bias observed in the left cortex for CI listening could indicate that cortical specialization

to non-speech stimuli has either not yet emerged and that contralateral afferent input still dominates

auditory activity in these adolescents, as it does in the immature auditory cortex of younger implanted

peers (Gordon, Wong et al. 2013). Alternatively, it could also mean that the brain has re-allocated

cortical resources to support processing in the hemisphere that is specialized for speech. The latter

suggestion is supported by excellent speech perception scores on the PBK open-set speech test

(Figure 4.7A) and the significant positive correlation of these scores with lateralization and greater

dipole strength in the left hemisphere compared to the right (Figure 4.7B).

Differences in hemispheric asymmetries between CI users and normal hearing listeners might

be explained by differences in stimulus feature properties of the acoustic signal (in normal hearing

peers) versus electric signal delivered by the implant device to the auditory system (Sandmann, Eichele

et al. 2009). CIs were designed to establish and promote speech perception. Most digital signal

processing strategies encode the coarse features of auditory signals only (Zeng, Rebscher et al. 2008).

Current devices extract the temporal envelope of sound at a given rate of stimulation and band-pass

filter its frequency contents into a set number of channels. The number of channels with the largest

amplitude envelope are then selected and allowed to stimulate the specific electrodes corresponding

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to the allocated frequency of the given filter (Rubinstein 2004; Zeng, Rebscher et al. 2008). In current

processing strategies this is usually limited to a maximum of ~8 channels (known as maxima),

regardless of the number of working electrodes (Henry and Turner 2003; Vaerenberg, Smits et al.

2014). The advantage of these envelope-based processing strategies is that they support high levels of

speech recognition in quiet. Unfortunately, they fare poorly in noise and with interfering speech

signals. In addition, acquisition and perception of tonal languages have proven to be particularly

challenging for CI listeners who use current digital processing strategies (Lee, Van Hasselt et al. 2002;

Wei, Cao et al. 2004; Xu and Zhou 2012). The same is true of music appreciation with an implant

(Drennan and Rubinstein 2008; Hopyan, Gordon et al. 2011; Hopyan, Peretz et al. 2012). It is

particularly difficult for CIs users to perceive pitch-related information (Rubinstein 2004; Drennan and

Rubinstein 2008), and perception of timbre and melody are impoverished (Hopyan, Gordon et al.

2011; Hopyan, Peretz et al. 2012). This is not surprising because electric stimulation with an implant

does not deliver fine structure and distorts detailed spectral information (i.e., CIs do not explicitly code

spectral information) that is normally used by the normal auditory system to recognize patterns of

tones (Xu and Zhou 2012) and extract complexities in music (Drennan and Rubinstein 2008).

Differences in hemispheric lateralization with right ear stimulation observed from normal hearing

adolescents and experienced CI users (Figure 4.5) might thus reflect differences in auditory experience

between the two groups. It is possible that absence of spectral and fine-structure auditory details with

CI stimulation over the long-term compromised mechanisms of cortical specialization in the right

hemisphere of the mature brain (which is known to be biased for spectral processing) and resulted in

an increased response bias in the left cortex. We are now investigating whether the same asymmetry

in the left cortex exists in adolescents who received an implant in their left ear as their first CI. Future

studies should work more closely with engineers and manufacturers of CIs to investigate whether

increasing the number of maxima and/or using higher stimulation rates to better represent fine-

structure information might normalize lateralization/specialization of auditory input with CI listening

while still preserving the gain in speech perception.

In addition to the reduced auditory cues delivered by the CI compared to normal hearing

listening, asymmetric strengthening of the contralateral pathways from the right-experienced ear could

be explained by increased excitability of postsynaptic currents in the stimulated ear and reduced

inhibition from the opposite ear, resulting from long-term unilateral deprivation (Sanes and Takács

1993; Vale, Juíz et al. 2004; Kotak, Fujisawa et al. 2005; Takesian, Kotak et al. 2009; Sanes and Kotak

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2011). Unilateral auditory deprivation disrupts the delicate balance of excitatory and inhibitory inputs

in the afferent auditory system (Kitzes 1984; Moore and Kowalchuk 1988; Moore 1990; Kil,

Hkageyama et al. 1995; Kitzes, Kageyama et al. 1995; Mossop, Wilson et al. 2000; Nordeen, Killackey

et al. 2004; Popescu and Polley 2010; Kral, Heid et al. 2013; Kral, Hubka et al. 2013) that would have

normally occurred with bilateral hearing (Grothe, Pecka et al. 2010). A loss of inhibitory activity from

the contralateral ear (i.e., the deprived ear) would allow input from the stimulated side to be projected

to the contralateral cortex without suppression. This would in turn allow the left auditory cortex to

dominate auditory input in adolescents with pre- or peri-lingual deafness who were implanted in the

right ear as babies. Neural synchrony analyses in Figure 5.2 showing increased coordinated theta and

gamma band activity in pathways from the experienced right ear to the left temporo-parietal areas and

frontal regions in both hemispheres compared to normal might reflect such increased excitability from

this ear to the cortex.

Enhanced activity from this ear could also mark plastic changes in the brain occurring as a

compensatory mechanism for the abnormal electrical input provided by the implant device and/or

stimulation of the auditory pathways from only one side. The larger-than-normal P2 amplitude

observed in Figures 3.3 and 3.5 and additional source activation in the frontal and precuneus regions

(Figure 4.6) with increased long-range neural synchrony in the gamma and theta frequencies of these

cortical regions (Figure 5.2C and 5.2D) coupled with a reduction in local alpha activity (Figure 5.2B)

compared to normal all indicate recruitment of additional cortical processes to facilitate listening with

a unilateral CI. The observed pattern of activity suggests that adolescents with long-term implant

experience rely on brain networks linked to attention (Picton and Hillyard 1974; Hocherman, Benson

et al. 1976; Rif, Hari et al. 1991; García-Larrea, Lukaszewicz et al. 1992; Posner and Dehaene 1994;

Pugh, Shaywitz et al. 1996; Grady, Van Meter et al. 1997; Benedict, Lockwood et al. 1998; Fujiwara,

Nagamine et al. 1998; Jäncke, Mirzazade et al. 1999; Fan, McCandliss et al. 2002; Fan, McCandliss et

al. 2005; Okamoto, Stracke et al. 2007; Tremblay, Shahin et al. 2009) and multi-sensory integration

(Hari 1990; García-Larrea, Lukaszewicz et al. 1992; Levänen, Jousmäki et al. 1998; Webster and Colrain

2000; Moller and Rollins 2002; Crowley and Colrain 2004; Johnson and Zatorre 2005) for CI listening

of a non-speech auditory input.

Individuals using CIs have already been shown to use multi-perceptual (Jeong Lee, Kang et al.

2005; Lee, Giraud et al. 2007; Pisoni, Conway et al. 2010; Pisoni, Kronenberger et al. 2011; Geers,

Pisoni et al. 2012; Kronenberger, Colson et al. 2014) and multi-sensory (Nishimura, Hashikawa et al.

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1999; Giraud, Price et al. 2001; Giraud, Price et al. 2001; Doucet, Bergeron et al. 2006; Giraud and Lee

2007; Hopyan-Misakyan, Gordon et al. 2009; Sandmann 2012; Sandmann, Dillier et al. 2012)

information more effectively than their peers with normal hearing to facilitate complex auditory

processing (Hopyan-Misakyan et al., 2009; Brenner & Geers, 2011). This is not surprising since

unilateral CI hearing only provide a crude representation of acoustic sounds and eliminates access to

binaural hearing. This in turn, makes listening and oral communication in general more difficult, more

tiring, more stressful, more unpleasant, and more effortful particularly in challenging listening

environments (Gordon, Jiwani et al. 2011; Gordon, Jiwani et al. 2013). Given that CIs do not restore

normal hearing and that bilateral and unilateral deafness drives changes in the normal organization of

the auditory system, it is reasonable that children who are deaf and have heard with a CI for most of

their lives would capitalize on intact senses and perceptual and cognitive strategies to supplement their

hearing.

Of note, imaging studies have shown increased recruitment of attentional cortical networks in

children who are deaf compared to normal hearing peers (Giraud, Price et al. 2001; Giraud, Price et al.

2001; Jeong Lee, Kang et al. 2005; Lee, Giraud et al. 2007). Consistent with our findings in Chapters

Four and Five, investigators have indicated that children who used their CIs successfully activated

cortical regions in the left posterior dorsolateral prefrontal gyrus which is involved with attention,

working memory, reasoning, and executive function (Jeong Lee, Kang et al. 2005; Lee, Giraud et al.

2007), and the right precuneous region which is involved with self-reflection, episodic memory,

visuospatial processing, and imageability (i.e., visual imagery) (Giraud, Price et al. 2001; Jeong Lee,

Kang et al. 2005). CI users might use these general cognitive strategies to form a visual representation

of the sound to aid sound recognition and comprehension (Giraud, Price et al. 2001). In addition,

activation of these cortical areas during listening might facilitate perceptual learning and speech

learning during rehabilitation (Jeong Lee, Kang et al. 2005; Alain, Snyder et al. 2007). In support,

Pisoni and colleagues suggested that successful CI users recruit increased attention demands and have

better memory capacity compared those children who are less successful with their implants (Pisoni,

Conway et al. 2010; Pisoni, Kronenberger et al. 2011; Kronenberger, Colson et al. 2014).

CI users also supplement their hearing with vision. Even normal hearing individuals use

multisensory input, notably vision, to support listening (Ross, Saint-Amour et al. 2007). However,

greater-than-normal cortical connectivity of theta and gamma oscillations in visual cortical areas in

experienced CI users shown in Figure 5.3 compared to normal hearing peers suggests a better ability

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of these adolescents to utilize visual cues to compensate for the imperfect implant signal. In a recent

study (data shown in Figure 2.10) we found that adolescents who received a unilateral CI within

limited durations of bilateral deafness and had ~8 years of hearing experience with this device depend

on visual cues more heavily than their peers with normal hearing to identify emotions carried in speech

(Hopyan-Misakyan, Gordon et al. 2009; Gordon, Jiwani et al. 2013). The increased reliance on vision

to process auditory input is consistent with functional neuroimaging studies, which find abnormally

increased activation of the visual cortex in users of CIs when listening to meaningful speech (Giraud,

Price et al. 2001; Lee, Giraud et al. 2007; Lee, Truy et al. 2007). This may reflect maladaptive

(Nishimura, Hashikawa et al. 1999; Doucet, Bergeron et al. 2006; Lee, Truy et al. 2007; Sandmann

2012; Sandmann, Dillier et al. 2012) or compensatory (Kral and Sharma 2012; Campbell and Sharma

2013; Sharma, Campbell et al. 2014) plasticity of the auditory and visual systems without normal

hearing

Increased dependence on attention and other cognitive mechanisms with greater reliance on

vision might mean better functional hearing, but unfortunately, it could also mean increased effort and

perhaps reduced efficiency for listening. We suggest that the reduced gamma-band activity in

frequencies over 35Hz observed in Figure 5.3 from the experienced-right side of CI users and not

normal hearing peers reflects a general slowing of cortical processing that is likely attributed to more

effortful listening. As described earlier in this section, adolescents with long-term unilateral CI

experience activated regions of the frontal and precuneus cortices with greater than normal dipole

activity, suggesting that they require greater-than-normal cognitive resources during listening.

Unfortunately, this activity has been associated with increased listening effort (Pichora-Fuller 2003;

Collette, Hogge et al. 2006; Pichora-Fuller and Singh 2006; Hughes and Galvin 2013; Pals, Sarampalis

et al. 2013). Findings of increased reaction times in Figure 2.10B and changes in pupil diameter

reflective of increased mental resources (Steel, Papsin et al. Submitted) observed from CI listeners

compared to normal hearing peers provide evidence to support this. It is not surprising that listening

to a distorted auditory signal delivered by a single CI would be more effortful for CI users. Of concern,

however, increased expenditure of mental processing for children and adolescents who use CIs to hear

may negatively affect learning and perhaps even social interactions, as well as cause frustration and

exhaustion when listening. On the other hand, it is also possible that this might lend a supportive role

for CI listening. At the moment, it is unclear whether increased reliance on attention and vision for

listening with perhaps increased effort helps or hinders auditory processing. However, if the cognitive

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load imposed on CI listening could be reduced, perhaps adolescents using CIs would be able to

respond to complex speech more quickly, fare better in challenging listening environments and better

keep up with their normal hearing peers in school, at work and in social situations.

In sum, the present data shows that while unilateral cochlear implantation promotes the

development of mature and normal-like activity in the auditory pathways over the long-term,

functional abnormalities persist. Long-term unilateral CI stimulation seems to drive a compensatory

plasticity of the auditory brain to re-allocate cortical resources across a larger functional network to

support hearing with the single implant. Auditory evoked activity in the contralateral left cortex (that

is normally specialized for speech) and occurring with increased oscillatory synchronization in cortical

areas linked to attention, general cognitive/perceptual processing and vision during listening could

reflect compensation for: 1) deleterious or irreversible changes to neural reorganization that occurred

during the period of auditory deprivation in early life, 2) abnormal representation of sound through

electrical pulses stimulation of the auditory system, and/or 3) absence of auditory input to the deprived

pathways from the opposite un-implanted ear.

6.3 Long-term unilateral deprivation drives abnormally altered and

disorganized activity in the unstimulated pathways

Many adolescents from this study who were implanted in their right ear as babies and have

already had over a decade of unilateral hearing experience, recently asked for a CI in their opposite

and deprived left ear in the hopes of deriving benefits of bilateral implantation. This provided us with

a unique opportunity to stimulate the deaf ear for the first time and study the effects of long-term

unilateral implant stimulation on the deprived pathways. We hypothesized that driving maturation of

the auditory cortex with over a decade of unilateral CI stimulation in the right ear would lead to

permanent abnormalities and reorganization of cortical activity in pathways from the deprived left ear.

Cortical responses were recorded from this second implanted left ear within a week of initial activation

on that side. Responses were measured at this early stage of activation to study cortical plasticity

associated with long-term unilateral deprivation before auditory input could be established in this ear

with CI stimulation.

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As shown in Chapters Four and Five, despite long durations of inactivity to the auditory

pathways prior to implantation, the deprived ear was able to respond to sounds delivered by a CI, as

evidenced by the ability to record a responses from the brainstem (Figure 4.1) and cortex (Figure

4.4G and 5.2E) at initial device activation. However, the latency of wave eV of the brainstem response

was abnormally delayed compared to the experienced side. The lack of significant auditory input in

early life may have compromised or arrested the development of activity-dependent neural tracts in

these brainstem pathways. In normal hearing individuals, such activity-dependent development in

early life has been associated with the formation of more efficient synaptic transmission at gap

junctions, increased neural synchronization of spiral ganglion cells in response to auditory stimuli and

faster neural conduction in the auditory pathways from increased myelination of axonal tracts (Moore

and Goldberg 1963; Huttenlocher 1967; Huttenlocher 1970; Huttenlocher and Dabholkar 1997;

Moore and Guan 2001; Moore 2002; Moore and Linthicum 2007). It has also been shown that

spontaneous activity in the developing auditory system is required for neuronal survival, formation of

appropriate connectivity in the auditory pathways, and fine-tuning of tonotopic maps (Tritsch, Yi et

al. 2007). All of these mechanisms are reduced and/or hindered by bilateral deafness in early life prior

to cochlear implantation and may further be exacerbated by unilateral deprivation thereafter. In

support, the cortical response recorded from the naïve side also had an atypical waveform morphology

compared to the opposite experienced ear and both the right and left ears of age-matched normal

hearing peers. This indicated further disruptions/disorganization of activity in the unilaterally deprived

auditory pathways. The cortical waveform was characterized by a biphasic response of abnormally

large peak-to-peak amplitude (labelled N(ci)-P(ci)) and dominated by the negative peak, N(ci).

A similar cortical response has been observed from normal hearing pre-term infants younger

than 35 weeks gestational age (Weitzman and Graziani 1968; Wunderlich and Cone-Wesson 2006;

Wunderlich, Cone-Wesson et al. 2006) and was described as being characteristic of earlier stages of

cortical immaturity in the auditory pathways. This response type has also been recorded from

congenitally deaf children who were implanted after 7 years of age following long durations of bilateral

deafness (Sharma, Dorman et al. 2002; Jiwani, Tanaka et al. In Preparation) and in CI users who have

difficulty recognizing spoken language (Gordon, Tanaka et al. 2008). This abnormal response suggests

that a difference in cortical processing might exist in children who have difficulty recognizing spoken

language (Gordon, Tanaka et al. 2005; Gordon, Tanaka et al. 2008) compared to early implanted

children who have good auditory functions. Consistent with findings from congenitally deaf white

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cats (Klinke, Kral et al. 1999; Kral, Hartmann et al. 2002), at initial CI activation, 49% of children with

bilateral deafness also produced a similar cortical response (Gordon, Tanaka et al. 2011). Of those,

79% were children with deafness related to bilallelic mutations on the GJB-2 gene (Gordon, Tanaka

et al. 2011). GJB-2 associated deafness results from a deficit in encoding the connexin 26 protein

which is necessary for cells to communicate with each other (Propst, Papsin et al. 2006). Such a deficit

would result in limited spontaneous activity in the auditory system and limited access to sound both in

utero and at birth prior to implantation (Propst, Papsin et al. 2006; Gordon, Tanaka et al. 2011). Thus,

the negative peaked cortical response type observed from the naïve pathways after initial stimulation

of this side might represent: 1) cortical immaturity of the auditory pathways, 2) restricted auditory

stimulation and disorganized activity in the pathways, 3) poor functional hearing outcomes.

We questioned whether this large negative peaked response might be homologous to the

negative peak N1 that emerges with maturation in normal hearing adults (Ponton, Eggermont et al.

2000) and adolescents with long-term CI experience (Jiwani, Papsin et al. 2013), since both of these

peaks have similar latencies. Of interest however, we noted several differences: 1) the amplitude of

peak N(ci) (Figure 4.4 and 5.2) is significantly larger than N1 (Figure 4.2 and 5.1); 2) dipoles underlying

peak N(ci) (Figure 4.4 and 4.6) are significantly larger than N1 (Figure 4.2); 3) they are also much more

widespread across the cortex (Figure 4.4 and 4.6), whereas this activity is more focused in the mature

response (Figure 4.2); 4) cortical lateralization is symmetrical between both hemispheres for peak N(ci)

(Figure 4.4 and 4.5). However, this activity shows asymmetric hemispheric lateralization for N1

(Figure 4.2 and 4.5), perhaps reflecting cortical specialization; 5) neural oscillations in the theta and

gamma frequencies are de-synchronized for the negative peaked waveform (Figure 5.2 and 5.3). On

the other hand this activity is increased for the mature cortical response (Figure 5.1 and 5.3); 6) the

latency and amplitude of peak N(ci) is not affected by changes in stimulus frequency, but both of these

peak properties change significantly with changes in frequency for N1, perhaps reflecting tonotopicity

in the auditory cortex (Gordon, Tanaka et al. 2008); 7) the negative peaked response N(ci) tends to be

associated with poor functional outcomes as shown in Figure 4.7 and in Gordon et al., 2005, 2008.

By contrast however, emergence of peak N1 tends to coincide with the development of complex

auditory perceptual skills such as hearing in noise and hearing degraded speech – these skills begin to

develop during adolescence (Ponton et al., 2000). In support, both normal hearing individuals and CI

users with long-term hearing experience who have developed a mature cortical response (with peak

N1) performed well on simple and complex listening tasks (average PBK speech score = 73.5 ± 3.2%

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on the experienced CI side). However, these skills were significantly impaired in the newly implanted

ear, as shown in Figure 4.7 (simple open-set speech discrimination task had very poor performance

with only 26.8 ± 5.7% accuracy). Of interest, the amplitude of peak N(ci) has been correlated with poor

speech perception outcomes (Gordon, Tanaka et al. 2008). This negative-peaked response type might

thus represent an electrophysiological marker of immaturity in the auditory pathways and suggests that

different cortical trajectories and different cortical activity underlie peaks N(ci) and N1.

Nonetheless, it is possible that neural generators are still shared between the two responses.

As described in Section 5.1, a cortical peak with a negative deflection that is recorded from a midline-

cephalic location and referenced to the earlobe reflects activation in superficial layers of the cortex. N1

is believed to be generated by cortico-cortical input in these superficial layers and reflects maturation

of axon neurofilaments in layer II (Ponton, Eggermont et al. 2000; Moore and Guan 2001; Moore and

Linthicum 2007; Eggermont 2008). This developmental process only occurs around 9 to 12 years of

age (Ponton, Eggermont et al. 2000; Moore and Linthicum 2007) and is activity-dependent (Jiwani,

Papsin et al. 2013). In the same way, it is possible that the large peak N(ci) also reflects superficial

cortical activity. However, since this response type has been observed in pre-term normal hearing

babies (Weitzman and Graziani 1968; Wunderlich and Cone-Wesson 2006; Wunderlich, Cone-Wesson

et al. 2006) and at early device activation in implanted peers with little access to sound prior to

implantation due to GJB-2 deafness (Propst, Papsin et al. 2006; Gordon, Tanaka et al. 2011) who were

all younger than 9 years of age, N(ci) cannot reflect mature superficial layer axons. Rather, it is possible

that this response reflects immaturity of these axons in these cortical layers.

The large amplitude (Figures 4.4 and 5.2) and dipoles (Figure 4.4 and 4.6) underlying this

response may be a result of delayed or arrested mechanisms of synaptogenesis in the auditory cortex.

Indeed, early formation of synaptic contacts and age-dependent elimination of synapses have been

suggested to be an activity-dependent mechanism (Huttenlocher and Dabholkar 1997). Without

auditory input in the deprived pathways, it is possible that the areas that generate peak N(ci) have not

yet undergone synaptic pruning. In support, Ponton and colleagues similarly suggested that in the

normal hearing system, the fact that the amplitude of early developing peak P2 does not change with

maturation might indicate that its generators do not undergo synaptic pruning (Ponton, Eggermont et

al. 2000). If the same holds true for peak N(ci), the lack of cortical development in its generators would

be in contrast to the synaptic development that normally occurs in the maturing auditory cortex for

peak N1 (Huttenlocher and Dabholkar 1997), and rather more similar to the findings of delayed

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synaptogenesis reported from cats with congenital bilateral deafness (Huttenlocher and Dabholkar

1997; Kral and O'Donoghue 2010; Kral and Sharma 2012).

Since the process of synapse elimination in the auditory cortex is normally complete by

adolescence (Huttenlocher and Dabholkar 1997), we are concerned that leaving the auditory pathways

unilaterally deprived beyond this important developmental period may lead to permanent

abnormalities. “In the visual cortex, unilateral deprivation of formed visual input during the period of

synapse elimination resulted in asymmetric synaptic input from the two eyes (Hubel et al., 1977;

Goodman and Shatz, 1993), and in permanent visual deficits (VonNoorden and Crawford, 1979; Assaf,

1982)” (p. 177, Huttenlocher and Dabholkar 1997). If long-term unilateral auditory deprivation drives

parallel changes in the auditory system, auditory development in the newly implanted side may be

challenging to promote. Of concern, unilateral auditory deprivation in the developing auditory system

has been associated with many subcortical and cortical structural and functional changes. Specifically,

long-term absence of hearing from one side alters the normal balance of excitatory-inhibitory activity

in the ascending auditory system (Vale, Juíz et al. 2004; Kotak, Fujisawa et al. 2005; Takesian, Kotak

et al. 2009) and results in suppressed input strength in the deprived pathways from brainstem (Moore

and Kowalchuk 1988; Kil, Hkageyama et al. 1995; Kitzes, Kageyama et al. 1995; Nordeen, Killackey

et al. 2004; Popescu and Polley 2010) to cortex (Popescu and Polley 2010; Kral, Heid et al. 2013; Kral,

Hubka et al. 2013). These abnormal changes persist even after hearing is restored to this side with a

CI (Gordon, Wong et al. 2013; Kral, Heid et al. 2013; Kral, Hubka et al. 2013). By contrast, this activity

becomes abnormally enhanced in pathways from the hearing side (Popescu and Polley 2010; Gordon,

Wong et al. 2013; Kral, Heid et al. 2013; Kral, Hubka et al. 2013).

Unfortunately, developmentally imbalanced auditory input between the two ears places the

deprived side at a disadvantage in competition for cortical resources compared to the hearing ear (Kral,

Heid et al. 2013) and leads to long-lasting and often irreversible perceptual deficits (Popescu and Polley

2010). Cortical consequences of unilateral deprivation was first shown in the visual system (Hubel and

Wiesel 1970; Blakemore and Van Sluyters 1974; Hubel, Wiesel et al. 1977; Cynader, Timney et al. 1980;

Le Vay, Wiesel et al. 1980; Cynader, Leporé et al. 1981; Cynader 1983; Blakemore 1988; Woodruff,

Hiscox et al. 1994; Holmes, Kraker et al. 2003; Williams, Northstone et al. 2003; Jeffrey, Wang et al.

2004) and later confirmed in the auditory system (Brookhouser, Worthington et al. 1991; Gordon,

Valero et al. 2008; Hine, Thornton et al. 2008; Gordon and Papsin 2009; Graham, Vickers et al. 2009;

Salloum, Valero et al. 2010; Chadha, Papsin et al. 2011; Gordon, Jiwani et al. 2011; Graham and Vickers

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2011; Fitzgerald, Green et al. 2013; Gordon, Jiwani et al. 2013; Gordon, Wong et al. 2013; Hughes and

Galvin 2013; Illg, Giourgas et al. 2013; Kral, Heid et al. 2013; Kral, Hubka et al. 2013). In the visual

system, monocular deprivation resulted in permanently deficient visual acuity in the deprived eye,

impaired contrast sensitivity, reduced sensitivity to motion detection and deficient stereoscopic vision

(Hubel and Wiesel 1970; Hubel, Wiesel et al. 1977; Cynader, Timney et al. 1980; Le Vay, Wiesel et al.

1980; Cynader, Leporé et al. 1981; Cynader 1983; Blakemore 1988). These abnormalities persisted

even after years of treatment and re-training therapy of the poor eye. The same is true of the impaired

ear in children who have recurrent or long-lasting childhood conductive hearing losses (Popescu and

Polley 2010), asymmetric hearing losses (Bess and Tharpe 1984; Bess and Tharpe 1986; Tharpe 2008;

Hughes and Galvin 2013) and bilaterally deaf children with unilateral CIs (Gordon and Papsin 2009;

Salloum, Valero et al. 2010; Chadha, Papsin et al. 2011; Gordon, Jiwani et al. 2011; Gordon, Jiwani et

al. 2013; Gordon, Wong et al. 2013).

Perhaps the second implanted ear is left with a competitive disadvantage compared to the

experienced side for listening because activity in the deprived pathways has become slow, undefined

and disorganized. This would mean that these pathways may no longer be able to integrate and process

the incoming auditory input with clarity and accuracy. Representation of auditory input in the brain

might in turn become smeared or jittered, as it becomes in the visual cortex after long-term monocular

deprivation (Jeffrey, Wang et al. 2004). In support, the pattern of globally de-synchronized activity in

the theta and gamma frequency bands together with increased alpha oscillations shown in Figures 5.2

and 5.3 might reflect cortical slowing in the unstimulated pathways as a result of long-term unilateral

deafness (Monastra, Lubar et al. 1999; Monastra, Lubar et al. 2001; Uhlhaas and Singer 2006; Stoffers,

Bosboom et al. 2007; Englot, Yang et al. 2010; Uhlhaas and Singer 2010; Doesburg, Ribary et al. 2011;

Uhlhaas and Singer 2011; Doesburg, Moiseev et al. 2013). It might also reflect a general lack of

familiarity/meaninglessness with the novel stimulus or incongruency between the auditory input and

its representation in the brain (Rodriguez et al 1999, Doesburg 2008a). This would explain the

impaired speech perception performance observed from this side after months of hearing experience

with the implant (Figure 4.7). Poor functional hearing in the naïve ear might also be attributed to the

lack of asymmetry between the two hemispheres in the cortex, as shown in Figures 4.4 and 4.5.

Indeed, reduced cortical lateralization has been associated with poor auditory processing abilities,

reduced academic performance and impaired reading and writing skills (Abrams, Nicol et al. 2006).

Perhaps it is for this reason that early implanted adolescents who receive sequential CIs after years of

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unilateral hearing are more likely to reject or inconsistently use their second implant (Fitzgerald, Green

et al. 2013). In line with our hypothesis, we suggest that the abnormal activity evoked by initial CI

stimulation of the deprived ear might reflect segregation of these pathways from the cortical hearing

network.

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7. Chapter Seven – Current and future directions

7.1 Does bilateral cochlear implant experience promote auditory development

in pathways from the newly implanted side?

Having assessed the cortical effects of long-term unilateral stimulation/deprivation on the

auditory pathways in the adolescent brain, we are now asking about the longer term effects of single-

sided deafness in children after hearing is established in the deprived ear. To explore this, we have

been tracking cortical development in the deprived pathways in our cohort of bilaterally implanted

adolescents from chapters Four and Five as they gain more hearing experience with their second

implant. This will allow us to determine whether achieving maturation of the auditory cortex with

only one CI marks the closure of a sensitive period for restoring auditory function on the deprived

side. We have measured the cortical responses from this group of adolescents who have over a decade

of unilateral right implant experience after 1 month and 9 months of bilateral CI use. Cortical

waveform morphology from both the experienced and later implanted ears remained unchanged from

the first day of bilateral implant activation. As expected, on the experienced side, the cortical response

remained characterized by obligatory peaks P1-N1-P2-N2. Little changes in the response occurred in

the second implanted side over the first months of bilateral implant use. The response remained

dominated by the N(ci)-P(ci) complex, with little change in latency or amplitude to either peak despite

time after cochlear implantation. The lack of cortical development evoked by stimulation of the

second implanted side is in contrast to the rapid developmental change that occurs at early stages of

unilateral CI use in young children (Sharma, Dorman et al. 2002; Sharma and Dorman 2006) and

rather, more similar to the limited change reported in older children implanted after long durations of

bilateral deafness (Sharma, Dorman et al. 2002; Gordon, Tanaka et al. 2005; Gordon, Tanaka et al.

2008). Using beamformer and connectivity analyses, we will continue to explore the extent to which

9 months of CI experience on the second implanted side after a decade of deprivation promotes

auditory development on this side. We suggest that there are multiple sensitive periods in the maturing

auditory system. The first sensitive period closes with maturation of the brainstem. Missing this

sensitive period for restoring auditory input to both ears will compromise the normal lateralization of

auditory activity in both auditory cortices. We hypothesize that the results will indicate that a second

sensitive period coincides with maturation of the cortex, and that missing this second sensitive period

will compromise our ability to restore auditory development in the deprived pathways, perhaps

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permanently. We speculate that this will be shown by similar underlying cortical activity at 9 months

following bilateral cochlear implantation as that of initial activation, shown in Chapters Four and Five.

7.2 Does the presence of residual hearing in the un-implanted ear protect these

pathways from abnormal effects of unilateral deprivation?

Recently in our lab, we have been asking whether the deprived pathways can be protected from

deleterious effects of deafness by promoting auditory stimulation in these pathways with the use of a

hearing aid. A recent paper by Hopyan and colleagues (2012) indicated that children who had better

hearing at 250Hz tended to use their hearing aids for longer durations prior to receiving a CI. Of

interest, these children performed significantly better on tests of music perception with their implants,

particularly for detecting differences in rhythm, compared to children who did not have acoustical

access to these low frequencies (Hopyan, Peretz et al. 2012). These findings suggest that capitalizing

on auditory development using acoustic input prior to cochlear implantation, even if only in the lower

frequencies, may be necessary to promote optimal implant hearing in children. The question of how

much residual hearing is needed in the un-implanted ear to provide a potential protective effect against

effects of unilateral stimulation/deprivation and whether receiving access to acoustic input in one ear

through the use of hearing aids and electric CI stimulation in the other (i.e., bimodal hearing) can be

used to restore binaural hearing is currently being examined in our lab.

Given that candidacy criteria for cochlear implantation were traditionally limited to individuals

with severe-to-profound hearing losses, surgical techniques for insertion of CIs were developed to

cause minimal damage to cochlear structure with little attention directed at preserving residual hearing

(Briggs, Tykocinski et al. 2005). More recently however, investigators indicated that individuals with

greater residual hearing prior to implantation had better functional outcomes with their implants

compared to their peers with no prior access to sounds (Turner, Gantz et al. 2004; Gantz, Turner et

al. 2005; Ching, van Wanrooy et al. 2007; Luntz, Yehudai et al. 2007; Campbell, Dillon et al. 2013).

Candidacy criteria for cochlear implantation have thus changed to include those with greater residual

hearing. Newer electrode designs, device technology and digital processing algorithms from CI

manufacturers (Campbell, Dillon et al. 2013) and advances in surgical techniques for cochlear

implantation now aim to preserve as much residual hearing in the implanted ear as possible to stimulate

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the auditory pathway with both acoustic and electric hearing (with a hearing aid and a CI) in the same

ear (known as hybrid hearing), at the same time. This might restrict deafness-induced reorganization

in the auditory brain and promote development of the auditory cortex at normal rates. While positive

effects of stimulating the auditory pathways with both inputs in adults have been indicated (Turner,

Gantz et al. 2004; Briggs, Tykocinski et al. 2005; Gantz, Turner et al. 2005; Campbell, Dillon et al.

2013), this is still unclear in children. We suggest that this should be explored further in children as

preservation of residual hearing and the ability to use that hearing with CI stimulation is a tremendous

milestone in cochlear implantation. We suspect that hybrid hearing will provide a protective effect

against abnormal reorganization in the stimulated pathways and might support improved hearing in

noise, enjoyment of music and greater ease of listening in children. Given the large heterogeneity in

the cause and onset of deafness in children, as well as the degree of hearing loss across the frequency

range, understanding how much hearing was present prior implantation and how long the system was

left deprived of auditory input is essential to better predict the effects of deafness on auditory

development and outcomes after cochlear implantation.

7.3 Can auditory development in the second implanted ear be promoted by

using an aural patching method?

It is clear that providing CIs to children who are deaf within limited durations of bilateral

deafness and in both ears is essential to promote optimal hearing and auditory development of the

auditory pathways. In a recent study, Gordon and colleagues demonstrated that a sensitive period of

1.5 years exists for bilateral implantation to protect unilaterally deprived pathways from abnormal

development (Gordon, Wong et al. 2013). Unfortunately, providing a second CI to children within

this short time frame is not always possible. We have been exploring the benefits of different

rehabilitation strategies and have been asking whether the sensitive period for binaural development

can be re-opened in sequentially implanted children to promote hearing and auditory development

from the deprived ear. Recent work from our lab has been exploring whether this might be achieved

by using an aural patching method. Aural patching refers to a rehabilitation method which would

require children to remove the first implant and use the second implant alone for periods of time every

day. Successful outcomes of patching were first reported by Hubel and Weisel in kittens with

monocular deprivation (Hubel and Wiesel 1970) and was later confirmed in children with Amblyopia

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who suffered from visual asymmetries following deprivation in one eye (Holmes, Kraker et al. 2003;

Williams, Northstone et al. 2003). Monocular patching allowed visual connections from the weaker

eye to become stronger, which in turn promoted development of binocular vision. Improvements

were found even when patching was introduced at older ages (Holmes, Kraker et al. 2003; Repka, Beck

et al. 2003; Group 2004; Menon, Shailesh et al. 2008). We wondered whether using a similar

intervention method in our sequentially implanted CI users might promote development in the

binaural pathways. We piloted this study in our lab by asking children/adolescents to use their second

implanted ear alone for 2, 8 or 24 hours per week. Unfortunately, it was difficult to encourage

children/teenagers to do this consistently. Perhaps if this therapy could be incorporated with clinical

rehabilitation techniques and tracked with the new data logging features of CIs, children may derive

benefits of aural patching.

7.4 Is auditory activity evoked by cochlear implants stimulation mediated by

mechanisms of attention or multi-sensory stimulation?

Behavioural experiments have shown that selectively directing attention to an auditory percept

is required for listeners to form an appropriate auditory image to extract meaning from words and

perceive the intended message (Hocherman, Benson et al. 1976; Rif, Hari et al. 1991; Pugh, Shaywitz

et al. 1996; Benedict, Lockwood et al. 1998; Fujiwara, Nagamine et al. 1998; Gomes, Molholm et al.

2000; Lavie 2005; Chun and Turk-Browne 2007; Okamoto, Stracke et al. 2007; Shinn-Cunningham

and Best 2008). Attention failures (i.e., disengaging attention) or alterations (i.e., over-focusing on a

stimulus), particularly for individuals with hearing impairments can significantly impact their ability to

perceive and understand speech, even when using an appropriate auditory prosthesis (Smith, Quittner

et al. 1998; Dye, Baril et al. 2007; Shinn-Cunningham and Best 2008). As suggested in the present

Thesis, children who use CIs to hear, depend on contributions from non-auditory systems when

listening to speech. We suggest that measuring the enhanced role for attention and degree of reliance

on multi-sensory input in children who are deaf and use CIs to hear is important to develop targeted

rehabilitation therapies. Busse and colleagues showed that an intimate relationship exists between

auditory and visual attention in normal hearing individuals (Busse, Roberts et al. 2005). Specifically,

visual attention has been shown to modulate auditory perception when attention is directed to a co-

occurring auditory-visual task (Oatman 1976; Alho, Woods et al. 1992; Woods, Alho et al. 1992; Alho,

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Woods et al. 1994; Benson, Bandettini et al. 1996; Johansen-Berg, Christensen et al. 2000; Webster and

Colrain 2000; Eimer 2001; Hötting, Rösler et al. 2003; Shomstein and Yantis 2004; Sokolov, Pavlova

et al. 2004; Busse, Roberts et al. 2005; Johnson and Zatorre 2005; Rinne 2010).

Thus, given behavioural evidence for better hearing with selective attention and indications

that multi-modal attention is an important component of listening (Fujiwara, Nagamine et al. 1998;

Busse, Roberts et al. 2005; Lavie 2005; Obleser, Wise et al. 2007; Okamoto, Stracke et al. 2007; Rinne

2010), we suggest that it may be recruited differently in children who are trying to compensate for

limitations in auditory cues provided by a CI. Specifically, we wonder: Is auditory activity evoked by

CI stimulation in children modulated by multi-modal attention? Are these modulations over- or under-

expressed relative to normal? Using our beamformer and connectivity analyses, can we map the

cortical areas that mediate these changes in response to different sensory input and perceptual states?

To investigate this, we need to assess the influence of vision and touch on auditory perception by

recording cortical responses to auditory only, auditory-visual, auditory-somatosensory, and auditory-

visual-somatosensory stimuli in both a passive listening task and in a task of directed attention.

7.5 Can attention-driven and/or multi-modal auditory therapy drive

improvements in auditory processing and ease of listening?

If children using CIs are indeed subject to larger effects of attention for hearing, novel therapies

focused on training selective attention may be needed to help them capitalize on this unique way of

listening and promote optimal language and hearing skills for these children.

Current oral and aural rehabilitation therapies rely exclusively on auditory-verbal (A-V) input

to encourage acquisition of speech and language. These therapies (i.e., Lindamood Phoneme

Sequencing Program, Laureate Learning Systems and Earobics) use analytic bottom-up techniques to

rehabilitate the auditory system at a peripheral level. In general, these consist of ten 1-hour speech

perception training sessions with an A-V therapist. The focus of these interventions is on the elements

of speech to teach the listener to distinguish between sounds and to perceive simple auditory signals

provided by a CI to acquire oral speech and language. A-V therapy focuses on repetition of single

words, phrases or sentences, and it is generally administered in quiet listening environments. However,

speech is complex and conversation exchanges very seldomly take place in quiet environments.

173

Current therapies do not train the auditory system to pick out target auditory signals amidst a number

of sources, which makes it very challenging for children to transfer their skills to real-world situations.

In addition, these therapies do not target complex multi-sensory listening skills, and none have shown

any influence on selective attention processes (Fu et al., 2005; 2007; Stevens et al, 2009).

It seems that there is a gap in the generalization of rehabilitation from the laboratory to the

real-world. Rehabilitation strategies should teach CI users to use top-down processes to hear, listen

and process speech in difficult listening situations such a noise. This would enable them to learn to

suppress interfering auditory (i.e., multiple talkers – cocktail party effect) and/or non-auditory (i.e.,

integrating in a multi-sensory environment including visual, somatosensory, olfactory stimuli) inputs.

A more holistic approach to rehabilitation is needed to combine bottom-up and top-down approaches

for more effective generalization of the aural rehabilitation programs to real-world benefits. We

suggest that attention-driven auditory therapies may serve to reduce distractibility from non-auditory

inputs and teach CI users to focus auditory attentional resources to better encode, process and integrate

target auditory signals in challenging listening environments. In addition, A-V therapy is typically only

provided between 6 months to 2 years following initial cochlear implantation. However, basic

cognitive skills such as selective attention, strategic memory, planning and problem solving show rapid

development around 5 to 7 years of age in typically developing normal hearing children and around 8

to 9 years of age in CI users (Smith et al., 1998; Tharpe et al., 2002). I suggest that it may be necessary

to re-enrol these children in auditory rehabilitation therapy programs once these basic cognitive skills

have developed (Tharpe et al., 2002). More research is necessary to determine the age or duration of

CI experience needed to derive the most benefits from re-entering an auditory therapy program.

A proposed auditory rehabilitation program which targets neural mechanisms of attention is

called the Computer-Assisted Speech Training (CAST) program, developed at the House Ear Institute

(Fu et al., 2005; 2007). The CAST can be used at home and training is conducted for 1 hour per day,

5 days a week for a period of 1 month. The CAST was designed to accelerate CI users’ rehabilitation

process through intensive, repetitive and complex speech training. The CAST targets expressive and

receptive oral language skills. Over time, complexity of the tasks is increased by introducing multiple

speaker as well as background noise. A mean improvement in receptive language scores of up to 28%

in different conditions was reported and the improved performance was retained for a period of 8

weeks beyond the training period (Fu et al., 2005; 2007).

174

In the same way, Stevens and colleagues (2009) found that providing more focused high-

intensity language-training with a computerized intervention program led to increased activity in

auditory attentional networks and significant improvements in receptive language scores. This

intervention program, called Fast ForWord (FFW), targets oral language skills by training auditory

attention through intensive computer based sessions using speech and non-speech receptive and

expressive language subtests (Cohen et al., 2005; Stevens et al, 2009). The FFW training is conducted

for 100 minutes per day, 5 days a week for a period of 4 to 6 weeks, and requires the child to attend to

complex auditory stimuli. Neuroimaging evidence found increased activity in the anterior cingulate

gyrus and the lateral prefrontal cortex following FFW training (Temple et al., 2003). These areas have

strong connectivity with the inferior frontal gyrus, the dorso-lateral pre-frontal cortex and the parietal

cortex, which are crucial for attention control. Investigators reported that increased activity in this

area indicated an improvement in selective attention skills related to FFW training (Bush et al., 2000;

Stevens et al., 2009; Temple et al., 2003) and led to significant improvements on measures of executive

attention and non-verbal intelligence (Rueda et al., 2005). This suggests that attention training can

serve not only to enhance oral language skills, but also generalized intelligence and cognition (Rueda

et al., 2005; Stevens et al., 2009) in children. We suggest that developing task-specific multi-sensory

attention-driven training approaches may prove to be more appropriate for CI listening than simpler

auditory therapies. Incorporating attention-driven auditory rehabilitation programs such as FFW may

target auditory processing at a more central/integrative level, and would allow CI users to use and

manipulate the increased dependency that they have on multi-sensory/multi-perceptual input to

enhance encoding, processing and integration of auditory input in everyday, real-world challenging

listening environments.

7.6 Can holistic therapies that incorporate music and/or exercise promote

improvements in auditory processing and accelerate auditory

development after cochlear implantation?

The developing brain has a remarkable capacity to change in response to environmental

demands. It is therefore possible that alternative and holistic rehabilitation techniques which include

musical training and/or exercise therapy may also promote improvements in hearing after cochlear

implantation. Many studies have shown that musical training in early life (Moreno, Marques et al.

175

2009; Strait, Parbery-Clark et al. 2012) drives structural (Hyde, Lerch et al. 2009, Herholz and Zatorre

2012) and functional (Hyde, Lerch et al. 2009; Moreno, Marques et al. 2009; Strait, Kraus et al. 2009;

Kraus and Chandrasekaran 2010; Strait, Kraus et al. 2010; Strait and Kraus 2011; Herholz and Zatorre

2012; Strait, Parbery-Clark et al. 2012; Zendel and Alain 2012; Alain, Zendel et al. 2014) changes in the

brain which correlate with improved attention and memory capacity (Hyde, Lerch et al. 2009; Moreno,

Marques et al. 2009; Herholz and Zatorre 2012; Strait, Kraus et al. 2009; Strait, Kraus et al. 2010; Strait

and Kraus 2011), higher intelligent quotient (Moreno, Marques et al. 2009), increased reading abilities

(Moreno, Marques et al. 2009; Strait, Kraus et al. 2009; Strait, Kraus et al. 2010; Strait and Kraus 2011)

and better auditory skills in both quiet and noisy environments (Hyde, Lerch et al. 2009; Moreno,

Marques et al. 2009; Strait, Kraus et al. 2009; Kraus and Chandrasekaran 2010; Strait, Kraus et al. 2010;

Strait and Kraus 2011; Herholz and Zatorre 2012; Strait, Parbery-Clark et al. 2012). This has been

attributed to enhanced neural efficiency (i.e., activation of a larger population of neurons or increased

synchronized activity of these neurons) in response to sound and/or greater recruitment of attention

processes to discriminate auditory complexities embedded in music.

In addition to the tremendous benefits of music to auditory development and processing,

musical training in young adults with normal hearing showed significantly reduced age-related declines

in gap detection and speech-in-noise tests compared to non-musicians (Zendel and Alain 2012; Alain,

Zendel et al. 2014). This suggests that musical training may have a protective effect on general

cognitive and perceptual processes and may in turn serve to improve or accelerate auditory

development in children using CI to hear. In the same way, forms of exercise therapies have also been

shown to promote plasticity in individuals with autism (Lang, Koegel et al. 2010; Pan 2011; Sowa and

Meulenbroek 2012), influence brain recovery after a stroke in adults (Dickstein, Hocherman et al. 1986)

and lessen effects of Parkinson’s Disease (Murray, Sacheli et al. 2014). Regular, graded, customized

and integrated physical exercise improves mental health in general (Byrne and Byrne 1993; Blumenthal,

Babyak et al. 1999; Daley 2002; Colcombe and Kramer 2003) and slows down cognitive aging (Daley

2002; Heyn, Abreu et al. 2004). Thus, given the many reported positive effects of both music and

exercise therapy on brain development, plasticity and recovery, we suggest that incorporating a more

holistic approach to CI rehabilitation may help children capitalize on non-auditory functions and

develop enhanced abilities to utilize general cognitive strategies to support learning and promote

optimal hearing with a CI.

176

8. Chapter Eight – Conclusion

Data presented in this Thesis demonstrates the use of innovative methods/techniques to assess

the plasticity and development of the central auditory system in children with normal hearing and

children who are deaf and hear with a CI. We provide evidence that normal mechanisms of maturation

and specialization in the brain are experience-dependent and require hearing in both ears to be normal

with intact structure and function in the auditory pathways. Unfortunately, cortical organization in the

auditory system of adolescents who have been bilaterally deaf from early life and received a unilateral

CI as babies differs from normal in both ears. We have shown that while long-term unilateral CI

stimulation promotes maturation of auditory activity in the brainstem, midbrain and cortex, functional

abnormalities persist. Abnormally increased cortical activity in pathways from the hearing ear to the

contralateral cortex, coupled with increased recruitment of cortical areas beyond the auditory cortex

with increased neural synchrony in response to sound and compared to normal hearing peers, suggests

that CI users have developed a 1) processing bias in the left cortex, perhaps to support speech, and 2)

reliance on multi-perceptual and multi-sensory information for CI listening. These plastic changes

likely reflect cortical compensation for reorganization of the brain caused by bilateral deafness prior

to implantation, unilateral deprivation afterward, and the abnormal auditory input delivered by the CI

device. Whether this helps or hinders auditory processing remains to be understood. Increased

reliance on these non-auditory mechanisms however might mean more effortful listening and thus

reduced efficiency of CI hearing.

Despite these differences, children using CIs amaze us with their remarkable improvements in

auditory function over time and leave us hopeful that at least some degree of auditory development

proceeds normally with long-term unilateral CI use. Of concern however, some of this development

might have occurred at the expense of pathways from the opposite and deprived ear. Findings of

abnormal cortical waveform morphologies underlied by abnormally large, widespread and

disorganized/dis-connected cortical activity suggests that implanting the deprived side after the period

of brainstem and cortical maturation has passed leads to restricted and aberrant auditory development

in those pathways. It is unfortunate that abnormal changes in these pathways could not be prevented,

protected or reversed by unilateral stimulation with an implant in the opposite ear. Our current

findings highlight the deleterious effects of unilateral deprivation on the brain. We are now concerned

that these adolescents may not benefit from implantation on the second side. We must strive to

177

develop targeted therapies to exploit the parts of the auditory network that are activated by sound in

CI users to encourage optimal hearing for these children and promote their integration into the

mainstream with strong hearing and spoken language skills, educational and professional opportunities,

and social and cultural well-being with improved quality of life.

178

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Appendices

What is the optimal timing for bilateral cochlear implantation in

children?


Gordon, K. A., Jiwani, S., & Papsin, B. C. (2011). What is the optimal timing for bilateral cochlear

implantation in children? Cochlear Implants Int, 12 Suppl 2, S8-14.

Abstract

Bilateral cochlear implants have been provided to children who are deaf in both ears with intent

to promote binaural hearing. If it is possible to establish binaural hearing with two cochlear implants,

these children would be able to make use of interaural level and timing differences to localize sound

and to distinguish between sounds separated in space. These skills are central to the ability to attend

to one particular sound amidst a number of sound sources. This may be particularly important for

children because they are typically learning and interacting in groups. However, the development of

binaural processing could be disrupted by effects of bilateral deafness, effects of unilateral cochlear

implant use, or issues related to the child’s age at onset of deafness and age at the time of the first and

second cochlear implantation. This research aims to determine whether binaural auditory processing

is affected by these variables in an effort to determine the optimal timing for bilateral cochlear

implantation in children. It is now clear that the duration of bilateral deafness should be limited in

children in order to restrict reorganization in the auditory thalamo-cortical pathways. It has also been

shown that unilateral cochlear implant use can halt such reorganization to some extent and promote

auditory development. At the same time however, unilateral input might compromise the development

of binaural processing if cochlear implants are provided sequentially. Mismatches in responses from

the auditory brainstem and cortex evoked by the first and second cochlear implant after a long period

of unilateral cochlear implant use suggest asymmetry in the bilateral auditory pathways which is

significantly more pronounced than in children receiving bilateral implants simultaneously. Moreover,

behavioral responses to level and timing differences between implants suggest that these important

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binaural cues are not being processed normally by children who received a second cochlear implant

after a long period of unilateral cochlear implant use and at older ages. In sum, there may be multiple

sensitive periods in the developing auditory system which must be considered when determining the

optimal timing for bilateral cochlear implantation.

Introduction

The benefits of bilateral cochlear implantation have been examined in our laboratory by studying

auditory activity in the developing auditory system using both electrophysiological recordings and

behavioural measures of speech perception. We are asking the following questions: (1) Is the auditory

system in children who are deaf and receive cochlear implants able to integrate electrical information

provided by the two independent implants? (2) Does a period of unilateral cochlear implant use change

the bilateral auditory pathways? (3) Does a period of unilateral cochlear implant use disrupt binaural

processing once bilateral cochlear implants are provided? (4) Should bilateral cochlear implants be

provided simultaneously or sequentially?

Children who are deaf and benefit little or not at all from their hearing aids are now able to hear,

communicate and develop oral speech and language skills through the use of cochlear implants.

Indeed, research has shown that providing chronic auditory stimulation with a cochlear implant

promotes development in the auditory brainstem (Gordon, Papsin et al. 2003; Gordon, Papsin et al.

2006; Gordon, Papsin et al. 2007; Thai-Van, Cozma et al. 2007) and thalamo-cortex (Gordon et al.,

2005a, 2005b, 2008a, 2010b; Sharma et al., 2002a, 2002b, 2005, 2009) in children who are deaf from

infancy. Children who use a unilateral cochlear implant show significant improvements, such that

many are able to develop speech and language, learn in mainstream environments and communicate

effectively. Nonetheless, these children still require extensive therapy to achieve optimal

communication outcomes and their hearing deteriorates significantly in noise (Basura et al., 2009;

Gordon and Papsin, 2009a, 2009b; Papsin and Gordon, 2008). Bilateral cochlear implants are now

being provided to children who are deaf with an aim to improve hearing in both quiet and noisy

environments. The two cochlear implants have been provided in the same surgery (simultaneously)

or in two different surgeries with an inter-implantation delay (sequentially) (Kühn-Inackera et al.,

2004).

http://www.ijporlonline.com/article/S0165-5876%2804%2900147-8/abstract

http://www.ijporlonline.com/article/S0165-5876%2804%2900147-8/abstract

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It is clear that cochlear implants should be provided in a timely manner to minimize abnormal

changes in the auditory system caused by bilateral auditory deprivation 2010b; Gilley et al., 2005, 2008;

; Gordon, Tanaka et al. 2005; 2008; 2010b; Gilley et al., 2005, 2008; Lee, Lee et al. 2001; Lomber et

al., 2010; Sharma et al., 2002a, 2009). We are now studying whether using a cochlear implant on one

side and leaving the other side deprived from auditory stimulation also causes abnormal re-

organization in the auditory system. If such changes occur during a sensitive period in development,

they could disrupt binaural processing permanently. We therefore hypothesize that minimizing both

bilateral and unilateral auditory deprivation is important to promote optimal auditory development and

maturation of the auditory system. It is important to test this hypothesis in order to determine the

optimal timing for bilateral cochlear implantation in children.

The auditory system is able to process and integrate auditory information by comparing subtle

differences in level and timing of sounds reaching the two ears. Research has shown that advantages

of binaural hearing, compared to monaural hearing, come from the improved ability to identify the

location of sound sources in space (sound localization) (Basura et al., 2009; Brown and Balkany, 2007;

Ching et al., 2007; Litovsky, 2008a, 2008b) as well as from binaural summation, which allows for

increased loudness perception and ease of listening (Ching et al., 2007; van Hoesel and Tyler, 2003;

Steffens et al., 2008). Binaural hearing also enhances speech intelligibility in the presence of competing

noise and in reverberant environments using the head shadow and squelch effects (Basura et al., 2009;

Brown and Balkany, 2007; Ching et al., 2007; van Hoesel and Tyler, 2003). Moreover, binaural hearing

reduces the risk of auditory deprivation in the unaided ear (Gordon and Papsin, 2009a, 2009b).

Binaural processing is particularly important for children because they are rarely in one location

listening to a single talker in a quiet environment. Indeed, children need to be able to attend to several

sound sources when interacting and playing in groups (i.e., in playgrounds). In addition, learning often

takes place in environments where noise, reverberation and distance pose particular challenges for

hearing and listening (i.e., classroom situations). Children who use only one cochlear implant do not

have access to important binaural cues to aid listening in such challenging conditions. It follows then

that we should always strive to provide binaural hearing to children with hearing loss.

For children who are affected by profound hearing loss and limited residual hearing in both ears,

binaural hearing might only be achieved through bilateral cochlear implantation at the present time

(Basura et al., 2009; Eapen and Buchman, 2009; Papsin and Gordon, 2008). Functional outcomes of

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bilateral cochlear implantation in children are becoming available; however, it remains unclear to what

extent the developing auditory system is able to process electrical input delivered bilaterally from two

independent cochlear implants.

This paper will review data from a large group of children who were prospectively recruited to

participate in our study of bilateral cochlear implantation in children. The duration of bilateral deafness

was limited to less than 3 years in 3 of 4 groups and the duration of unilateral cochlear implant use

ranged from nil to > 2 years. Current findings show that: 1) unilateral cochlear implant use sets up a

mismatch in responses evoked by the right and left cochlear implants, and 2) improvements in speech

perception when using bilateral versus unilateral cochlear implants are clearest when the duration of

bilateral deafness and unilateral cochlear implant use are limited.

Groups of Study Participants

As of April 2010, 156 children had been recruited into the bilateral cochlear implant study at the

Hospital for Sick Children in Toronto, Canada. Details of these children are shown in Table 1. Of

these, 146 had a short duration of bilateral deafness (< 3 years) and 10 had longer periods of bilateral

auditory deprivation. Of the children with limited bilateral deafness, 72 children received both

implants in the same surgery (Simultaneous group), 19 had a short inter-implant delay of less than 1

year (Short Delay group) and 55 of the children had an average of 5 years of unilateral cochlear implant

use before they received their second implant (Long Delay group). The group with longer durations

of bilateral deafness also had long periods (> 2 years) of unilateral cochlear implant use (Long Deaf-

Long Delay group). The majority of the children had early onset severe-to-profound sensorineural

hearing loss and the etiologies for deafness were often unknown. Any period of usable hearing

(defined by audiometric thresholds with or without hearing aids of ≤ 40 dBHL at any test frequency)

was subtracted from the period of bilateral deafness. This meant that several children had access to

some sounds in normal conversational speech prior to cochlear implantation and were therefore older

than 3 years of age when they received their first implant.

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Table 1: Demographic variables of bilateral cochlear implant (CI) groups

Mismatches in bilateral activity following a period of unilateral

cochlear implant use

Auditory brainstem responses

We were interested in the ability of the developing auditory system to compare electrical

information delivered by two cochlear implants. Because unilateral cochlear implant use has already

been shown to promote latency decreases in responses from the auditory brainstem (Gordon et al.,

2003, 2006, 2007b, 2007c, 2008b) and cortex (Sharma et al., 2002a, 2002b, 2005), we hypothesized that

evoked responses from the newly implanted side would be prolonged relative to the more experienced

side in children receiving cochlear implants sequentially. If so, this could set up abnormal differences

along the bilateral auditory pathways and potentially compromise binaural processing.

Figure 1 shows two examples of auditory brainstem responses measured on the first day of

bilateral cochlear implant use in a child from the Simultaneous group and a child from the Long Delay

Sequential group. Waves eII, eIII, and eV are clear in waveforms evoked by the right and left cochlear

implants in both children. Wave latencies are similar for right and left evoked responses in the child

who received bilateral cochlear implants simultaneously. Latencies from this child are highlighted in

gray and reproduced in the plot of responses from the child receiving bilateral cochlear implants

sequentially. Responses from that child, who was in the Long Delay group, show mismatches in wave

latencies in line with our hypothesis. Because electrically evoked auditory brainstem responses were

found not to change after the first year of life in children with bilateral deafness (Gordon et al., 2010a),

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these findings likely reflect the effect of unilateral cochlear implant use rather than increasing age. In

addition, latencies of both responses from the child in the Long Delay group are decreased relative to

the child in the Simultaneous group (shown by the gray highlighted lines).

Figure 1: Brainstem response waveforms of a child receiving bilateral cochlear implants simultaneously

and another child receiving bilateral cochlear implants sequentially with a long inter-implant delay.

Responses from the latter child show a mismatch in timing of brainstem activity evoked by the right

versus left sides. The two traces on each plot represent responses evoked by the right and left sides.

Mean wave eV latency differences between groups are plotted in Figure 2 and confirm that there

was no significant latency differences between sides in the Simultaneous group but that significant

differences were found in both the Short Delay and Long Delay groups. Data from this test time

(initial bilateral cochlear implant use) (Gordon et al., 2007b) were compared with results measured

after bilateral cochlear implant experience (Gordon et al., 2007c, 2008b). Data from the groups studied

at that time showed that wave eV differences in the Short Delay group resolved by 9 months of bilateral

cochlear implant use (Gordon et al., 2007c, 2008b) but did not resolve even after 1 year of bilateral

cochlear implant use in the Long Delay group (Gordon et al., 2007c). Given previous findings that

the time course for maturation of electrically evoked auditory brainstem latencies was approximately

12 months (for wave eV) (Gordon et al., 2006), we would expect wave eV latency differences to resolve

within a similar time period of bilateral cochlear implant use. The persistent delay between wave eV

evoked by the second implanted side relative to the first suggests that auditory brainstem development

promoted after long periods of unilateral cochlear implant use will be different from that which occurs

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after bilateral deafness. We have also been interested in the decrease of wave latencies from both sides

in the Sequential group compared to the Simultaneous group at initial bilateral implant use. This

finding was expected in the response from the experienced side, as latencies are known to decrease

with unilateral cochlear implant use (Gordon et al., 2003, 2006), but was unexpected for responses

from the newly implanted side. We are presently examining whether this effect can be explained by

the difference in age at testing between the groups or whether this reflects a cross-over effect of

unilateral cochlear implant use to the pathways from the opposite ear. We also need to consider

whether this change has positive implications for bilateral auditory development as suggested by others

(Bauer et al., 2006) or whether this reflects re-organization along the pathways which may be

detrimental to binaural processing.

Figure 2: Brainstem response latencies for waves eV of the naïve ear relative to the experienced ear on

the first day of bilateral device activation. Responses from 13 children in the Simultaneous group, 15

in the Short Delay group and 16 children in the Long Delay group were included in this analysis.

Children with short and long inter-implant delays showed significant mismatches in brainstem activity

evoked from the naïve ear, relative to the experienced ear. This was not seen in the children who

received both cochlear implants simultaneously.

The mismatched timing found between auditory brainstem responses evoked by the right and

left cochlear implants in children implanted sequentially was also found in the binaural difference

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response (Gordon et al., 2007c, 2008b). This response is calculated by summing responses evoked by

the right and left cochlear implants and then subtracting the response evoked by the coordinated

stimulation from both implants. The resulting amplitude difference, found at (mean ± SD) 0.09 ±

0.00 ms for children in the Simultaneous group, 0.07 ± 0.22 ms for the Short Delay group, 0.15 ± 0.07

ms for children in the Long Delay group and 0.35 ± 0.35 ms for the Older Long Delay group (Gordon

et al., 2007c), is thought to reflect an inhibitory interaction in the auditory brainstem in response to

bilateral input and indicates that the brainstem detects the presence of bilateral input. Because binaural

processing first occurs in the auditory brainstem, the presence of binaural difference responses in most

children receiving bilateral cochlear implants suggests that the auditory pathways at this level of the

system retain the ability to detect bilateral electrical input (Gordon et al., 2007b, 2007c, 2008b). The

consequence of abnormal timing of this response in children who receive bilateral cochlear implants

sequentially rather than simultaneously remains unclear. Interestingly, a similar prolongation in timing

of the binaural difference response has been reported in response to interaural timing cues in normal

hearing individuals (Furst et al., 1985; Riedel and Kollmeier, 2006). Thus, it may be possible that the

mismatch in timing of auditory brainstem activity in some children using bilateral cochlear implants

creates abnormal increases in timing differences between the two ears. The functional consequences

for sound localization and other binaural processing should be explored. Our own efforts to measure

perception of inter-implant level and timing cues are reviewed below (see Section, Perception of speech

and inter-implant timing and level cues).

Cortical responses

Along with measures from the auditory brainstem, we have been exploring effects of bilateral

cochlear implantation with different inter-implant delays on the auditory cortex. Figure 3, shows

examples of cortical responses from three children in the Simultaneous group and one child in the

Long Delay group. Children in the Simultaneous group show a variety of response waveform types as

recently reported (Gordon, Tanaka et al. in press) but each child shows a similar response to right as

to left cochlear implant stimulation. On the other hand, responses in the child who had used a

unilateral cochlear implant for > 2 years are very different from one another (Gordon et al., 2005b,

2008a, 2010b). Given the variability in cortical responses found at the initial stage of bilateral cochlear

implant use in ears with no prior cochlear implant stimulation, we have been unable to determine

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which of these peaks, if any, are similar to the P1 peak found in children with normal hearing or with

unilateral cochlear implant experience (Sharma et al., 2002a, 2002b, 2005, 2009). Group data, shown

in Figure 4, confirm that most children receiving bilateral cochlear implants simultaneously have similar

cortical responses to right and left cochlear implant stimulation (62 of 72 children – i.e., 86%), whereas

the majority of children receiving a second cochlear implant at older ages and after unilateral implant

use showed differences in cortical response waveforms. Why cortical responses should show this

degree of variability upon acute cochlear implant stimulation in children with both bilateral and

unilateral auditory deprivation remains an interesting question which will need to be addressed by

defining the cortical generators of these responses. We have begun to do this work using our own

beamforming analysis (Wong and Gordon, 2009; Gordon et al., 2010b) which has allowed us to focus

specifically on activity generated in the auditory cortex in response to cochlear implant stimulation. In

addition, we need to determine whether there are functional implications for the mismatches in cortical

responses evoked by right and left cochlear implant stimulation in children receiving cochlear implants

sequentially.

Figure 3: Cortical response waveforms of 3 children receiving bilateral cochlear implants

simultaneously and 2 children receiving a second cochlear implant after a long inter-implant delay.

Several waveform types occur in the children in the Simultaneous group but responses were similar

within children. Cortical responses were very different when evoked by the newly implanted side

compared to the experienced side in the children with long inter-implant delays. The two traces on

each plot represent responses evoked by the right and left sides.

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Figure 4: Cortical responses were similar in most children in the Simultaneous group and were largely

mismatched in children receiving bilateral cochlear implants sequentially.

Perception of speech and inter-implant timing and level cues

We have been exploring whether mismatches in timing of auditory brainstem activity and

mismatches in cortical responses between right and left evoked responses in children receiving bilateral

cochlear implants sequentially are associated with differences in auditory function in these children

compared to those receiving bilateral devices simultaneously. We are assessing both the ability of

children using bilateral cochlear implants to perceive differences in level and timing cues between two

cochlear implants and their ability to understand speech in quiet and noise.

Findings from these studies revealed that children who receive a second cochlear implant

following a long inter-implant delay (4.9 ± 2.8 years) are able to perceive changes in electrical pulses

when level cues are different between the two implants, but have more difficulty detecting changes in

inter-implant timing cues (Salloum et al., 2010). These findings are consistent with previous reports

showing that adults who use bilateral cochlear implants also interpret inter-implant level differences

more effectively than timing differences (van Hoesel & Tyler, 2003). In addition, findings also revealed

that children who have a long period of unilateral cochlear implant use before receiving their second

implant do not normally hear changes in lateralization of sounds with increasing difference in inter-

implant timing cues (Gordon et al., 2010b; Salloum et al., 2010). Using a behavioural lateralization

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task, we showed that children often heard bilateral input as coming from their second (less

experienced) implanted side when electrical pulses of the same current level were presented to both

implants simultaneously. This likely occurs when two different cochlear implant devices are used. In

addition, unlike their normal hearing peers, children receiving bilateral cochlear implants after a long

inter-implant delay rarely perceived the sound as coming from the mid-line of the head and sometimes

reported that they heard bilateral input as coming from the left and right sides separately (Salloum et

al., 2010). It is still unclear whether these children are using unilateral or bilateral processing, but the

poor ability to lateralize sound based on timing cues and the absence of bilateral inputs perceived at

the mid-line of the head, suggest that binaural processing may be hindered in children receiving

bilateral cochlear implants following a long period of unilateral cochlear implant use and at older ages.

To examine the effects of bilateral and unilateral deafness on development and on speech

perception outcomes, we have been further investigating speech perception performance in quiet and

in noise, in all four groups indicated in Table 1 after 6 to 12 months of bilateral cochlear implant

experience. Speech perception has been measured using standardized tests which are appropriate for

the age and language level of each child. We have previously reported results in a smaller group

(Gordon and Papsin, 2009b). In order to control for differences in test and age, we calculated the

change in speech perception test scores in bilateral conditions (in quiet and noise) relative to the scores

obtained using the first cochlear implant in quiet. For children in the Simultaneous group, scores

obtained while using the right implant alone in quiet were used, because most children in the sequential

groups had received the first implant in the right ear. Speech perception when the children were

wearing one cochlear implant in the side opposite to the more experienced/right ear in quiet was also

examined. Findings revealed that all groups of children found it most challenging to recognize speech

in noise. However, children who received both of their cochlear implants with a limited duration of

bilateral deafness and with minimal inter-implant delays achieved the largest bilateral improvements in

speech perception scores in both quiet and noise (over unilateral implant use) compared to older

children who had inter-implant delays longer than 2 years (Gordon and Papsin, 2009b). Children with

longer inter-implant delays showed poorer abilities to perceive speech in quiet when using their new

implant compared with an implant on their more experienced side. In contrast, children with minimal

inter-implant delays showed similar performance between ears, when listening to speech with either

the first or second implant alone (Gordon and Papsin, 2009b).

241

Conclusion

We used electrophysiological measures to assess auditory activity at the level of the brainstem

and cortex in children who received cochlear implants bilaterally. We found that children who were

implanted at an early age with a short duration of bilateral deafness and inter-implant delays shorter

than 12 months derived the most benefits from bilateral implantation. Mismatches of timing in

auditory activity in the brainstem and cortex, evoked by the experienced and naïve sides at initial

bilateral device activation resolved by 9 months of consistent bilateral cochlear implant use, suggesting

maturation of the binaural pathways from the brainstem to the cortex within the first year of bilateral

implantation. These children also showed clear improvements in speech perception in quiet and in

noise when using bilateral rather than unilateral cochlear implants during the same period of time. By

contrast, children who received their cochlear implants with an inter-implant delay longer than 2 years

showed mismatched timing of auditory activity in the brainstem and in the cortex. Behavioural

responses show that these children have difficulties perceiving inter-implant timing differences and

have poorer speech perception when using the second cochlear implant compared to the first during

the first 6 to 12 months of bilateral cochlear implant use. At this stage of bilateral implant use, they

do not show a clear improvement in speech perception in noise with bilateral rather than unilateral

implant use. Our findings suggest that children receiving bilateral cochlear implants simultaneously

have the best chance for development of bilateral auditory pathways capable of processing binaural

cues.

Bilateral implants have demonstrated a clear advantage to unilateral stimulation and bilateral

cochlear implantation has been supported and applied in many clinical settings. Through universal

newborn hearing screening initiatives we are now able to identify hearing loss early and provide timely

intervention with the use of auditory prostheses, with the aim of limiting the duration of bilateral and

unilateral deafness in children. We are continuing to expand our research in this domain to better

understand the effects of childhood hearing loss on the developing auditory system and to promote

better hearing through binaural development for all children with hearing loss. Further research will

determine whether this is possible by providing bilateral cochlear implants at young ages and with a

minimal inter-implant delay.

242

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Benefits and detriments of unilateral cochlear implant use on bilateral

auditory development in children who are deaf


Gordon, K. A., S. Jiwani and B. C. Papsin (2013). Benefits and detriments of unilateral cochlear

implant use on bilateral auditory development in children who are deaf. Front Psychol 4(719):

1-14.

Abstract

We have explored both the benefits and detriments of providing electrical input through a

cochlear implant in one ear to the auditory system of young children. A cochlear implant delivers

electrical pulses to stimulate the auditory nerve, providing children who are deaf with access to sound.

The goals of implantation are to restrict reorganization of the deprived immature auditory brain and

promote development of hearing and spoken language. It is clear that limiting the duration of

deprivation is a key factor. Additional considerations are the onset, etiology, and use of residual hearing

as each of these can have unique effects on auditory development in the pre-implant period. New

findings show that many children receiving unilateral cochlear implants are developing mature-like

brainstem and thalamo-cortical responses to sound with long term use despite these sources of

variability; however, there remain considerable abnormalities in cortical function. The most apparent,

determined by implanting the other ear and measuring responses to acute stimulation, is a loss of

normal cortical response from the deprived ear. Recent data reveal that this can be avoided in children

by early implantation of both ears simultaneously or with limited delay. We conclude that auditory

development requires input early in development and from both ears.

Introduction

A cochlear implant is an auditory prosthesis which is surgically implanted into the cochlea (inner

ear), and allows children who are deaf to develop oral speech and language. Because the brain is most

247

susceptible to changes in early life, providing access to sound at a young age is essential to promote

auditory development (Papsin and Gordon, 2007;Kral and O'Donoghue, 2010). The implant cannot

restore normal hearing. It provides only a crude representation of acoustic sounds, eliminates

important cochlear processing, and may not be able to completely reverse the effects of deafness. In

addition, cochlear implants were traditionally provided unilaterally (i.e., in only one ear) in children,

leaving the opposite pathways deprived of input and susceptible to degeneration and reorganization

(O'Neil et al., 2010;Gordon et al., 2013;Kral et al., 2013). Yet, despite these disadvantages, many

children achieve excellent listening and oral communication abilities. In the present review, we share

findings from studies exploring whether cochlear implantation can limit reorganization of the deprived

immature auditory brain and promote appropriate and normal-like development along the auditory

pathways.

The auditory system reorganizes when bilaterally deprived

Prior to cochlear implantation, the absence of auditory input to the auditory system leaves the

brain vulnerable to reorganization (Nishimura et al., 1999;Bavelier et al., 2000;Finney et al., 2001;Lee

et al., 2001;Bavelier and Neville, 2002;Bavelier et al., 2006;Merabet and Pascual-Leone, 2010).

Secondary and association auditory areas, including parts of the planum temporale, all of which

respond to multi-sensory input including hearing, vision and touch (Pandya and Yeterian, 1985;Giard

and Peronnet, 1999;Calvert et al., 2001;Calvert and Thesen, 2004), become recruited by the visual

(Finney et al., 2001;Lee et al., 2001;Lee et al., 2007b;Lomber et al., 2010;Meredith and Lomber, 2011)

and somatosensory (Levänen et al., 1998;Levänen and Hamdorf, 2001;Auer Jr et al., 2007;Meredith

and Lomber, 2011) systems to perform non-auditory functions. As a consequence of early auditory

deprivation, processing of visual peripheral localization by the posterior auditory field (Lomber et al.,

2010), visual motion detection by the dorsal zone of the auditory cortex (Lomber et al., 2010), and

somatosensory sensation by the anterior auditory field (Meredith and Lomber, 2011) become enhanced

in individuals who are deaf. These changes appear to result from a direct competition for resources in

areas which receive multi-sensory input. If governed by principals of Hebbian processing (Hebb,

1949;Abbott and Nelson, 2000;Song et al., 2000), neurons in these areas might preferentially form

viable connections with non-auditory inputs to the detriment of inputs carrying auditory information.

We must be concerned by the reorganization of the deaf auditory cortex because, depending on how

248

quickly these processes occur, they may be impossible to reverse and could impair outcomes after

cochlear implantation. It is also becoming clear that these changes do not occur uniformly in children

who are deaf and may be related to the heterogeneity in the onset and cause of pediatric deafness

(Gordon et al., 2011a;Gordon et al., 2011c).

Limiting the period of bilateral deafness in early life is essential to drive maturation in the

auditory pathways (O’Donoghue, 1999;Kral et al., 2001;Ponton and Eggermont, 2001; Sharma et al.,

2005;Papsin and Gordon, 2007;Gordon et al., 2008;Nikolopoulos et al., 2009;Gordon et al., 2010), and

promote optimal hearing and speech and language development (Beadle et al., 2005;Harrison et al.,

2005;Nicholas and Geers, 2007;Geers and Sedey, 2011). Many studies investigating auditory

development after cochlear implantation focus on children who are deaf in infancy, but do not examine

the larger heterogeneity in etiology, onset and/or degree of deafness. These factors may each have

unique effects on auditory activity in the brain prior to implantation. For example, bilallelic mutations

of the Gap Junction Beta-2 (GJB-2) gene causes deficits in the cochlea at likely very early stages of

development with possible consequences for auditory function after implantation (Propst et al., 2006).

The GJB-2 gene normally codes for the connexin-26 protein, which creates gap junctions in the

cochlea necessary for the appropriate release and maintenance of electrochemical gradients. This in

turn, generates action potentials and stimulates the auditory nerve (Kelley et al., 1998;Cohn and Kelley,

1999;Gualandi et al., 2002). Electrophysiological recordings of auditory evoked cortical activity at

initial cochlear implant activation in children with severe GJB-2 mutations revealed that responses

from the cortex were more homogenous in this cohort compared to those children who did not have

such a mutation. Auditory evoked cortical responses in children with GJB-2 mutations were

characteristic of earlier stages of cortical development, perhaps reflecting restricted spontaneous

activity in the auditory system and more limited access to sound prior to implantation compared to

their peers who did not have a GJB-2 related deafness (Gordon et al., 2011c). This was further

supported by poorer hearing sensitivity in the low frequencies in the GJB-2 group (Propst et al., 2006).

The degree of residual hearing is another important predictive factor for cochlear implant

outcomes. Traditional candidacy criteria for cochlear implantation in children include a diagnosis of

permanent severe-to-profound hearing loss bilaterally with little or limited access to acoustic input

through hearing aids (Osberger et al., 2002). We recently reported that children who had better hearing

at 250Hz used their hearing aids for longer durations prior to receiving a cochlear implant (Hopyan et

al., 2012). Of interest, these children performed significantly better on tests of music perception with

249

their implants, particularly when detecting differences in rhythm, compared to children who did not

have acoustical access to these low frequencies prior to implantation (Hopyan et al., 2012). Thus, there

are advantages of acoustical input for auditory development which can be capitalized upon after

cochlear implantation. In general, we are learning that the cause, onset and degree of deafness in any

one child will be important to understand in order to ensure that he/she makes the best possible use

of his/her device.

Unilateral cochlear implantation restores hearing and promotes

auditory development

The cochlear implant was made available to children in North America in the early 1990s and

works by stimulating the auditory pathways with electrical pulses. The implant contains an array of

electrodes which is surgically placed in the scala tympani of the cochlea. These electrodes each deliver

electrical pulses to stimulate the auditory nerve. External equipment is worn which takes in acoustic

sound through the microphone, extracts frequency and intensity information in a speech processor

and sends instructions to an internal device through an FM transmitting coil. The internal receiver-

stimulator sends this information to the electrodes which are organized to mimic the normal cochlea;

high frequency sounds are allocated to basal electrodes with lower frequencies being allocated to

progressively more apical electrodes. In this way, the child receives an electrical representation of the

acoustic world and learns to understand sounds including speech.

Auditory brainstem development, measured by decreasing latencies of evoked potential peaks,

is largely complete by the first year of cochlear implant use in children with early onset deafness

(Gordon et al., 2003;Gordon et al., 2006), indicating increasing efficiency of neural conduction and

improved neural synchrony with exposure to sound (Gordon et al., 2003). Similar changes have been

reported from the auditory brainstems of normal hearing children over a similar time-course (Salamy

and McKean, 1976;Starr et al., 1977;Jerger and Hall, 1980;Salamy, 1984;Hecox and Burkard, 2006).

Data from Gordon et al (2006) is shown in Figure 1a; on the left is an example of an electrically evoked

auditory brainstem response. The stimulus artifact is shown at time 0ms followed by waves eII, eIII

and eV, and on the right, the latency values of wave eV are plotted at initial device activation and over

the first year following cochlear implant use in 44 children who had early onset deafness and were

250

implanted unilaterally (Gordon et al., 2006). Recently, we recorded these same responses in 2 children

who were in the original study once they had over a decade of unilateral cochlear implant experience.

Their responses are shown in Figures 1b and 1c. In both cases, wave eV latency clearly decreases over

the first year of cochlear implant use, with no further changes thereafter. This suggests that activity in

auditory brainstem is largely complete by the first year (Gordon et al., 2006).

252

Figure 1: (A) Example of an electrically evoked auditory brainstem response waveform is shown on

the left. The onset of the cochlear implant artifact is shown at time 0ms, followed by peaks eII, eIII

and eV. Data from Gordon et al. (2006) are plotted on the right and show the mean wave eV latency

values of 44 children recorded at initial activation of the implant, and at months 2, 6 and 12 following

unilateral cochlear implantation. Figures (B) and (C) on the right show the changes in the brainstem

responses of 2 children who were in the original study (Gordon et al., 2006), recorded from initial

activation of the device to different intervals over the first year of cochlear implantation use. New

responses recorded after 10 years of unilateral cochlear implant experience are also shown further

confirming that little change in the eV latency occurs beyond the first year of implant use. The wave

eV latencies at each time-point are represented on the right for each child.

Further studies concentrated on the development of cortical auditory activity in children with

time after cochlear implantation. Cochlear implants provided to children who are congenitally deaf

within 3.5 years of bilateral deafness promote age-appropriate cortical responses over the first 3-6

months of implant use (Sharma et al., 2002a). After this initial period, these responses change at a rate

which is similar to normal (Eggermont et al., 1997;Eggermont and Ponton, 2003). We recently

assessed changes in cortical responses after longer term unilateral cochlear implant use in children

implanted early (Jiwani et al., 2013a). Grand mean cortical evoked responses from 79 unilateral

cochlear implant users (red waveforms) are plotted in Figure 2 along with the grand mean responses

from 58 normal hearing peers (black waveforms) for different intervals of hearing experience. Figures

2a, 2b and 2c show grand mean cortical evoked waveforms from children who have between 0 to 7

years (40 cochlear implant users; 11 normal hearing), 7 to 12 years (21 cochlear implant users; 18

normal hearing) and over 12 years (18 cochlear implant users; 29 normal hearing) of hearing

experience, respectively. Cochlear implant users represented in these Figures had limited durations of

bilateral deafness prior to implantation (2.03 ± 1.36 years) with typical heterogeneity in their etiologies

of deafness.

253

Figure 2: Grand mean cortical evoked responses from 79 cochlear implant users (red waveform)

(Jiwani et al., 2013a) are plotted for children who have (A) under 7 years of hearing experience (4.3 ±

1.7 years; n=40), (B) between 7 to 12 years of hearing experience (9.4 ± 1.6 years; n=21), and (C) those

who have more than 12 years of hearing experience (13.8 ± 0.9 years; n=18). Mean responses for each

range of hearing experience are compared to a normal and mature cortical waveform (black waveform)

(Jiwani et al., 2013a), recorded from normal hearing peers who are matched for hearing age (n=58).

As shown in Figure 2a, responses from children with up to 7 years of hearing experience with

an implant or with normal bilateral hearing are dominated by a large and broad positive amplitude

peak, labelled P1/P2. Comparison of peak latencies (t(47.3)=-1.63; p>0.05) and amplitudes (t(42.1)=-0.64;

p>0.05) reveal no significant differences between the two groups. This positive-peaked response is

believed to reflect either excitatory auditory activity from the thalamus to deep layers of the auditory

cortex (Liegeois-Chauvel et al., 1994), or auditory driven activity from association auditory areas to the

reticular activating system in the non-lemniscal auditory pathways (Kraus et al., 1992;Ponton et al.,

2000;Ponton and Eggermont, 2001). As thalamo-cortical and cortico-cortical connections develop

around 9 to 12 years of age in superficial layers of the auditory cortex, a small negative amplitude peak,

labelled N1, develops in the cortical evoked response and bifurcates the large P1/P2 response into three

peaks: P1, N1 and P2. Similar developmental changes to the cortical response are observed in early

implanted cochlear implant users who have equal durations of hearing experience. Indeed, as shown

254

in Figure 2b, with 7 to 12 years of auditory experience (9.38 ± 1.57 years in cochlear implant users;

9.92 ± 1.57 years in normal hearing individuals), the cortical response in both groups begins to develop

into a polyphasic waveform. The grand mean response from all 21 unilaterally implanted children

begins to bifurcate into a 3-peaked cortical response at this stage of implant use (Figure 2b).

Differences in the wavepeak latencies (P1: t(10)=-0.88, p>0.05; N1: t(10.18)=-1.3, p>0.05; P2: t(10.77)=1.43,

p>0.05) and peak-to-peak amplitudes (P1-N1: t(6.87)=1.75, p>0.05; N1-P2: t(10.67)=2.2, p>0.05) between

both groups were not significant. This response continues to develop with time. As auditory pathways

mature in the auditory cortex, peaks P1-N1-P2-N2 become clearly present (Figure 2c) when auditory

experience exceeds 12 years in all 18 cochlear implant users (13.81 ± 0.92 years of unilateral implant

experience) and 29 normal hearing peers (15.30 ± 1.81 years of age and hearing) (Jiwani et al., 2013a).

The data from individuals with normal hearing shown in Figure 2 is consistent with findings by

Ponton, Eggermont and colleagues who suggested that peak N1 normally emerges around 9 to 12 years

of age reflecting maturation of thalamo-cortical and cortico-cortical loops in superficial layers of the

auditory cortex (Ponton et al., 2000;Eggermont and Ponton, 2003). These pathways mediate the

transfer of primary auditory and multi-sensory input from the thalamus to various regions of the

ipsilateral and contralateral auditory cortices (Winer et al., 2001;Winer et al., 2005;Razak et al., 2009),

and the transmission of information from the auditory cortex to primary and secondary sensory areas

in both hemispheres (Read et al., 2002;Lee and Winer, 2005;Klinge et al., 2010). The developmental

trajectory of the electrically evoked cortical waveform suggests that similar development is taking place

in children using cochlear implant (Jiwani et al., 2013a), perhaps establishing: 1) appropriate relay of

auditory input from the ear to the cortex, via the thalamus; 2) communication between the two cortical

hemispheres; and/or 3) connectivity between different sensory areas. These normal-like

developmental changes to the auditory cortex may underlie the impressive improvements in auditory

function observed with cochlear implant use, over time (Beadle et al., 2005;Nicholas and Geers,

2007;Geers and Sedey, 2011).

255

Differences from normal persist in auditory processing despite long

durations of unilateral cochlear implant use

Although early implantation of young children results in normal-like cortical response peaks, as

shown in Figure 2c, the waveform has at least one abnormality. Specifically, the amplitude of the P2

peak in cochlear implant users is larger than in normal hearing peers (t(14.51)=2.49, p<0.05) (Jiwani et

al., 2013a). The importance of this recent finding is that it suggests deviations from normal cortical

processing remain in these young people despite long-term unilateral implant use. Enhanced P2 peak

amplitudes in normal hearing adults are known to reflect increases in selective attention (Picton and

Hillyard, 1974;Hocherman et al., 1976;Rif et al., 1991;García-Larrea et al., 1992;Posner and Dehaene,

1994;Grady et al., 1997;Fujiwara et al., 1998;Tremblay et al., 2009) and increases in multi-sensory

integration during auditory processing (Hari, 1990;García-Larrea et al., 1992;Levänen et al.,

1998;Webster and Colrain, 2000;Moller and Rollins, 2002;Crowley and Colrain, 2004;Johnson and

Zatorre, 2005). These processes cause a reduction in the primary network which becomes

supplemented by the frontal and parietal areas through increased neural recruitment and synchrony

(Tremblay et al., 2001;Tremblay and Kraus, 2002;Tremblay, 2007;Tremblay et al., 2009) from the non-

primary and association auditory pathways (Hocherman et al., 1976;Kraus and McGee, 1993;Kraus et

al., 1994;Grady et al., 1997;Busse et al., 2005). It is therefore possible that the larger than normal

amplitude of peak P2 observed in children with long-term cochlear implant experience reflects

increased cognitive demands for attention and multi-sensory system integration during hearing. This

may reflect compensatory mechanisms to offset: 1) the reorganization in the auditory brain potentially

occurring during the period of deafness prior to implantation; 2) the abnormal auditory input provided

by the cochlear implant; and/or, 3) the absence of sound to the un-implanted ear which may lead to

reorganization in the deprived pathways.

Cochlear implant users compensate for the abnormal input they receive through the device

(Doucet et al., 2006;Giraud and Lee, 2007;Lee et al., 2007a;Lee et al., 2007b;Hopyan-Misakyan et al.,

2009;Strelnikov et al., 2010;Hopyan et al., 2011;Kral and Sharma, 2011;Lazard et al., 2011;Hopyan et

al., 2012;Lazard et al., 2012;Sandmann et al., 2012). We found that children using cochlear implants

depend on visual cues more heavily than normal to listen for complex information embedded in

speech. Emotion perception was tested using 2 subtests of the standardized Diagnostic Analysis of

Nonverbal Behavior-2 (DANVA-2) in 18 cochlear implant users who received one implant by 2.9 ±

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0.9 years, had 7.2 ± 1.3 years of cochlear implant experience at the time of the test, and had good

speech perception skills. In the first test, children listened to the spoken sentence: “I’m going out of

the room now and I’ll be back later” (24 trials), and had to decide which 1 of 4 emotions (happy, sad,

angry or fearful) was conveyed by the voice. In the second test, children watched pictures of other

children’s faces, each depicting 1 of the same 4 emotions, and had to decide which emotion was

conveyed by the photographs. Performance accuracy was assessed for each task, and compared to 18

normal hearing controls who were matched for age (10.3 ± 1.5 years of age) (Hopyan-Misakyan et al.,

2009).

Children using cochlear implants showed significantly poorer than normal performance on the

emotion identification task in the auditory subtest (F(1,34) = 43.7, p>0.01). This deficit does not

reflect a general failure to identify emotions, however, since they performed as well as their peers with

normal hearing when the emotions were presented in the visual modality (F(1,34) = 0.1, p>0.05)

(Hopyan-Misakyan et al., 2009). The inability of these children to perceive emotions in speech might

reflect abnormal development of cortical representation of emotional prosody in speech without

normal hearing (Nishimura et al., 1999;Lee et al., 2001;Doucet et al., 2006;Lee et al., 2007b;Meredith

and Lomber, 2011;Sandmann, 2012;Sandmann et al., 2012).

In sum, unilateral cochlear implantation promotes the development of normal-like activity in the

auditory pathways over the long-term, but functional abnormalities persist. These could reflect: 1)

deleterious or irreversible changes to neural reorganization which occurred during the period of

auditory deprivation in early life, 2) abnormal representation of sound through electrical pulses

stimulation of the auditory system, and/or 3) abnormal cortical development driven by the absence of

auditory input to the deprived pathways from the opposite un-implanted ear. We have been studying

effects of the latter issue in children.

Binaural hearing is not available to traditional unilateral cochlear

implant users

Hearing through only one cochlear implant eliminates access to binaural hearing, which is the

ability of the auditory system to process and integrate auditory input from both ears. Binaural hearing

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is especially important for children because they are rarely in one place and listening to a single speaker

at a time. Children need to attend to and discriminate between several sound sources when playing

and learning. The noise, reverberation and distance, predominant in most situations including typical

classrooms, make it challenging for children to listen and learn when binaural cues are not accessible.

For children who are deaf in both ears, binaural hearing might achieved with bilateral cochlear

implantation (i.e., cochlear implants in both ears) (van Hoesel and Tyler, 2003;Litovsky et al.,

2004;Litovsky et al., 2006;Brown and Balkany, 2007;Litovsky, 2008;Steffens et al., 2008b;Basura et al.,

2009;Eapen and Buchman, 2009;Gordon et al., 2010;Salloum et al., 2010;Chadha et al., 2011;Gordon

et al., 2011b). Bilateral cochlear implantation is now being increasingly provided to children either in

the same surgery (simultaneously) or in two different surgeries following a period of unilateral implant

use (sequentially).

Bilateral cochlear implants attempt to restore binaural hearing by providing information to both

ears. Normally, the auditory system compares, processes and integrates subtle differences between

level and timing of sounds reaching each ear. In this way, binaural hearing allows: 1) the

identification/localization of sound sources in space (Batteau, 1967;Lorenzi et al., 1999;Van Deun et

al., 2009b;Grothe et al., 2010); 2) increased perception of loudness through binaural summation

(Bocca, 1955;Blegvad, 1975); and 3) improved hearing in quiet and in noisy environments through the

head shadow and squelch effects (Hawley et al., 2004;Van Wanrooij and Van Opstal, 2004). Binaural

hearing also makes communication less tiring which enables listening and communication to be a more

pleasant experience. Although restoring binaural hearing is the goal of bilateral implantation, this has

not been completely realized in either adults or children (van Hoesel and Tyler, 2003;Seeber and Fastl,

2008;Grieco-Calub and Litovsky, 2010;Salloum et al., 2010).

Children who are deaf in both ears hear speech better with bilateral cochlear implants than

unilateral implants (Litovsky et al., 2004;Brown and Balkany, 2007;Ching et al., 2007;Galvin et al.,

2007;Peters et al., 2007;Litovsky, 2008;Seeber and Fastl, 2008;Steffens et al., 2008a;Basura et al.,

2009;Eapen and Buchman, 2009;Gordon and Papsin, 2009;Van Deun et al., 2009a;Salloum et al.,

2010;Chadha et al., 2011), but do not hear binaural cues normally (Grieco-Calub and Litovsky,

2010;Salloum et al., 2010). Outcomes improve when both implants are provided with limited delays

and at young ages (van Hoesel and Tyler, 2003;Gordon and Papsin, 2009;Van Deun et al.,

2009a;Gordon et al., 2010;Chadha et al., 2011). As the duration of inter-implant delay decreases, the

two ears develop more symmetric speech perception abilities and children show increasing advantages

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of bilateral over unilateral implantation (Gordon and Papsin, 2009). Significant improvements on

standardized speech perception tests are seen as early as 6 months following bilateral cochlear implant

stimulation in children who receive their second implant simultaneously or within short delays

(Gordon and Papsin, 2009). Furthermore, children implanted with both cochlear implants

simultaneously derive significantly more benefit from spatial separation of noise compared to children

who have longer delays between implants (Chadha et al., 2011). Sound localization improves in

children who are provided access to sound early and in both ears (Van Deun et al., 2009a). By contrast,

children who receive both cochlear implants sequentially after long inter-implant delays (>2 years)

have persistent asymmetries in auditory function and compromised bilateral benefits for speech

perception, even after 36 months of bilateral cochlear implant use (Gordon and Papsin, 2009).

Sequentially implanted children also seem to depend more on their first implanted ear than their second

for speech perception, and show less bilateral improvement (relative to unilateral implant use) on

speech outcomes than children implanted simultaneously or with limited delay (Gordon and Papsin,

2009). These children localize sound inaccurately and rely heavily on level cues to do so (Grieco-Calub

and Litovsky, 2010). The negative effect of inter-implant delay might be explained by underlying

changes to the developing auditory pathways before and after unilateral and bilateral implantation.

Evidence of a short sensitive period for bilateral input in human

auditory development

Data presented in Figures 1 and 2 shows that unilateral stimulation promotes development of

the auditory pathways (Jiwani et al., 2013a), thus limiting effects of deafness. At the same time, this

development might occur at the expense of pathways from the opposite and deprived ear. This might

be explained by the absence of inhibition which would normally have come from input from the

opposite ear during binaural hearing (Grothe et al., 2010). Without this inhibition, ascending

projections from the stimulated ear may be abnormally strengthened in children who are deaf and use

unilateral cochlear implants.

We studied bilateral auditory function in children who had different durations of unilateral

exposure. We hypothesized that the stage of unilaterally driven brainstem development would be an

important factor to consider. Perhaps changes occurring in the brainstem at earlier stages of

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unilaterally driven development would have less long lasting consequences on the bilateral pathways

than after the unilaterally stimulated brainstem reached maturity. Development in the auditory

brainstem is largely complete by 1 year of unilateral implant use (Gordon et al., 2006). Thus, children

with >2 years of unilateral experience were categorized as having mature auditory brainstem function

and long-term unilateral use. Children with <1 year of unilateral experience were considered to have

short-term use with continuing auditory brainstem development. Auditory development in these

children was compared to that of children who were deaf and had not yet used cochlear implants (i.e.,

limited to no auditory brainstem development). All children were implanted bilaterally, allowing us to

assess auditory brainstem function evoked by stimulation from each ear. All children receiving bilateral

implants sequentially showed brainstem responses which were faster when evoked by the experienced

ear compared to the newly implanted ear at initial bilateral implant use (Gordon et al., 2008b). This

was expected and confirmed earlier findings that the first implant promoted improved neural

conduction through the brainstem. Repeated tests completed after 1.7 ± 1.65 year of bilateral implant

use indicated mismatches in response latencies persisted in a group of children receiving the second

implant after a long delay (>2 years) (Gordon et al., 2012). Increased response latencies in response

to sound from the second implanted side could reflect decreased axonal myelination, longer neural

conduction times, slower or weaker synapses or more asynchronous neural activity – all signs of more

limited brainstem development. Abnormal mismatches between brainstem response latencies were

never present in children receiving bilateral implants simultaneously and resolved with bilateral implant

use in children who received both implants after a short inter-implant delay (<1 year) (Gordon et al.,

2007b;Gordon et al., 2008b;Gordon et al., 2011b;Gordon et al., 2012). Thus, allowing the brainstem

to develop unilaterally for >2 years compromises the later promotion of symmetrically functioning

bilateral auditory brainstem pathways.

Mismatched bilateral auditory development in sequentially implanted children was not restricted

to the brainstem. Effects of asymmetric activity in the pathways from the first stimulated ear were

also found in the auditory cortex. Consistent with the brainstem findings, cortical abnormalities were

not resolved by chronic bilateral implant use (3.57 ± 0.74 years) when unilateral experience exceeded

1.5 years in children who were implanted early (1.87 ± 1.25 years of age). These findings were recently

reported by Gordon et al. (2013) and are shown in Figure 3 (re-printed from that paper). We used a

unique and validated ‘Time Restricted Artifact and Coherent Suppression’ (TRACS) beamformer

method (Wong and Gordon, 2009) to suppress the electrical artifact from the cochlear implant device

260

and spatially localize areas of cortical activity in hemispheres ipsilateral and contralateral to stimulation.

Like many imaging methods, the brain was divided into thousands of 3-dimensional coordinate spaces

(voxels). Responses were recorded at 64-cephalic surface electrodes and the contribution of the dipole

centered in each voxel to the measured field was assessed by the adaptive spatial filter of the TRACS

beamformer. Dipole moments for a given voxel were calculated across latency (virtual sensor) and

peak values were used for analyses.

Cortical responses were evoked by unilateral electrical pulse trains delivered from one implant

electrode in 7 children with normal hearing, 8 children who were implanted unilaterally in the right ear

(2.32 ± 1.61 years) and had 7.21 ± 2.48 years of hearing experience and 26 children who used bilateral

cochlear implants for 3.42 ± 0.59 years. Of the bilateral implant users, 10 children received both

cochlear implants simultaneously and 16 were sequentially implanted (right ear implanted first with no

hearing aid in the left ear). Bilateral deafness prior to implantation was limited (1.74 ± 0.90 years) in

all children. The children in this study had less than 12 years of hearing experience, and therefore all

produced a cortical evoked response which was dominated by an immature large amplitude positive

peak, similar to the one shown in Figure 2a. The differences between the dipoles from the left and

right auditory cortices were normalized as a percent lateralization (% lateralization = (dipole right –

dipole left) / (dipole right + dipole left) x 100).

A larger than normal variability in the lateralization of cortical dipoles was found in children

receiving bilateral cochlear implants sequentially. A factor analysis of multiple demographic variables

identified the duration of unilateral implant use as the factor which best accounted for the spread of

cortical responses. We thus further analyzed the cortical lateralization data for effects of duration of

unilateral implant use occurring prior to bilateral implantation. When responses were evoked by the

first (i.e., right) implant, there was an increase in lateralization of activity to the contralateral left

auditory cortex with unilateral implant use. This became significantly larger than the percent of cortical

lateralization in the simultaneously implanted group at 1.48 years of unilateral implant use. Consistent

results were obtained in data evoked by the second (i.e., left) implant but, in this case, cortical

lateralization changed from the normally expected contralateral direction to ipsilateral lateralization

with unilateral implant use. This abnormal switch to larger activity in the ipsilateral auditory cortex

became significantly different from responses in the simultaneously implanted group by 1.37 years of

unilateral implant use. These analyses indicated that children with longer than approximately 1.5 years

of unilateral implant use had experienced an abnormal strengthening of pathways from their first

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implanted right ear through the auditory brainstem (Gordon et al., 2008b;Gordon et al., 2012) to their

left contralateral cortex. This was not resolved by several years of bilateral implant use and was

associated with poorer speech perception in the second than first implanted ear (Gordon et al., 2013).

The importance of restricting unilateral implant use to less than 1.5 years is further evident in

Figure 3 (reprinted from Gordon et al., 2013). Here, the grand mean lateralization of cortical activity

are shown (Figure 3a), as well as the grand mean dipole moments identified from the virtual sensors

in each hemisphere (Figure 3b). The group of 16 sequentially implanted children have been divided

into two groups based the cut off of 1.5 years of unilateral implant use. The Short Delay group includes

7 children who had 0.86 ± 0.1 years of unilateral implant experience at the time of testing. The other

9 children, the Long Delay group, had more than 2 years of unilateral implant use (3.44 ± 1.27 years).

The single positive peaked response is clear in all of the group averaged waveforms shown in Figure

3b. The maximum dipoles were marked and analyzed in each child. The left plot of Figure 3c shows

that dipoles evoked by stimulation from the first/right implanted ear resulted in significantly higher

dipoles in the left auditory cortex (blue bars) of children who had >1.5 years of unilateral implant use

(Unilateral and Long Delay groups) than other groups of children (F(4,36)=3.52, p<0.05). The similar

findings for these two groups confirm that unilaterally driven strengthening of projections to the

contralateral left auditory cortex was not reversed by the addition of a second cochlear implant. This

was true despite the children in the Long Delay group having had several years of bilateral implant

experience at the time of the test. The right plot in Figure 3c shows mean dipoles for each auditory

cortex in response to left/second cochlear implant stimulation. The Long Delay group shows

significantly higher dipole moments in the left auditory cortex than the other groups of children

(F(3,29)=5.31, p<0.01). Thus, regardless of which ear was stimulated, the left auditory cortex

(contralateral to the first/right implanted ear) was the more active side of the brain in children who

had used one implant for >1.5 years. One explanation for this finding is that the specialized processing

of language in left auditory cortex (Zatorre and Belin, 2001;Zatorre et al., 2002;Tervaniemi and

Hugdahl, 2003;Firszt et al., 2006) is abnormally increased in unilateral cochlear implant users. It is not

clear, however, how such a network would have been recruited by the simple non-speech stimuli used

in the present experiment. An alternate explanation is that unilateral stimulation allowed abnormal

strengthening of pathways from that ear.

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Figure 3: Re-printed with permission from Gordon et al. (2013). “(A) Per cent cortical lateralization

(mean ± 1 standard error) is plotted for each participant group. Greater than normal contralateral

lateralization to right/CI-1 stimuli was found in long delay and unilateral cochlear implant users

(P<0.05 and <0.0001, respectively) but not in short delay and simultaneous groups (P>0.05). The long

delay group showed a decrease in contralateral lateralization/increase in ipsilateral lateralization relative

to those with normal hearing in response to left/CI-2 stimulation. This did not occur in the short delay

and simultaneous groups. (B) Grand mean virtual sensor data for left and right hemispheric sources

of P1 (normal hearing) and P1ci (cochlear implant users for stimulation from right/CI-1 and left/CI-

2). Large peaks in responses to CI-1 (right) stimulation can be seen in the long delay and unilateral

group data. (C) Left and right hemispheric dipole moments (mean ± 1 SE) for P1/P1ci in each group

in response to right/CI-1 and left/CI-2 stimulation. In response to CI-1 (right) stimulation, there is a

marked increase in left hemispheric dipole moments in participant groups with >2 years of unilateral

hearing experience (long delay and unilateral; P<0.05).” (Gordon et al., 2013, Brain, Figure 7, p.11)

Further evidence that the cortical changes were due to unilaterally driven strengthening was

found by assessing activity in the ipsilateral/right auditory cortex. We assessed which ear preferentially

activated the hemisphere contralateral to the ear deprived during the period of unilateral implant use

(i.e., the right auditory cortex). The right auditory cortex was expected to respond more strongly to

input from the left than right ear because the majority of neurons from one ear normally cross to the

contralateral brainstem and ascend ipsilaterally from there. This was confirmed in the group of

children with normal hearing and children with limited unilateral implant use prior to bilateral

implantation (Short Delay and Simultaneous). By contrast, this pattern was reversed in children in the

Long Delay group. This meant that this group of children had experienced a strengthening of

pathways from their hearing ear to both the ipsilateral (right) cortex, as shown by the reversal of aural

preference, as well as the contralateral (left) cortex as shown by the data in Figure 3. The same reversal

of aural preference in the cortex ipsilateral to the hearing ear has recently been reported in congenitally

deaf white cats (Kral et al., 2013).

The abnormal strengthening of pathways from the unilaterally hearing ear to the immature brain

seems to initially occur at the level of the brainstem. This is supported by evidence of mismatched

brainstem latencies observed from children with long (>2 years) unilateral hearing experience (Gordon

264

et al., 2012). The shorter wave eV latencies evoked from the more experienced ear suggest an

increasing efficiency of activity from this side and a weakening of pathways from the opposite ear, as

reflected by slower peak latencies on the second implanted side. This could result from a lack of

inhibitory processes in the brainstem which are normally present during binaural hearing (Grothe et

al., 2010). Listening from one side would allow auditory input from the first right implanted side to

be projected to the cortex with abnormally high excitation during development thus strengthening

pathways to the contralateral cortex. It appears that if this is allowed to occur until the brainstem is

largely developed (i.e., >1 year of unilateral implant use), it establishes asymmetric activity in the

auditory pathways which is not easily reversed by providing a second implant in the deprived ear.

Limiting the period of unilateral hearing in children by providing bilateral cochlear implants with little

or no delay appears to protect the bilateral pathways from this abnormal development. These findings

thus suggest that there is a sensitive period of 1.5 years for binaural auditory development in children.

Long-term unilateral implant use in older children causes lasting

asymmetry in the bilateral auditory pathways

We make the case above that unilateral implant use in children who have been deaf since infancy

should be limited to less than 1.5 years to promote normal-like symmetrical development of the

auditory pathways from both ears. However, providing bilateral implants within this time frame may

not always be possible. For example, many adolescents/young adults who were implanted as babies

and have already had many years of unilateral hearing experience are now seeking a cochlear implant

for their opposite ear in hopes of deriving benefits of bilateral implantation. These children are

different in several ways from our previous research cohorts of sequentially implanted children. They

have had very long periods of unilateral cochlear implant use concurrently with long durations of

deprivation in their non-implanted ear, and they are no longer children. We thus expect unique cortical

development in this new group of bilateral implant users relative to our previous study groups.

Figure 4 shows the cortical responses recorded at a midline cephalic location on the head (Cz)

and evoked by cochlear implant stimulation from each ear on the first day of activation of the second

implant in a child who had 15.95 years of hearing experience on the right side and was deprived of

auditory input in the left ear. These measures were repeated after 1 month of bilateral implant use and

265

then again after 9 months. Responses from the latter two time points are shown in Figures 4b and 4c,

respectively. The red waveform shows the grand mean response recorded from the side with long-

term unilateral cochlear implant experience, and the blue is the cortical waveform evoked by

stimulation of the newly implanted side (naïve side). The two responses are very different from one

another at all time points. Consistent with previous findings, the cortical responses from the

experienced side (red waveform) in Figure 4 were dominated by a mature-like morphology, comprised

of the obligatory peaks P1-N1-P2-N2, similar to those expected in same aged peers with normal hearing

(Jiwani et al., 2013a). By contrast, responses recorded from the newly implanted ear (blue waveform)

were characterized by different peaks occurring with much larger amplitudes than the responses from

the side with long-term hearing experience; a large negative peak (N(ci), followed by a large positive

peak (P(ci)) can be seen (Jiwani et al., 2013b;Jiwani et al., 2013c). Little changes to either response

occurred over the first months of bilateral implant use. Slight decreases in the latencies and amplitudes

of the peaks evoked by the newly implanted ear were found after one month (Figure 4b), with almost

no change in latency, amplitude or waveform morphology thereafter. This is shown by the response

recorded at 9 months following activation of the second implant in Figure 4c.

Figure 4: Example of cortical evoked responses from an adolescent in the Jiwani et al. (2013b) and

Jiwani et al. (2013c) study cohorts. She received a right unilateral cochlear implant (red waveform)

within limited durations of bilateral deafness (3 years of age) and used it unilaterally to hear for 15.95

years. She then received a second implant in the opposite and deprived left side (naïve side) (blue

waveform). Cortical responses evoked from both implants are shown at: (A) the first day of activation

of the second implanted ear (Jiwani et al., 2013b), (B) one month after bilateral implantation (Jiwani et

al., 2013c) and (C) nine months following bilateral cochlear implant experience (Jiwani et al., 2013c).

266

The lack of cortical development evoked by stimulation of the second implanted side is in

contrast to the rapid developmental change expected to occur at early stages of unilateral cochlear

implant use in young children (Sharma et al., 2002a;Sharma and Dorman, 2006), and, rather, more

similar to the limited change reported in older children implanted after long durations of bilateral

deafness (Sharma et al., 2002b;Gordon et al., 2005;Gordon et al., 2008a). This might reflect immaturity

or abnormalities in auditory development from the second implanted side, driven by either long

duration of auditory deprivation or by maturation of the auditory cortex from unilateral cochlear

implant use. Providing a second implant to children after this period has passed may prevent the naïve

cortical pathways from developing after an important period in cortical auditory development has been

missed. The findings from our previous study (Gordon et al., 2013) (discussed above and shown in

Figure 3) suggest that there is an early sensitive period for bilateral brainstem development (exceeded

after 1.5 years of unilateral implant use) and a later cortical maturation promoted by unilateral use of

over 10 years (Jiwani et al., 2013a), as shown by the data in Figure 4 (Jiwani et al., 2013b;Jiwani et al.,

2013c). Together, these results suggest that there are multiple sensitive periods in the developing

auditory system.

Bilateral implantation within a sensitive period improves perception of

binaural timing cues

As reviewed above, several lines of investigation suggest that the potential for promoting

binaural hearing in children who are deaf will be best realized by limiting the period of bilateral deafness

and providing bilateral implants with little delay. We have been studying the perception of binaural

level and timing cues in children who received bilateral cochlear implants because these cues are

important for binaural hearing. Interaural level and timing cues arise because sounds coming from

one side of the head reach the closer ear at higher intensities and/or faster than the other ear. Level

and timing differences are coded in the auditory brainstem by the degree of inhibition (Grothe et al.,

2010).

We found that 19 children receiving one implant at 2.1 ± 1.1 years of age and the second after

4.9 ± 2.8 years of unilateral implant use can hear changes in interaural level differences but have

particularly poor abilities to detect interaural timing cues even after several years of bilateral cochlear

267

implant use (Salloum et al., 2010). Poor detection of binaural timing cues by sequentially implanted

children was surprising given evidence from a similar group showing that the auditory brainstem

integrates input from both implants as measured by the electrophysiological binaural interaction

component (Gordon et al., 2012). This measure is a calculated difference between the sum of the left

and right evoked auditory brainstem responses and the bilaterally evoked brainstem response. Peaks

in the difference response reflect inhibition occurring with binaural processing (Dobie and Berlin,

1979;Dobie and Norton, 1980;Brantberg et al., 1999). Using this difference measure, we found that

tonotopic organization is maintained in the bilateral brainstem of children who are deaf and that the

pathways continue to code interaural level cues despite development driven from one ear before the

other. There are consequences of the mismatches in development resulting from unilateral implant

use. Although the auditory brainstem codes interaural timing differences, this does not occur normally

(Gordon et al., 2008b). A miscalculation of binaural brainstem interactions results from the mismatch

in neural conduction (measured by shorter peak latencies responses from the more experienced ear).

More recent findings show that a sound arriving first to the more experienced ear by 1ms, for example,

reduces the binaural interaural component more than when it arrives first by the same amount to the

second implanted ear (Gordon, et al., in preparation). Nonetheless, coding of interaural timing remains

(albeit abnormally calibrated); thus abnormal brainstem processing cannot account for the profound

difficulties these children have detecting timing differences sent by their bilateral implants. This

suggests a deficit for interaural timing processing in more central areas of the auditory system which

likely occurred during the period before bilateral implantation. In support, the numbers of cortical

neurons specialized to respond to interaural timing cues are reduced in congenitally deaf white cats

(Tillein et al., 2010) as are numbers of neurons in auditory cortices responsible for sound localization

(Malhotra et al., 2008). In more recent work, we are asking whether binaural timing cues are better

heard by children who received bilateral cochlear implants simultaneously. Preliminary findings

suggest good potential for development of binaural hearing in children who have limited durations of

bilateral and unilateral deafness, but is compromised in children with long unilateral cochlear implants

experience (>1.5 years).

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Conclusions

We have reviewed evidence showing that access to sound within limited durations of bilateral

deafness in early life promotes normal-like development of activity along the auditory pathways in

children who have many years of hearing experience with a unilateral cochlear implant. At the same

time, however, the unilaterally driven stimulation leaves the opposite pathways deprived of input and

susceptible to reorganization. We find that providing bilateral cochlear implants to children after a

period of unilateral deafness of longer than 1.5 years drives abnormal mismatches in activity at the

level of the brainstem and cortex. This is characterized by abnormal strengthening of activity to both

the contralateral and ipsilateral auditory cortices from the first implanted ear. These abnormalities in

auditory development are associated with more asymmetric speech perception, poorer hearing in noise,

abnormal sound localization, and an inability to identify inter-aural timing cues. These skills are

important for normal integration and processing of auditory input. We therefore suggest that binaural

hearing is compromised in children who receive bilateral cochlear implants after a period of unilateral

implant use exceeding 1.5 years. With that in mind, cochlear implants should be provided to children

early as well as bilaterally within very limited or no delays between implants (i.e., simultaneously). Our

current studies are now examining how much residual hearing is needed in the un-implanted ear to

provide a potential protective effect against unilaterally driven reorganization and whether bimodal

hearing (acoustic and electrical input) can be used to restore binaural hearing. Further, we are asking

whether the sensitive period for bilateral input can be “reopened” by attempting to strengthen

pathways from the second implanted ear to restore symmetric bilateral pathways and binaural hearing.

Our findings suggest that both bilateral and unilateral deprivation should be limited to promote

optimal binaural hearing in children who use cochlear implants, and enable them to function better

and more naturally in challenging listening situations such as the playground or classroom

environments.

269

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Copyright Acknowledgements

Peer-Reviewed Publications

Papers deriving from this thesis have been published in:

Gordon, K. A., Jiwani, S., & Papsin, B. C. (2013). Benefits and detriments of unilateral cochlear

implant use on bilateral auditory development in children who are deaf. Frontiers in

Psychology, 4(719): 1-14.

Jiwani, S., Papsin, B. C., & Gordon, K. A. (2013). Central auditory development after long-term

cochlear implant use. Clinical Neurophysiology, 124(9), 1868-1880.

Chapter 4 has been submitted for publication in Human Brain Mapping and is in review:

Jiwani, S., Papsin, B. C., & Gordon, K. A. Early unilateral cochlear implantation promotes mature

cortical asymmetries in adolescents who are deaf

Chapter 5 has been submitted for publication Cerebral Cortex and is in review:

Jiwani, S., Doesburg, S. M., Papsin, B. C., & Gordon, K. A. Temporally coordinated activity in the

brain is promoted by long-term unilateral cochlear implant use in adolescents

Figure 2.9 and Figure 3.2 have been published in:

Jiwani, S. & Gordon, K. A. (2012). “Figure 9-1”, Chapter 9 - p.134 in Objective Measures in Cochlear

Implants, Michelle L. Hughes, Editor. Plural Publishing Inc

Jiwani, S., & Gordon, K. A. (2012). “Figure 10-2”, Chapter 10 - p.142 in Objective Measures in

Cochlear Implants, Michelle L. Hughes, Editor. Plural Publishing Inc

283

Peer-Reviewed Presentations

Papers deriving from this thesis have been presented at the following conferences:

Jiwani, S., Doesburg, S. M., Papsin, B. C. and Gordon, K. A. (October 2014). Unilaterally driven

cortical maturation leads to lasting asymmetries in the bilateral auditory pathways in adolescents

who are deaf and use one cochlear implant. 8th International Symposium on Objective

Measures in Auditory Implants, Toronto-ON, Canada. Podium (Student Travel Award)

Jiwani, S., Doesburg, S. M., Papsin, B. C. and Gordon, K. A. (February 2014). Temporally

coordinated activity in the brain is promoted by long-term cochlear implant use in children.

Association for Research in otolaryngology 37th MidWinter Meeting, San Diego-CA,

USA (NIH NIDCD Audiologist Travel Award; The Hospital for Sick Children Travel Award)

Gordon, K. A., Wong, D., Jiwani, S., De Vreede, D. and Papsin, B. C. (February 2014).

Developmental consequences of unilateral stimulation/deprivation in children using one

cochlear implant. Association for Research in otolaryngology 37th MidWinter Meeting,

San Diego-CA, USA. Podium

Gordon, K. A., Jiwani, S., Wong, D. and Papsin, B. C. (November 2013). Does unilateral cochlear

implant use promote cortical development at the expense of pathways from the unstimulated

ear?. 1st Global Otology Research Forum, Antalya, Turkey. Podium

Jiwani, S. (October 2013). Understanding brain responses in adolescents who are new bilateral

cochlear implant users. 4th Annual MidWest Conference Miniconference on Cochlear

Implants, Madison-WI, USA. Podium

Jiwani, S., Papsin, B. C. and Gordon, K. A. (July 2013). Long durations of unilateral cochlear

implant use do not protect the un-stimulated pathways from effects of auditory deprivation.

Conference on Implantable Auditory Prosthesis, Lake Tahoe-CA, USA (NIH NIDCD

Podium Presenter Travel Award)

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Jiwani, S. (May 2013). Long durations of deafness and use of sign language do not promote auditory

development in adolescents who are unilateral cochlear implant users. Percy Ireland Day,

University of Toronto, Department of Otolaryngology, Toronto – ON. Podium (Best

Presentation Award - Graduate Students Category)

Jiwani, S., Wong, D. D. E., Papsin, B. C. and Gordon, K. A. (April 2013). Does a sensitive period

exist for the development of the bilateral auditory pathways in cochlear implant users?

American Academy of Audiology – Academy Research Conference, Anaheim-CA, USA.

Podium (NIH NIDCD Podium Presenter Travel Award - Ranked 1st)

Jiwani, S., Papsin, B. C. and Gordon, K. A. (February 2013). Extensive areas of the cortex are

evoked by stimulation from the newly implanted ear in children who were long-term unilateral

cochlear implant users. Association for Research in otolaryngology 36th MidWinter

Meeting, Baltimore-MD, USA (The Hospital for Sick Children Travel Award; NIH NIDCD

Audiologist Travel Award; NIH NIDCD Graduate Student Travel Award)

Jiwani, S., Tanaka, S., Papsin, B. C. and Gordon, K. A. (October 2012). “Auditory development

after cochlear implantation in children who use sign language as their primary mode of

communication”. Canadian Academy of Audiology Conference, Ottawa – ON. Podium

(University of Toronto School of Graduate Studies Conference Grant)

Jiwani, S. (May 2012). Stimulation from the newly implanted ear in children who were long-term

unilateral cochlear implant users drives diffuse activity in the brain. Percy Ireland Day,

University of Toronto, Toronto – ON. Podium

Jiwani, S., Papsin, B. C. and Gordon, K. A. (July 2011). Central auditory development after long-

term cochlear implant use. 13th International Symposium on Cochlear Implants in

Children, Chicago – Illinois, USA (NIH NIDCD Mentored Doctoral Student Award)

Jiwani, S., Valero, J., Jewell, S. Papsin, B. C. and Gordon, K. A. (September 2010). Electrically

evoked middle latency responses at initial bilateral cochlear implant use. 6th International

Symposium on Objective Measures in Auditory Implants, Washington University Medical

Center, St. Louis – Missouri, USA (NIH NIDCD Student Poster Travel Award)

Mapping long-term cortical maturation of the auditory ... · Salima Jiwani Doctor of Philosophy...

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