Clinical Study Acoustic Coordinated Reset Neuromodulation ...

Clinical StudyAcoustic Coordinated Reset Neuromodulation in a Real LifePatient Population with Chronic Tonal Tinnitus

Christian Hauptmann1 Armin Stroumlbel2 Mark Williams3 Nitesh Patel3 Hannes Wurzer4

Tatjana von Stackelberg5 Uwe Brinkmann6 Berthold Langguth7 and Peter A Tass189

1 Institute of Neuroscience and Medicine-Neuromodulation (INM-7) Julich Research Center 52425 Julich Germany2CERES GmbH Evaluation amp Research 79539 Lorrach Germany3The Tinnitus Clinic Inc London W1G 6AX UK4Tinnitus Zentrum Promenadeplatz 80333 Munchen Germany5Ear Nose andThroat (ENT) Center 40667 Meerbusch Germany6Ear Nose andThroat (ENT) Clinic Hamm-Ahlen-Oelde 59302 Oelde Germany7Department of Psychiatry and Psychotherapy University of Regensburg 93053 Regensburg Germany8Department of Neurosurgery Stanford University Stanford CA 94305 USA9Department of Neuromodulation University of Cologne 50923 Cologne Germany

Correspondence should be addressed to Christian Hauptmann chauptmannfz-juelichde

Received 3 November 2014 Accepted 11 January 2015

Academic Editor Aage R Moslashller

Copyright copy 2015 Christian Hauptmann et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Purpose Primary tinnitus has a severe negative influence on the quality of life of a significant portion of the general populationAcoustic coordinated reset neuromodulation is designed to induce a long-lasting reduction of tinnitus symptoms To test acousticcoordinated reset neuromodulation as a treatment for chronic tonal tinnitus under real life conditions an outpatient study ldquoRESETReal Liferdquo was commissioned by ANM GmbH Herein we present the results of this study Methods In a prospective open-labelnonrandomized noncontrolled multicenter clinical study with 200 chronic tinnitus patients tinnitus questionnaire TBF-12 andGlobal Clinical Improvement-Impression Scale (CGI-I7) are used to study the safety and efficacy of acoustic coordinated resetneuromodulation 189 patients completed the last 12-month visit 11 patients dropped out (8 because of nontreatment related reasons2 because tinnitus did not change and 1 because tinnitus got louder) Results Acoustic coordinated reset neuromodulation causeda statistically and clinically significant decrease in TBF-12 scores as well as in CGI-I7 after 12 months of therapy under real lifeconditions There were no persistent adverse events reported that were related to the therapy Conclusion The field study ldquoRESETReal Liferdquo provides evidence for safety and efficacy of acoustic coordinated reset neuromodulation in a prospective open-label reallife setting

1 Introduction

The perception of sound in the absence of a correspondingsound source is the definition of primary tinnitus which inits chronic form affects 10ndash15 of the general population inindustrialized countries [1] About 2 are severely impairedin their quality of life because of chronic tinnitus and rely onprofessional help [2 3]

A growing body of evidence suggests that altered spectralpower of neural signals that is altered statistical distribution

of power over frequency as measured by EEGMEG is theneuronal fingerprint of primary tinnitus [4ndash10] and that theperception of tinnitus requires the involvement of a largernetwork of brain areas [11ndash14] There are now several reportsof oscillatory brain activity changes recorded via EEG intinnitus patients that reveal a decrease in alpha wave power(10ndash14Hz) within the primary auditory cortices [4 9] andan increase in slow wave delta activity (15ndash4Hz) [4 9 15]when compared to controls Slow wave oscillations havebeen attributed to hyperpolarization of thalamic nuclei as

Hindawi Publishing CorporationBioMed Research InternationalVolume 2015 Article ID 569052 8 pageshttpdxdoiorg1011552015569052

2 BioMed Research International

a result of auditory deafferentation which may enhancethalamocortical oscillations thus inducing pathological neu-ral synchrony that has been proposed as the progenitor oftinnitus perception [16]

Various approaches have been investigated for the treat-ment of primary tinnitus [17] such as cognitive behavioraltherapy [18] hearing aids [19] sound maskers [20] tinni-tus retraining therapy [21] medication [22ndash24] hyperbaricoxygen therapy [25] acupuncture [26] andneuromodulation[27] However meta-analytic evidence has only been foundfor a beneficial effect from cognitive behavioral therapy onquality of life of tinnitus patients but not on tinnitus loudness[18]

Acoustic CR neuromodulation is a noninvasive acous-tic stimulation therapy for primary tonal tinnitus whichwas developed computationally [28ndash30] The therapy isdesigned to counteract pathological neural synchrony bysustainably reducing the strength of synaptic connectivitybetween neurons within an affected cell population [8 14]In order to target the synchronized focus in the tonotopicallyorganized auditory cortex four acoustic tones are deliveredwith different frequencies centered around the characteristicfrequency of the patientrsquos tinnitus percept [8] This approachaims to reduce pathologically enhanced neural synchronywithin the primary auditory cortices which in turn resultsin a net decrease in effective connectivity across the globalbrain network involved in tinnitus perception [9 14] alongwith a decrease of tinnitus-related abnormal cross-frequencycoupling [31] The tonotopically targeted stimulation tonesare presented to the patient via a handheld tone generator(T30 CR neurostimulator) which utilizes earphones thatare adapted from receiver-in-the-ear-canal (RIC) hearingaids These RIC adapted earphones ensure that the patientrsquosexternal auditory meatus is not occluded by the headphonereceiver and enables a high degree of acoustic environmentaltransparency during stimulation tone presentation

First evidence for acoustic CR neuromodulation as beingan effective therapy for primary tonal tinnitus was providedby a randomized proof of concept trial a statistically and clin-ically significant improvement in tinnitus questionnaire (TQ)and visual analogue scale (VAS) for loudnessannoyancescores was obtained [8 32 33] Furthermore the analysisof EEG recordings demonstrated a change in pathologicallyaltered EEG power (ie 120572 120574 and 120575 band) towards normal-ization [8 9]

To consolidate the results from the RESET proof ofconcept study in a larger patient population and in a reallife outpatient setting a second study named RESET RealLife (RRL ClinicalTrialsgov NCT01435317) was conductedThe goal of the interventional multicenter RRL study wasto collect data for the confirmation of efficacy and safetyof twelve months of acoustic CR neuromodulation as atreatment of chronic tinnitus using the CE marked therapysystem T30 CR Tinnitus burden was assessed with the TBF-12 [34] tinnitus loudness and annoyance were measuredwith numeric rating scales (NRS ranging from 0 to 100)and clinical global improvement with the CGI-I7 In total200 patients were included in this prospective open-labelnonrandomized noncontrolledmulticenter study at 23 study

sites Herein we present the final data after 12 months oftherapy

2 Materials

200 patients were enrolled in this multicenter clinical studyon Acoustic CR neuromodulation between November 2011and May 2012 in 23 study centers run by ENT specialistslocated in Germany Inclusion criteria were symptomaticprimary tonal chronic tinnitus (ge3 months) lt60 dB hearingloss for all tested frequencies (125Hzndash8 kHz) and men andwomen ge 18 years old Patients were not included in the studyif they were found to be suffering from serious neurologicpsychiatric or otological disease objective tinnitus (eg tin-nitus caused bymuscle movements vascular noise and othersomatosounds) Menierersquos disease and tinnitus triggered bycraniomandibular disorders

Regular visits took place 05 1 2 3 6 9 and 12 monthsafter treatment start The mean age of the patients was 506years at study start and 763 of the patients were male(Table 1) 621 of patients had undergone two or moretinnitus treatments prior to acoustic CR neuromodulationwithout significant relief Among them 187 of patients hadundergone more than 5 previous tinnitus treatments Only152 of patients were treated with Acoustic CR neurostim-ulation as a first line therapy Most of the patients (682)suffered from bilateral tinnitus (see Table 1)

Subjects were asked what they believe was responsiblefor inducing their tinnitus We are aware about the lim-ited reliability of subjective causal attributions to tinnitusonset Nevertheless the answer to this question providessome orientation about individual etiologic factors [35 36]19 (95) patients responded that it is noise trauma 22(109) hearing problems 95 (473) stress and 65 (328)other reasons (multiple responses were allowed) The tin-nitus severity (based on the initial TBF-12 measurement)was slight (no handicap) for 318 (TBF-12 0ndash8 pts) mildfor 344 (TBF-12 9ndash12 pts) moderate for 241 (TBF-12 13ndash17 pts) and severe for 97 of the patients (TBF-12 18ndash24 pts) Tinnitus duration was less than six monthfor 20 between six months and four years for 320between four years and ten years for 294 and more thanten years for 366 of the patients 431113 showedno hearing impairment (averagedmaximal hearing impair-ment le20 dBHL) 528195 a mild hearing impairment(averagedmaximal hearing impairment between 20 dBHLand 40 dBHL) 41420 a moderate hearing impairment(averagedmaximal hearing impairment between 40 dBHLand 60 dBHL) and 00272 a severe hearing impairment(averagedmaximal hearing impairment gt60 dBHL)

The treatment with acoustic CR neuromodulationrequired regular visits to ENT clinics At the first visita thorough pitch matching process was carried out todetermine the tinnitus frequency Based on the evaluatedtinnitus frequency 119891

119879 four stimulation tones were defined

two below and two above the individual tinnitus frequency(frequency range [076119891

119879 14119891

119879]) The amplitudes of the

stimulation tones were adjusted in order to ensure that

BioMed Research International 3

Table 1 Demographic data of study population

Gendermale 151 (763)female 47 (237)

Agemean (std) 506 yrs (104)

Perception of tinnitusunilateral 63 (318)bilateral 135 (682)

Pretreatmentnone 30 (152)one 45 (227)getwo 123 (621)

Cause of tinnitusnoise trauma 19 (95)hearing problems 22 (109)stress 95 (473)

Tinnitus severityslight (no handicap) 62 (318)mild 67 (344)moderate 47 (241)severe 19 (97)

Tinnitus durationlt6 months 4 (20)6 months to 4 years 63 (320)4 years to 10 years 58 (294)gt10 years 72 (366)

Hearing impairment250Hzndash8000Hz(averagedmaximal)le20 dBHL 84 (431)22 (113)20 dBHLndash40 dBHL 103 (528)38 (195)40 dBHLndash60 dBHL 8 (41)82 (420)gt60 dBHL 0 (00)53 (272)

The information concerning the cause of tinnitus is based on a self-assessment of the patient and the tinnitus severity is based on the TBF-12 scores (missing values are not taken into account the total number ofsubjects varies between variables and percentages are calculated withouttaking missing values into account) Hearing impairment is listed with twovalues the averaged hearing impairment (in dBHL asmeasured by pure toneaudiometry as described inDINEN ISO8253-1within the range from250Hzto 8000Hz) for example averaged over all frequencies of the audiogramand themaximal hearing impairment for example themaximal impairmentobserved at one frequency

all tones were comfortably audible at the same subjectiveloudness level and slightly above the patientrsquos hearingthreshold

With this information (frequency and amplitude of stim-ulation tones) the handheld T30 CR device was programmedwith a randomized tone sequence which consisted of therepetitive application of the four stimulation tones with arepetition rate of 15Hz Short pauses within the stimulationsignal (CycOn = 3 CycOff = 2) are utilized in order to

enhance the process of unlearning pathological tinnitusactivity [37] The stimulation pattern containing the fourstimulation frequencies is designed to induce a phase reset ofabnormal delta oscillations at different locations within thetonotopically organized auditory cortex (see Figure 1)

The therapy was applied using the T30 CR neurostim-ulator which consists of a programmable battery-powereddevice combined with a customized open fit earphone thatutilizes a receiver-in-the-ear-canal (RIC) technology Theprescribing clinician uses propriety software to program theT30 CR neurostimulatorThe patients were asked to use theirT30 CR neurostimulator device every day for 4ndash6 hoursapplying the therapy signals either continuously or splittingup the stimulation time into sessions not shorter than onehour Visits to the ENT clinic took place at the beginningof the therapy and then 05 1 2 3 6 9 and 12 months afterbeginning of the therapy At each visit to the ENT clinic thetinnitus tone was measured by a thorough pitch matchingprocess and the device was reprogrammed when the tinnitustone was found to have changed

The primary outcome measure of the study is theanalysis of changes in tinnitus severity measured by theGerman version of tinnitus handicap inventory (TBF-12Tinnitus-Beeintrachtigungs-Fragebogen) or improvement ofthe Clinical Global Impression-Improvement Scale (CGI-I7)Improvement was defined as a statistically significant (119875 lt005) reduction of scores comparing baseline values to end oftreatment (visit after 12 months) All scores were obtained inthe off-stimulation situation

The TBF-12 tinnitus handicap inventory consists of 12questions leading to a total score of 24 points (worst result)Scores were categorized depending on the score recordedslight (no handicap) (0ndash8 pts) mild handicap (9ndash12 pts)moderate handicap (13ndash17 pts) and severe handicap (18ndash24 pts) [38] CGI-I7 consists of the seven categories verymuch improvedmuch improved slightly improved no changeslightly worse much worse and very much worse expressedby the numbers 1 to 7 (1 equals the very much improvementcategory)

For the final analysis outcome measurements for thefull 12 months of therapy were analyzed For the statisticalanalyses the 119905-test was utilized to evaluate the TBF-12 andthe sign test to evaluate the CGI-I7This final analysis reportsthe results of the primary (TBF-12 CGI-17) and secondaryendpoints (numeric rating scale (NRS) for tinnitus loudnessand annoyance) Additionally the patients were asked toreport their device usage pattern to allow for the assessmentof compliance

The 119905-tests were applied as paired one sided equalvariances equal sample size tests to TBF-12 (total score) NRSloudness and NRS annoyance Scores before and after treat-ment were compared Null hypothesis was the acquisitionof equal mean scores before and after treatment Alternativehypothesis was the acquisition of smaller means after treat-mentThe sign test was applied to CGI CGI was grouped in 2categories ldquoimprovementrdquo and ldquoequalworserdquoNull hypothesiswas the acquisition of same number of patients in ldquoimprove-mentrdquo and ldquoequalworserdquo categoryAlternative hypothesiswasmore patients in the ldquoimprovementrdquo category Significance


Primaryauditory cortex

Secondaryauditory cortex

Tinnitusactivity 05

1

8

16

1st cycle 2nd cycle 3rd cycle 1st cycle 2nd cycle 3rd cyclePause

Tone 1

Tone 2

Tone 3

Tone 4

Time

Freq

uenc

y

Tinnitus frequency (fT)2

4

Figure 1 Stimulation signal of acoustic CR neuromodulation

level was set to 005 No multiple testing corrections wereapplied Missing values in the data were treated as missingfor the analysis Data from drop-out patients was treated byLOCF (last observation carried forward) To determine thepredictors for therapy success receiver operating characteris-tics (ROC) curves were calculated using the 12-month dataTBF-12 total score NRS loudness and NRS annoyance wereused as potential predictors and therapy success was definedas CGI-I7 le 3

The study was performed in accordance with goodclinical practice guidelines and local ethics committees Allparticipating patients gave their written informed consentIndependent external clinical research associates and a clini-cal physician monitored the safety of the study Data analysiswas performed by an external contract research organization

3 Results

189 patients finished the 12-month treatment and 11 patientsdropped out for different reasons eight stated nontreatmentrelated reasons two stated that their tinnitus did not changeand one stated that his tinnitus got louder

The treatment was well tolerated and no serious adverseevents (AE) were reported An adverse event was defined asany untoward medical occurrence Technical and handlingproblems were also documented as AE for this study 89product-related AEs were reported Of these 89 product-related AEs 40 were device related (ie technical andhandling problems rapidly solved) The other 49 AEs areconsidered to be therapy related These were an additionalatonal noise (15) additional tinnitus tone (3) increase intinnitus burden (2) increase in loudness (13) tinnitus fre-quency shift (1) headaches (2) anxiety (1) tinnitus frequencyincreased to gt10 kHz (2) discomfort (7) itching of ear canals(2) and otalgia (1) All adverse events were recorded as beingtemporary with no permanent or sustainable features

After 12 months TBF-12 (total score) showed a meanreduction of 41 points (minus379) compared to baseline (119875 lt001 df = 191 119905 = minus123 Table 2 Figures 2(a) and 2(b))mean TBF-12 score at baseline was 108 points and after3 (612) months 79 (7567) points After 12 months thenumber of patients within the TBF-12 categories moderateand severe handicap decreased from 338 to 139 while

Table 2 Results of TBF-12 and CGI-I7 scores

(a)

Variable Visit [month] 119873 Mean SD Delta 119875 value

TBF-12 Score

0 195 108 50 na na3 193 79 47 minus273 lt0016 193 75 47 minus308 lt00112 195 67 50 minus379 lt001

(b)

CGI-I7 Patients(after 12 months119873 = 196) Number Relative number 119875 valueVery much improved (1) 17 87

lt001

Much improved (2) 49 25Slightly improved (3) 65 332No change (4) 48 245Slightly worse (5) 14 71Much worse (6) 2 1Very much worse (7) 1 05

the number of patients within the category slight (no hand-icap) increased from 318 to 641 The TBF-12 based effectsize of the treatment is 089 which corresponds to a largeeffect size

At the visit after 12 months the results of CGI-I7 revealedthat 131 (669) patients reported an improvement of theirtinnitus that is CGI-I7 categories 1 2 or 3 (119875 lt 001 119896 = 131119873 = 196 Table 2 Figure 2(c)) 245 felt no change (category4) and 86 reported feeling that their tinnitus had becomeworse (categories 5 6 and 7) (Table 2) After 3 months oftreatment 5859 (119875 lt 001 119896 = 116 119873 = 198) of thepatients reported an improvement of their tinnitus

After 12 months of treatment the loudness of tinnitus asobtained by a numeric rating scale (0ndash100) was reduced by111 points (189) compared to baseline (119875 lt 001 df = 194119905 = minus453 Table 3) mean NRS loudness at baseline was586 points and after 3 (612) months 537 (510475) pointsTinnitus related annoyance (also obtained by a numericrating scale (0ndash100)) was reduced by 147 points (252) after12 months of treatment as compared to baseline (119875 lt 001df = 197 119905 = minus3 14 Table 3) When asked if they are


0 3 6

TBF-

12

Month of visit12

0

5

10

15

20

25

1 6TBF-12 score at baseline

12 1824Re

lativ

e TBF

-12

chan

ge(

)

Impr

ovem

ent w

orse

ning

minus100

minus50

0

50

100

CGI-

I7 (

)

Month of visit

Very muchimproved

Much improvedSlightly improved

No changeSlightly worseMuch worseVery much worse

3 6 120

20

40

60

80

100

(a) (b) (c)

Figure 2 (a) TBF-12 scores at baseline and after 3 6 and 12 months of treatment (b) Relative TBF-12 change for the individual patientsThe position of the bar on the 119909-axis indicates the TBF-12 score at baseline (c) Distribution of the CGI-I7 scores after 3 6 and 12 months oftreatment Stars indicate statistically significant results (995333995333119875 lt 001)

Table 3 NRS scales for loudness and annoyance


NRS loudness

0 197 586 219 n a n a3 198 537 206 minus84 lt0056 197 510 215 minus130 lt00112 196 475 249 minus189 lt001

NRS annoyance


free of tinnitus after 12 months of treatment 544 of thepatients reported either that they are tinnitus-free (41) orthat tinnitus has no negative influence on their life any more(503)

In the course of the treatment the tinnitus pitch changedIn average a reduction of tinnitus pitch was observed (minus112after 3 months (119875 lt 005 df = 361 119905 = minus244) and minus156after 12 months of treatment (119875 lt 001 df = 359 119905 =minus320)) 556 of the patients showed a reduction of tinnitusfrequency of more than 10 331 of the patient showed anincrease of tinnitus frequency of more than 10 and for theremaining 113 of patients the tinnitus frequency changedless than 10 800587 of patients with a reduction oftinnitus frequency gt10 showed an improvement of TBF-12NRS loudness while this correlation is not significant(chi-squared test) These tinnitus pitch changes imply anadjustment of the therapy tones which was done during theregular visits

Based on the TBF-12 scores at baseline the patients weredivided into four separate subgroups relating to tinnitusseverity slight (no handicap) mild moderate and severe Atthe end of the study these scores were recorded as beingreduced by 341 364 390 and 415 respectivelycompared to the scores recorded at the beginning of therapyThe NRS loudness was reduced for these same subgroups by207 172 176 and 247 while the NRS annoyance wasreduced by 185 219 322 and 327 respectively

On average the stimulation device was used by patientsfor five hours per day Compliance was 87 at the beginningand fell to 73 after 12 months ldquoCompliancerdquo was self-expressed by the patients and was defined as at least 4-hour daily stimulation If the stimulation was split then eachstimulation block should be at least 1 hour longWe calculatedreceiver operating characteristics (ROC) curves to identifypredictors for therapy success (therapy success was definedas CGI le 3) Based on the 12-month data the area under thecurve (AUC) was as follows TBF-12 total score 073 NRSloudness 082 and NRS annoyance 083

4 Discussion

This prospective open-label nonrandomized noncontrolledmulticenter clinical study with 200 chronic tinnitus patientsdemonstrates safety and good applicability that is goodpatient compliance and low drop-out rate of acoustic CRNeuromodulation 189 patients finished the 12-month treat-ment which demonstrates a good patient adherence

The applied treatment acoustic CR neuromodulationconsists of a particular temporal pattern of stimulationtones intending the induction of local desynchronization ofpathologically enhanced neuronal synchronization which is


the neuronal correlate of the tinnitus symptoms By inducingdesynchronization which also affects limbic structures asso-ciated with the emotional perception of tinnitus [8 9 14]the stimulation signals start the process of unlearning thepathological signal with the aim of resulting in a long-termreduction of the tinnitus symptoms

Analysis of the results of this multicenter clinical studydemonstrates significant results in both primary endpointsBoth the TBF-12 and CGI-I7 results are statistically and clin-ically significant after 12 months of treatment [39]The initialtinnitus severity had only moderate effects on the treatmenteffect Furthermore this study serves to demonstrate thesafety of acoustic CR neuromodulation since of all device-related adverse events none was serious (ie life threateningor caused a hospitalization of the patient or disablement etc)

The final results of the RRL study including data from200 patients support the results of the original RESETstudy similar results were obtained within the larger patientpopulation under ldquoreal liferdquo conditions While in the RESETstudy after 3 months of treatment (group 1 same treatmentas in RRL) a change of minus288 was obtained for the tinnitusquestionnaire (TQ) the current study revealed a change ofminus273 in TBF-12 scores after a similar duration (visit after3 months) and minus379 after 12 months This indicates that acontinuation of the treatment beyond the initial 3months canbe very beneficial for the patient Continuous improvementover the whole duration of the study was also found fortinnitus loudness and annoyance and may suggest that atreatment duration beyond 12 months may further increasetreatment efficacy

The authors are aware of the limitations of this studywhich has been designed as an open study without a controlgroupThus it is not possible to reach a final conclusion withregards to what extent the observed effects are unspecific andto what extent they actually represent the specific effects ofCR neurostimulation However the ongoing improvement ofpatients over 12 months and their relatively high resistanceto previous treatments make placebo effects highly unlikelyA spontaneous recovery is unlikely as well given the relativelong tinnitus duration of most patients In 881 of thepatients a positive treatment effect over the first 3 months(ie CGI-I7 le 3 at month 3) correlated with a positivetreatment outcome after 12 months of therapy (ie CGI-I7le 3 at month 12) 586 of the patients recorded a positiveeffect after 3 months of treatment and 665 after 12 monthsTBF-12 improvement was seen to augment in this CGI-I7-based responder population from minus319 (3 months) tominus508 (12 months) NRS annoyance changed by minus216 (3months) andminus356 (12months) andNRS loudness changedby minus167 (3 months) and minus317 (12 months) while theCGI-I7-based nonresponders showed onlymoderate changes(TBF-12 minus213 and minus206 NRS annoyance +01 andminus54 and NRS loudness +39 and minus03 at 3 months andat 12 months resp) NRS annoyance resulted in the highestvalue in the ROC test which indicates that it is a good metricfor therapy successTherefore CGI-I7 combinedwith TBF-12and NRS annoyance seems to be a reliable and easy to handle

set of questionnaires and metrics which can be used in ENToutpatient settings as indicators of treatment effects

Our data (minus379 mean change in TBF-12) can be com-pared with recent results on effects of standard tinnitus careand cognitive behavior therapy (CBT) [40] Standard care(hearing aid or tinnitus masker 119899 = 161 8-month treatment)resulted in a change of tinnitus handicap inventory (THI)and tinnitus questionnaire (TQ) by minus119 and minus133respectively while specialized care (CBT 119899 = 175 8 monthstreatment) resulted in a change of THI andTQbyminus265 andminus262 respectively

Thus in summary the RRL study reveals that acoustic CRneuromodulation when applied for 12 months and used 4ndash6hours per day in patients suffering from primary and tonal ortone-like tinnitus is a safe and feasible technique and exertsencouraging effects on tinnitus loudness and severity

Conflict of Interests

ChristianHauptmann is employed by Julich Research Centerformerly working with ANM GmbH (Cologne Germany)He works as consultant for Brook Henderson Group and hasreceived research funding from the European Communitythe Federal Ministry of Education and Research (Germany)the Deutsche Forschungsgemeinschaft and the HelmholtzAssociation Armin Strobel is employed by CERES GmbHand worked as statistician of the CRO during the RRL studyHe was responsible for the statistical analysis of the traildata Mark Williams has a contractual relationship with TheTinnitus Clinic Ltd The Tinnitus Clinic Ltd is the UKdistributer for the acoustic coordinated reset neuromodula-tion therapy device Nitesh Patel has no financial intereststo declare Hannes Wurzer works as consultant of BrookHenderson Group Tatjana von Stackelberg has no financialinterests to declare Uwe Brinkmann has no financial inter-ests to declare Berthold Langguth received honoraria andspeakersrsquo fee from ANM Astra Zeneca Autifony LundbeckMerz MagVenture Novartis Pfizer and Servier researchfunding from the Tinnitus Research Initiative the GermanResearch Foundation the German Bundesministerium furBildung und Forschung the American Tinnitus AssociationAstraZeneca and Cerbomed funding for equipment fromMagVenture and travel and accommodation payments fromMedtronic Lilly Servier and Pfizer Peter A Tass is employedby Julich Research Center and works as Consulting Profes-sor at Stanford University formerly (till 072013) workingwith ANM GmbH (Cologne Germany) and shareholder ofANM He has received research funding from the Euro-pean Community the Federal Ministry of Education andResearch (Germany) the Deutsche Forschungsgemeinschaftthe Helmholtz Association Biomedical Primate and theMichael J Fox Foundation The clinical trial RRL was finan-cially supported by ANM GmbH Germany and BrookHenderson Group UK Patents protect acoustic CR neuro-modulation for example US patent 8423144 device andmethod for auditory stimulation Peter A Tass is an inventorof this patent and the assignee is Julich Research Center


Acknowledgments

The authors are very grateful for the contribution of the 23ENTrsquos that treated the 200 patients Namely this is the alpha-betic order Krister Bjorn Martin Bergmann (Nurtingen)Andreas Bodlien (Braunschweig) Uwe Brinkmann (Oelde)Christiane Fleissner (Freiburg) JoachimGubitz (Koln) Beat-rix Hahlbrock (Koblenz) Ute Hegemann-Gartner (Greven-broich) Kai Helling (Mainz) Mathias JoachimHugelschaffer(Philippsburg) Ovidiu Konig (Berlin) Jan Lohler (BadBramstedt) Olaf Muller (Augsburg) Daniel Osterland(Berlin) Tatjana von Stackelberg (Meerbusch) KathrinStolzer (HalleSaale) Axel Rosler (Radevormwald) Hans-Gunther Ullmann (Melsungen) Tobias-Sebastian Waller(Schweinfurt) Joachim Wichmann (Krefeld) Stephan Wolf(Furth) Hannes Wurzer (Munchen) Peter Ziegelmuller(Mannheim) andMarcus Zwingmann (Frankfurt)They alsowant to thank Christine Droll-Popilar and Violetta Pithan fordata entry and monitoring respectively

References

[1] J J Eggermont andL E Roberts ldquoTheneuroscience of tinnitusrdquoTrends in Neurosciences vol 27 no 11 pp 676ndash682 2004

[2] A Axelsson and A Ringdahl ldquoTinnitusmdasha study of its preva-lence and characteristicsrdquo British Journal of Audiology vol 23no 1 pp 53ndash62 1989

[3] B Langguth ldquoTinnitus the end of therapeutic nihilismrdquo TheLancet vol 379 no 9830 pp 1926ndash1928 2012

[4] N Weisz S Moratti M Meinzer K Dohrmann and T ElbertldquoTinnitus perception and distress is related to abnormal sponta-neous brain activity as measured by magnetoencephalographyrdquoPLoS Medicine vol 2 no 6 article e153 2005

[5] K Dohrmann T Elbert W Schlee and N Weisz ldquoTuning thetinnitus percept by modification of synchronous brain activityrdquoRestorative Neurology andNeuroscience vol 25 no 3-4 pp 371ndash378 2007

[6] N Kahlbrock and N Weisz ldquoTransient reduction of tinnitusintensity is marked by concomitant reductions of delta bandpowerrdquo BMC Biology vol 6 article 4 2008

[7] M Ortmann N Muller W Schlee and N Weisz ldquoRapidincreases of gamma power in the auditory cortex followingnoise trauma in humansrdquo European Journal of Neuroscience vol33 no 3 pp 568ndash575 2011

[8] P A Tass I Adamchic H J Freund T von Stackelbergand C Hauptmann ldquoCounteracting tinnitus by acoustic coor-dinated reset neuromodulationrdquo Restorative Neurology andNeuroscience vol 30 no 2 pp 137ndash159 2012

[9] I Adamchic T Toth C Hauptmann and P A Tass ldquoReversingpathologically increased EEG power by acoustic coordinatedreset neuromodulationrdquo Human Brain Mapping vol 35 no 5pp 2099ndash2118 2014

[10] J J Eggermont and P A Tass ldquoMaladaptive neural synchronyin tinnitus origin and restorationrdquo Frontiers in Neurology Inpress

[11] W Schlee N Weisz O Bertrand T Hartmann and T ElbertldquoUsing auditory steady state responses to outline the functionalconnectivity in the tinnitus brainrdquo PLoS ONE vol 3 no 11Article ID e3720 2008

[12] W Schlee T Hartmann B Langguth and NWeisz ldquoAbnormalresting-state cortical coupling in chronic tinnitusrdquo BMCNeuro-science vol 10 article 11 2009

[13] D De Ridder A B Elgoyhen R Romo and B LangguthldquoPhantom percepts tinnitus and pain as persisting aversivememory networksrdquo Proceedings of the National Academy ofSciences of the United States of America vol 108 no 20 pp8075ndash8080 2011

[14] A N Silchenko I Adamchic C Hauptmann and P A TassldquoImpact of acoustic coordinated reset neuromodulation oneffective connectivity in a neural network of phantom soundrdquoNeuroImage vol 77 pp 133ndash147 2013

[15] P Adjamian M Sereda O Zobay D A Hall and A RPalmer ldquoNeuromagnetic indicators of tinnitus and tinnitusmasking in patients with and without hearing lossrdquo Journal ofthe Association for Research in Otolaryngology vol 13 no 5 pp715ndash731 2012

[16] R Llinas F J Urbano E Leznik R R Ramırez and H J F VanMarle ldquoRhythmic and dysrhythmic thalamocortical dynamicsGABA systems and the edge effectrdquoTrends inNeurosciences vol28 no 6 pp 325ndash333 2005

[17] D E Tunkel C A Bauer and G H Sun ldquoClinical practiceguideline tinnitusrdquo OtolaryngologymdashHead and Neck Surgeryvol 151 no 2 supplement pp S1ndashS40 2014

[18] PMartinez-Devesa AWaddell R Perera andMTheodoulouldquoCognitive behavioural therapy for tinnitusrdquo CochraneDatabase of Systematic Reviews no 8 Article ID CD0052332010

[19] D J Hoare M Edmondson-Jones M Sereda M A Akeroydand D Hall ldquoAmplification with hearing aids for patients withtinnitus and co-existing hearing lossrdquoTheCochrane Database ofSystematic Reviews vol 1 Article ID CD010151 2014

[20] J Hobson E Chisholm and A El Refaie ldquoSound therapy(masking) in the management of tinnitus in adultsrdquo CochraneDatabase of Systematic Reviews no 11 Article ID CD0063712012

[21] J S Phillips and D McFerran ldquoTinnitus retraining therapy(TRT) for tinnitusrdquo Cochrane Database of Systematic Reviewsvol 3 Article ID CD007330 2010

[22] M P Hilton E F Zimmermann and W T Hunt ldquoGinkgobiloba for tinnitusrdquo The Cochrane Database of SystematicReviews vol 3 Article ID CD003852 2013

[23] P Baldo C Doree P Molin D McFerran and S CeccoldquoAntidepressants for patients with tinnitusrdquo Cochrane Databaseof Systematic Reviews vol 9 Article ID CD003853 2012

[24] C E Hoekstra S P Rynja G A van Zanten andMM RoversldquoAnticonvulsants for tinnitusrdquo Cochrane Database of SystematicReviews no 7 Article ID CD007960 2011

[25] M H Bennett T Kertesz M Perleth P Yeung and J PLehm ldquoHyperbaric oxygen for idiopathic sudden sensorineuralhearing loss and tinnitusrdquo Cochrane Database of SystematicReviews vol 10 Article ID CD004739 2012

[26] J I Kim J Y Choi D H Lee T Y Choi M S Lee and EErnst ldquoAcupuncture for the treatment of tinnitus a systematicreview of randomized clinical trialsrdquo BMC Complementary andAlternative Medicine vol 12 article 97 2012

[27] B Langguth and D de Ridder ldquoTinnitus therapeutic use ofsuperficial brain stimulationrdquo Handbook of Clinical Neurologyvol 116 pp 441ndash467 2013

[28] P A Tass ldquoA model of desynchronizing deep brain stimulationwith a demand-controlled coordinated reset of neural subpop-ulationsrdquo Biological Cybernetics vol 89 no 2 pp 81ndash88 2003


[29] P A Tass and M Majtanik ldquoLong-term anti-kindling effectsof desynchronizing brain stimulation a theoretical studyrdquoBiological Cybernetics vol 94 no 1 pp 58ndash66 2006

[30] P A Tass and O V Popovych ldquoUnlearning tinnitus-relatedcerebral synchrony with acoustic coordinated reset stimulationtheoretical concept and modellingrdquo Biological Cybernetics vol106 no 1 pp 27ndash36 2012

[31] I Adamchic B Langguth C Hauptmann and P A TassldquoAbnormal brain activity and cross-frequency coupling in thetinnitus networkrdquo Frontiers in Neuroscience vol 8 article 2842014

[32] I Adamchic B Langguth C Hauptmann and P A Tass ldquoPsy-chometric evaluation of visual analog scale for the assessmentof chronic tinnitusrdquoThe American Journal of Audiology vol 21no 2 pp 215ndash225 2012

[33] I Adamchic P A Tass B Langguth et al ldquoLinking the tinnitusquestionnaire and the subjective clinical global impressionwhich differences are clinically importantrdquoHealth and Qualityof Life Outcomes vol 10 article 79 2012

[34] R Gortelmeyer J Schmidt M Suckfull et al ldquoAssessment oftinnitus-related impairments and disabilities using the GermanTHI-12 sensitivity and stability of the scale over timerdquo Interna-tional Journal of Audiology vol 50 no 8 pp 523ndash529 2011

[35] B Langguth R Goodey A Azevedo et al ldquoConsensus for tin-nitus patient assessment and treatment outcome measurementtinnitus Research Initiative meeting Regensburg July 2006rdquoProgress in Brain Research vol 166 pp 525ndash536 2007

[36] P M Kreuzer M Landgrebe V Vielsmeier T Kleinjung D deRidder and B Langguth ldquoTrauma-associated tinnitusrdquo Journalof Head Trauma Rehabilitation vol 29 no 5 pp 432ndash442 2014

[37] B Lysyansky O V Popovych and P A Tass ldquoDesynchronizinganti-resonance effect of m N ONndashOFF coordinated resetstimulationrdquo Journal of Neural Engineering vol 8 no 3 ArticleID 036019 2011

[38] U S Bankstahl E P Elkin A Gebauer and R GortelmeyerldquoValidation of the THI-12 questionnaire for international usein assessing tinnitus Amulti-centre prospective observationalstudyrdquo International Journal of Audiology vol 51 no 9 pp 671ndash677 2012

[39] F Zeman M Koller M Schecklmann et al ldquoTinnitus assess-ment by means of standardized self-report questionnaires psy-chometric properties of the Tinnitus Questionnaire (TQ) theTinnitus Handicap Inventory (THI) and their short versions inan international and multi-lingual samplerdquo Health and Qualityof Life Outcomes vol 10 article 128 2012

[40] R F F Cima I H Maes M A Joore et al ldquoSpecialisedtreatment based on cognitive behaviour therapy versus usualcare for tinnitus a randomised controlled trialrdquoThe Lancet vol379 no 9830 pp 1951ndash1959 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



Computational and Mathematical Methods in Medicine

OphthalmologyJournal of


Diabetes ResearchJournal of



Research and TreatmentAIDS


Gastroenterology Research and Practice


Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


a result of auditory deafferentation which may enhancethalamocortical oscillations thus inducing pathological neu-ral synchrony that has been proposed as the progenitor oftinnitus perception [16]

Various approaches have been investigated for the treat-ment of primary tinnitus [17] such as cognitive behavioraltherapy [18] hearing aids [19] sound maskers [20] tinni-tus retraining therapy [21] medication [22ndash24] hyperbaricoxygen therapy [25] acupuncture [26] andneuromodulation[27] However meta-analytic evidence has only been foundfor a beneficial effect from cognitive behavioral therapy onquality of life of tinnitus patients but not on tinnitus loudness[18]

Acoustic CR neuromodulation is a noninvasive acous-tic stimulation therapy for primary tonal tinnitus whichwas developed computationally [28ndash30] The therapy isdesigned to counteract pathological neural synchrony bysustainably reducing the strength of synaptic connectivitybetween neurons within an affected cell population [8 14]In order to target the synchronized focus in the tonotopicallyorganized auditory cortex four acoustic tones are deliveredwith different frequencies centered around the characteristicfrequency of the patientrsquos tinnitus percept [8] This approachaims to reduce pathologically enhanced neural synchronywithin the primary auditory cortices which in turn resultsin a net decrease in effective connectivity across the globalbrain network involved in tinnitus perception [9 14] alongwith a decrease of tinnitus-related abnormal cross-frequencycoupling [31] The tonotopically targeted stimulation tonesare presented to the patient via a handheld tone generator(T30 CR neurostimulator) which utilizes earphones thatare adapted from receiver-in-the-ear-canal (RIC) hearingaids These RIC adapted earphones ensure that the patientrsquosexternal auditory meatus is not occluded by the headphonereceiver and enables a high degree of acoustic environmentaltransparency during stimulation tone presentation

First evidence for acoustic CR neuromodulation as beingan effective therapy for primary tonal tinnitus was providedby a randomized proof of concept trial a statistically and clin-ically significant improvement in tinnitus questionnaire (TQ)and visual analogue scale (VAS) for loudnessannoyancescores was obtained [8 32 33] Furthermore the analysisof EEG recordings demonstrated a change in pathologicallyaltered EEG power (ie 120572 120574 and 120575 band) towards normal-ization [8 9]

To consolidate the results from the RESET proof ofconcept study in a larger patient population and in a reallife outpatient setting a second study named RESET RealLife (RRL ClinicalTrialsgov NCT01435317) was conductedThe goal of the interventional multicenter RRL study wasto collect data for the confirmation of efficacy and safetyof twelve months of acoustic CR neuromodulation as atreatment of chronic tinnitus using the CE marked therapysystem T30 CR Tinnitus burden was assessed with the TBF-12 [34] tinnitus loudness and annoyance were measuredwith numeric rating scales (NRS ranging from 0 to 100)and clinical global improvement with the CGI-I7 In total200 patients were included in this prospective open-labelnonrandomized noncontrolledmulticenter study at 23 study

sites Herein we present the final data after 12 months oftherapy

2 Materials

200 patients were enrolled in this multicenter clinical studyon Acoustic CR neuromodulation between November 2011and May 2012 in 23 study centers run by ENT specialistslocated in Germany Inclusion criteria were symptomaticprimary tonal chronic tinnitus (ge3 months) lt60 dB hearingloss for all tested frequencies (125Hzndash8 kHz) and men andwomen ge 18 years old Patients were not included in the studyif they were found to be suffering from serious neurologicpsychiatric or otological disease objective tinnitus (eg tin-nitus caused bymuscle movements vascular noise and othersomatosounds) Menierersquos disease and tinnitus triggered bycraniomandibular disorders

Regular visits took place 05 1 2 3 6 9 and 12 monthsafter treatment start The mean age of the patients was 506years at study start and 763 of the patients were male(Table 1) 621 of patients had undergone two or moretinnitus treatments prior to acoustic CR neuromodulationwithout significant relief Among them 187 of patients hadundergone more than 5 previous tinnitus treatments Only152 of patients were treated with Acoustic CR neurostim-ulation as a first line therapy Most of the patients (682)suffered from bilateral tinnitus (see Table 1)

Subjects were asked what they believe was responsiblefor inducing their tinnitus We are aware about the lim-ited reliability of subjective causal attributions to tinnitusonset Nevertheless the answer to this question providessome orientation about individual etiologic factors [35 36]19 (95) patients responded that it is noise trauma 22(109) hearing problems 95 (473) stress and 65 (328)other reasons (multiple responses were allowed) The tin-nitus severity (based on the initial TBF-12 measurement)was slight (no handicap) for 318 (TBF-12 0ndash8 pts) mildfor 344 (TBF-12 9ndash12 pts) moderate for 241 (TBF-12 13ndash17 pts) and severe for 97 of the patients (TBF-12 18ndash24 pts) Tinnitus duration was less than six monthfor 20 between six months and four years for 320between four years and ten years for 294 and more thanten years for 366 of the patients 431113 showedno hearing impairment (averagedmaximal hearing impair-ment le20 dBHL) 528195 a mild hearing impairment(averagedmaximal hearing impairment between 20 dBHLand 40 dBHL) 41420 a moderate hearing impairment(averagedmaximal hearing impairment between 40 dBHLand 60 dBHL) and 00272 a severe hearing impairment(averagedmaximal hearing impairment gt60 dBHL)

The treatment with acoustic CR neuromodulationrequired regular visits to ENT clinics At the first visita thorough pitch matching process was carried out todetermine the tinnitus frequency Based on the evaluatedtinnitus frequency 119891

119879 four stimulation tones were defined

two below and two above the individual tinnitus frequency(frequency range [076119891

119879 14119891

119879]) The amplitudes of the

stimulation tones were adjusted in order to ensure that























Tinnitusactivity 05

1

8

16


Tone 1

Tone 2

Tone 3

Tone 4

Time

Freq

uenc

y


4




3 Results





(a)


TBF-12 Score


(b)


lt001






0 3 6

TBF-

12

Month of visit12

0

5

10

15

20

25


12 1824Re

lativ

e TBF

-12

chan

ge(

)

Impr

ovem

ent w

orse

ning

minus100

minus50

0

50

100

CGI-

I7 (

)

Month of visit

Very muchimproved



3 6 120

20

40

60

80

100

(a) (b) (c)




NRS loudness


NRS annoyance






4 Discussion














Acknowledgments


References















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of






































Tinnitusactivity 05

1

8

16


Tone 1

Tone 2

Tone 3

Tone 4

Time

Freq

uenc

y


4




3 Results





(a)


TBF-12 Score


(b)


lt001






0 3 6

TBF-

12

Month of visit12

0

5

10

15

20

25


12 1824Re

lativ

e TBF

-12

chan

ge(

)

Impr

ovem

ent w

orse

ning

minus100

minus50

0

50

100

CGI-

I7 (

)

Month of visit

Very muchimproved



3 6 120

20

40

60

80

100

(a) (b) (c)




NRS loudness


NRS annoyance






4 Discussion














Acknowledgments


References















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















0 3 6

TBF-

12

Month of visit12

0

5

10

15

20

25


12 1824Re

lativ

e TBF

-12

chan

ge(

)

Impr

ovem

ent w

orse

ning

minus100

minus50

0

50

100

CGI-

I7 (

)

Month of visit

Very muchimproved



3 6 120

20

40

60

80

100

(a) (b) (c)




NRS loudness


NRS annoyance






4 Discussion














Acknowledgments


References















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of



























Acknowledgments


References















































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of


































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Clinical Study Acoustic Coordinated Reset Neuromodulation ...

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Transcript of Clinical Study Acoustic Coordinated Reset Neuromodulation ...