This article was downloaded by: [Dr Yasmeen Faroqi-Shah]On: 19 November 2013, At: 08:36Publisher: RoutledgeInforma Ltd Registered in England and Wales Registered Number: 1072954Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK

AphasiologyPublication details, including instructions for authors andsubscription information:http://www.tandfonline.com/loi/paph20

Lesion analysis of languageproduction deficits in aphasiaYasmeen Faroqi-Shaha, Therese Klingb, Jeffrey Solomonc,Siyuan Liud, Grace Parkd & Allen Braund

a Department of Hearing and Speech Sciences, University ofMaryland, College Park, MD, USAb Johns Hopkins University Hospital, Baltimore, MD, USAc Medical Numerics, Germantown, MD, USAd National Institute of Deafness and Communication Disorders,Bethesda, MD, USAPublished online: 18 Nov 2013.

To cite this article: Yasmeen Faroqi-Shah, Therese Kling, Jeffrey Solomon, Siyuan Liu, GracePark & Allen Braun , Aphasiology (2013): Lesion analysis of language production deficits inaphasia, Aphasiology, DOI: 10.1080/02687038.2013.853023

To link to this article: http://dx.doi.org/10.1080/02687038.2013.853023

PLEASE SCROLL DOWN FOR ARTICLE

Taylor & Francis makes every effort to ensure the accuracy of all the information (the“Content”) contained in the publications on our platform. However, Taylor & Francis,our agents, and our licensors make no representations or warranties whatsoeveras to the accuracy, completeness, or suitability for any purpose of the Content. Anyopinions and views expressed in this publication are the opinions and views of theauthors, and are not the views of or endorsed by Taylor & Francis. The accuracyof the Content should not be relied upon and should be independently verifiedwith primary sources of information. Taylor and Francis shall not be liable for anylosses, actions, claims, proceedings, demands, costs, expenses, damages, and otherliabilities whatsoever or howsoever caused arising directly or indirectly in connectionwith, in relation to or arising out of the use of the Content.

This article may be used for research, teaching, and private study purposes. Anysubstantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,systematic supply, or distribution in any form to anyone is expressly forbidden. Terms

& Conditions of access and use can be found at http://www.tandfonline.com/page/terms-and-conditions

Dow

nloa

ded

by [

Dr

Yas

mee

n Fa

roqi

-Sha

h] a

t 08:

36 1

9 N

ovem

ber

2013

Lesion analysis of language production deficits in aphasia

Yasmeen Faroqi-Shah1, Therese Kling2, Jeffrey Solomon3,Siyuan Liu4, Grace Park4, and Allen Braun4

1Department of Hearing and Speech Sciences, University of Maryland, CollegePark, MD, USA2Johns Hopkins University Hospital, Baltimore, MD, USA3Medical Numerics, Germantown, MD, USA4National Institute of Deafness and Communication Disorders, Bethesda, MD,USA

Background: Three aspects of language production are impaired to different degrees inindividuals with post-stroke aphasia: ability to repeat words and nonwords, namepictures, and produce sentences. These impairments often persist into the chronic stages,and the neuroanatomical distribution of lesions associated with chronicity of each ofthese impairments is incompletely understood.Aims: The primary objective of this study was to investigate the lesion correlates ofpicture naming, sentence production, and nonword repetition deficits in the same parti-cipant group because most prior lesion studies have mapped single language impair-ments. The broader goal of this study was to investigate the extent and degree of overlapand uniqueness among lesions resulting in these deficits in order to advance the currentunderstanding of functional subdivision of neuroanatomical regions involved in lan-guage production.Methods & Procedures: In this study, lesion-symptom mapping was used to determine ifspecific cortical regions are associated with nonword repetition, picture naming, andsentence production scores. Structural brain images and behavioural performance of 31individuals with post-stroke left hemisphere lesions and a diagnosis of aphasia were usedin the lesion analysis.Outcomes & Results: Each impairment was associated with mostly unique, but a fewshared lesions. Overall, sentence and repetition deficits were associated with left anteriorperisylvian lesions, including the pars opercularis and triangularis of the inferior frontallobe, anterior superior temporal gyrus, anterior portions of the supramarginal gyrus, theputamen, and anterior portions of the insula. In contrast, impaired picture naming wasassociated with posterior perisylvian lesions including major portions of the inferiorparietal lobe and middle temporal gyrus. The distribution of lesions in the insula wasconsistent with this antero-posterior perisylvian gradient. Significant voxels in the pos-terior planum temporale were associated with a combination of all three deficits.Conclusions: These findings emphasise the participation of each perisylvian region inmultiple linguistic functions, suggesting a many(functions)-to-many(networks) frame-work while also identifying functional subdivisions within each region.

Keywords: Aphasia; Lesion analysis; Sentence production; Repetition; Inferior frontalgyrus; Superior temporal gyrus; Insula; Planum temporale.

Address correspondence to: Yasmeen Faroqi-Shah, Department of Hearing and Speech Sciences,University of Maryland, College Park, MD 20742, USA. E-mail: yfshah@umd.edu

The authors report no conflict of interest, financial or otherwise, and no source of financial support forthis study.

Aphasiology, 2013http://dx.doi.org/10.1080/02687038.2013.853023

This work was authored as part of the Contributor’s official duties as an Employee of the United StatesGovernment and is therefore a work of the United States Government. In accordance with 17 USC. 105,

no copyright protection is available for such works under US Law.

Dow

nloa

ded

by [

Dr

Yas

mee

n Fa

roqi

-Sha

h] a

t 08:

36 1

9 N

ovem

ber

2013

The ability to produce language is often severely impaired in individuals with aphasiafollowing left hemisphere damage. Language production is typically tested usingthree tasks: picture naming, elicitation of sentences with picture description, andrepetition. Individuals with aphasia experience different levels of difficulty witheach of these tasks, presumably because different underlying neurocognitive sub-strates are engaged in each task. Minimally, picture naming involves visual analysisand retrieval of a suitable lexical item, whereas sentence production involves addi-tional grammatical planning, and repetition minimally involves auditory-to-motorconversion with some sublexical analysis. All three tasks also engage phonologicaland articulatory planning (Levelt, 1999).

While the relative patterns of impairment of naming, repetition, and sentenceproduction in any given patient are used to clinically classify aphasia subtypes(conduction aphasia, Broca’s aphasia, etc.), the specific neuroanatomical lesioncorrelates of these tasks remain less clearly understood. The few prior lesion studiesof aphasia have investigated either comprehension impairments, clinical subtype(s) ofaphasia, or a single production deficit (Bates et al., 2003; Borovsky, Saygin, Bates, &Dronkers, 2007; Caplan, Gow, & Markis, 1995; Caplan, Hildebrandt, & Makris,1996; Damasio & Damasio, 1980; Damasio, Grabowski, Tranel, Hichwa, &Damasio, 1996; Dick et al., 2007; Saygin, Dick, Wilson, Dronkers, & Bates, 2003;Saygin, Wilson, Dronkers, & Bates, 2004; Willmes & Poeck, 1993). Similarly, there isfar less functional neuroimaging research on language production compared tolanguage processing1 in healthy adults. Hence, more systematic research is neededto uncover the lesion correlates of production deficits in aphasia in order to advanceour understanding of clinical manifestations of damage to different left hemisphereregions. The primary objective of this study was to extend previous lesion research ofaphasia by examining the lesion correlates of picture naming, sentence productionand nonword repetition deficits in the same participant group. The broader goal ofthis study was to investigate the extent and degree of overlap and uniqueness amonglesions resulting in these deficits in order to advance the current understanding offunctional subdivision of neuroanatomical regions involved in language production.

Predictions about lesion correlates of the three language production deficits inaphasia can be made based on prior functional neuroimaging investigations andlesion studies of language production. In lesion studies of lexical retrieval, lefttemporal lesions are found when lexical retrieval is guided by semantic features (asin category naming) and for noun naming deficits (Baldo, Schwartz, Wilkins, &Dronkers, 2006; Piras & Marangolo, 2007; Schwartz et al., 2009; Tranel, 2006).Phonologically guided lexical retrieval (as in letter-based word retrieval) and verbnaming deficits are associated with left frontal lesions (Baldo et al., 2006; Daniele,Giustolisi, Silveri, Colosimo, & Gainotti, 1994). Functional neuroimaging studies ofsingle word production in healthy adults have found (1) left anterior and middletemporal regions (especially the posterior middle temporal gyrus, MTG) to beassociated with retrieval of lexical representations (Binder & Desai, 2011;Bookheimer, 2002; Indefrey, 2011; Indefrey & Levelt, 2004), and (2) posterior por-tions of the left superior temporal gyrus (STG) and temporo-parietal regions areinvolved in retrieving phonological (word form) representations of the selected word(Buchsbaum & D‘Esposito, 2008; Graves, Grabowski, Mehta, & Gupta, 2008). For

1 We use the term processing to generally refer to input processes, while processes involved in comput-ing language output are referred to as production or encoding.

2 FAROQI-SHAH ET AL.

Dow

nloa

ded

by [

Dr

Yas

mee

n Fa

roqi

-Sha

h] a

t 08:

36 1

9 N

ovem

ber

2013

word production, the left inferior frontal gyrus (IFG) is associated with articulatory-phonological encoding (Bookheimer, 2002; Buchsbaum & D‘Esposito, 2008) andcontextual integration of meaning (Swaab, Brown, & Hagoort, 1997).

The lesion correlates of sentence production deficits have not been sufficientlyinvestigated. One lesion study of sentence production used an indirect measure ofgrammatical complexity called utterance length, the calculation of which disregardswhether the utterance is grammatically well-formed (Borovsky et al., 2007) andanother study dichotomously classified patients as agrammatic or not (Vanier &Caplan, 1990). Both studies found lesions of the left insula, one study found whitematter lesions (arcuate fasciculus) in all patients (Vanier & Caplan, 1990). In con-trast, neuroimaging studies of sentence production in healthy adults consistentlyreport involvement of the left IFG (Blank, Scott, & Wise, 2002; Heim, Opitz, &Friederici, 2002; Indefrey, Hellwig, Herzog, Seitz, & Hagoort, 2004). Additionally,activations of the left STG, anterior cingulate gyrus, and basal ganglia (BG) arereported (Heim et al., 2002; Indefrey et al., 2004).

Lesion correlates of speech repetition deficits have been traditionally associatedwith the left arcuate fasciculus given that this white matter tract connects auditoryareas in the superior temporal cortex with frontal regions associated with verbalproduction (Geschwind, 1972). However, lesions of arcuate fasciculus in previouslesion studies of repetition deficits are inconsistent (Baldo, Katseff, & Dronkers,2012; Fridriksson et al., 2010; see review by Bernal & Ardila, 2009). Lesions of leftposterior STG and left inferior parietal hypoperfusion are also implicated (Baldoet al., 2012; Fridriksson et al., 2010). Lesion correlates of nonword repetition deficit,which is also often tested in patients with aphasia, are less understood.

Based on the above studies, we hypothesised that nonword repetition deficits willbe associated with lesions in the IFG, inferior parietal lobule (IPL), and planumtemporale (PT), sentence production deficits with IFG lesions and picture namingdeficits with MTG, STG, and IPL lesions. In this study, we investigated lesion-deficitrelations in aphasia with voxel-based lesion-symptom mapping (VLSM) (Bates et al.,2003). In VLSM, continuous variables such as accuracy scores are used to correlatewith lesion information (instead of dichotomously categorising patients as impairedor spared on the basis of sometimes arbitrary score cut-offs), and statistical tests aredone at every voxel to compare test performance in patients. Hence, VLSM allowsprecise clinical–radiological correlations by testing all damaged voxels.

METHOD

Participants

Thirty-one persons with aphasia (21 male, 10 female) were recruited at the NationalInstitutes of Deafness and Communication Disorders (NIDCD). This study wasapproved by the Human Research Protection committee at NIDCD and all partici-pants gave informed consent prior to participation in the study. All patients hadsustained a single left hemisphere lesion secondary to a cerebrovascular accident(CVA) and were at least 10 months post-onset of the CVA. The neuroanatomicaldistribution of lesions observed in the participants is shown in Supplementary FigureS1. The number of participants who had lesions in each region and the percentage ofvoxels that were involved in any region that was lesioned in four or more participants

LESION ANALYSIS OF APHASIA 3

Dow

nloa

ded

by [

Dr

Yas

mee

n Fa

roqi

-Sha

h] a

t 08:

36 1

9 N

ovem

ber

2013

are listed in Supplementary Table S1. There were no regions that were lesioned acrossall patients.

All participants were native speakers of English, had at least high school educa-tion, and normal or corrected vision and hearing, and were pre-morbidly righthanded. They reported no psychiatric, neurological, and speech-language impair-ments prior to the CVA as per caregiver report, or no visual field deficits, or agnosiasas a result of the CVA. It was crucial to rule out motor speech impairments such asapraxia as these can negatively confound language production scores and are foundto co-occur with aphasia (Duffy, 2005; McNeil et al., 2000). Hence inclusionarycriteria were a normal or mild score on all subtests of the Apraxia Battery for Adults-2, (ABA-2, Dabul, 2000) and spontaneous speech with no more than four features inthe inventory of articulation characteristics in the ABA-2. Language measures admi-nistered to the participants included the Western Aphasia Battery (WAB) (Kertesz,1982), Psycholinguistic Assessment of Language Processing in Aphasia (PALPA)(Kay, Coltheart, & Lesser, 1992), and Psycholinguistic Assessment of Language(PAL) (Caplan, unpublished). Participants were diagnosed with aphasia by aspeech-language pathologist and a neurologist (see Table 1).

Language measures for lesion analysis

For the purpose of the lesion analysis, scores from the Picture Naming and NonwordRepetition subtests of PALPA (Kay et al., 1992) and the Picture Description subtestof the PAL (Caplan, unpublished) were used because these test stimuli are con-structed with control for relevant psycholinguistic attributes. Picture naming wasused as a measure of lexical ability, nonword repetition was the phonologicalmeasure and picture description subtest was the syntactic measure. The PictureNaming subtest of PALPA requires participants to name 40 pictured nouns, andaccuracy scoring ignored phonemic errors (e.g., abble for apple). Nonword repetitionwas chosen instead of real word repetition because of the confound of engagingsemantic strategies to assist task performance whenever real words are used.Nonword repetition is considered to be a purer measure of auditory-to-motor con-version (Hagoort et al., 1999; Herbster, Mintun, Nebes, & Becker, 1997; McGettiganet al., 2011). Nonword Repetition test of the PALPA examines the ability to repeat 30auditorily presented unfamiliar word forms that are legally valid in English (e.g.,drattle and polid). Scoring was based on the phonemic accuracy with which eachsyllable is repeated. We ensured that all 31 participants had no significant difficultiesin auditorily processing the stimuli (80% or higher score in the Minimal PairDiscrimination subtest of the PALPA). In the Picture Description subtest of thePAL, description of simple line drawings is used to elicit 25 sentences with differentsyntactic structures including actives, passives, datives, dative-passives, and relativeclauses. In order to limit the influence of word retrieval deficits on performance, theuninflected verb and nouns were listed in printed form and read aloud by the tester.Scoring was based on the accuracy with which the target syntactic structure isproduced, irrespective of the accuracy of lexical retrieval or presence of semanticand phonemic paraphasias. In sum, even though all three tasks used in this studyrequired verbal articulation of responses, scoring was based on parameters other thanarticulatory agility.

4 FAROQI-SHAH ET AL.

Dow

nloa

ded

by [

Dr

Yas

mee

n Fa

roqi

-Sha

h] a

t 08:

36 1

9 N

ovem

ber

2013

TABLE1

Characteristicsandtest

scoresofparticipants

withaphasia

WABsubtestscores

Lan

guagescores

forlesion

analysis

IDAge

Gender

MPO

Syndrom

e(W

AB)

AQ

(WAB)

Spontan

eous

speech

(Max

=20

)

Aud

itory

comprehension

(Max

=20

0)Repetition

(Max

=10

0)Nam

ing

(Max

=10

0)

Non

word

repetition

(Max

=80

)

Picture

description

(Max

=25

)

Picture

naming

(Max

=40

)

142

M57

Con

duction

58.96

1514

9.5

3238

30

162

65F

60Broca

49.4

919

628

3121

113

356

F14

2Ano

mic

90.2

1819

675

9848

1039

467

F37

WNL*

9720

188

100

9167

1436

556

M15

TM

72.2

1018

088

8351

235

653

M20

WNL*

9719

200

100

9580

840

749

M35

Ano

mic

80.6

1718

670

7077

731

867

M12

Ano

mic

82.6

1717

672

8324

436

968

M12

Ano

mic

88.6

1619

696

8940

1034

1070

F22

Ano

mic

90.2

1916

410

7980

833

1157

M23

Ano

mic

8816

190

100

8567

1437

1257

F12

Ano

mic

88.6

1719

088

9059

639

1364

M27

Wernicke

30.8

912

00

30

00

1466

F30

Con

duction

74.6

1518

457

7440

629

1562

M10

Ano

mic

8517

182

8877

4810

3016

49M

35Ano

mic

79.6

1319

280

9267

1736

1757

M14

Ano

mic

9315

192

9490

693

4018

68F

84WNL*

9619

200

100

9080

1639

1948

F65

Ano

mic

80.8

1515

693

8351

734

2069

F90

Con

duction

72.8

1417

865

7040

331

(Con

tinu

ed)

LESION ANALYSIS OF APHASIA 5

Dow

nloa

ded

by [

Dr

Yas

mee

n Fa

roqi

-Sha

h] a

t 08:

36 1

9 N

ovem

ber

2013

TABLE1

(Continued)

WABsubtestscores

Lan

guagescores

forlesion

analysis

IDAge

Gender

MPO

Syndrom

e(W

AB)

AQ

(WAB)

Spontan

eous

speech

(Max

=20

)

Aud

itory

comprehension

(Max

=20

0)Repetition

(Max

=10

0)Nam

ing

(Max

=10

0)

Non

word

repetition

(Max

=80

)

Picture

description

(Max

=25

)

Picture

naming

(Max

=40

)

2166

M22

Con

duction

72.8

818

250

5272

030

2267

M35

Ano

mic

84.3

1719

572

8264

835

2364

M46

Broca

13.4

010

24

120

00

2467

M12

Ano

mic

89.96

1819

1.5

100

7469

922

2559

M14

Ano

mic

82.8

1619

980

7953

638

2660

M20

Broca

11.45

610

90

00

00

2765

F10

Non

Fluent

5912

178

1670

00

2028

56M

31WNL*

95.5

1919

997

9172

038

2972

M34

Ano

mic

85.9

1519

993

8729

1438

3068

M60

Globa

l7.6

141

0.7

100

00

3145

M13

TM

44.5

819

584

8661

30

MPO

=mon

thspo

st-onset;WNL

=withinno

rmal

limits;

TM

=tran

scorticalmotor

apha

sia.

*These

four

patients

scored

withinno

rmal

limitson

theWestern

Aph

asia

Battery

(WAB)at

thetimeof

this

stud

y.Theyho

wever,demon

strateddeficits

onthemorespecific

subtests

ofthePsycholingu

isticAssessm

entof

Lan

guage(PAL)an

dPsycholingu

isticassessments

ofLan

guageProcessingin

Aph

asia

(PALPA)an

din

conv

ersation

alspeech.Theyalso

hadscored

lower

inpriorad

ministrations

oftheWAB.

6 FAROQI-SHAH ET AL.

Dow

nloa

ded

by [

Dr

Yas

mee

n Fa

roqi

-Sha

h] a

t 08:

36 1

9 N

ovem

ber

2013

Lesion analysis

T1-weighted magnetic resonance images (MRI) were obtained using a GE 1.5 TeslaMRI scanner at the National Institutes of Health. Brain lesions were manually tracedby one of the authors (TK) and verified for reliability by two persons with experiencein neuroradiology. All MRI images were normalised to the MNI (MontrealNeurological Institute) template space using ABLe 2.3 (Analysis of Brain Lesions)implemented in the MEDx medical imaging software package (Solomon, Raymont,Braun, Butman, & Grafman, 2007) after masking out the lesion. Spatial normal-isation was performed using the automated image registration (AIR) algorithm fromWoods, Grafton, Watson, Sicotte, and Maziotta (1998) using a 12-parameter affinemodel on de-skulled MRI scans. The AAL (Automated Anatomical Labelling) atlaswas used in the ABLe program to anatomically label lesioned brain regions (Tzourio-Mazoyer et al., 2002). Each participant’s language scores for nonword repetition,picture naming, and sentence production were entered into ABLe for VLSM (Bateset al., 2003). VLSM is performed by sorting language scores into two groups for eachvoxel, depending on whether the voxel is lesioned or spared. An unpaired t-test isperformed for every voxel to compare the language scores of patients with andwithout lesions in that voxel. The resulting map of t-values (t-map) depends on thestrength of association between a particular language score and the occurrence of alesion in a particular voxel (or cluster of voxels) across patients. An uncorrectedstatistical threshold of z = 1.96 (p < .05) and a minimum criterion of at least fourpatients with and without a lesion in each voxel was used. The fact that our resultsare not corrected for multiple comparisons clearly limits the conclusions that can bedrawn and generalised to larger populations of patients. Nevertheless, we elected todo this to avoid type II statistical error (a significant concern in a VLSM analysisconducted with 31 subjects). While eliminating fewer false positives, this approachallowed a more complete presentation of significant voxel patterns associated withlanguage performance in our patients.

A modified conjunction approach was used with the t-maps to identify (1) voxelscommonly lesioned for all three language measures, and (2) lesions shared bycombinations of two language measures (z-scores > 1.96) while excluding the thirdmeasure (z-score < 1.00). For example, the comparison map for [sentence + nonwordrepetition] minus picture naming shows voxels where the z-score exceeds 1.96 forboth sentence and nonword repetition deficits and a z-score lower than 1.00 forpicture naming deficits. All anatomical regions identified by AAL were verified bycomparing with anatomic atlases (Mai, Paxinos, & Voss, 2008; Talairach &Tournoux, 1988).

Finally, we performed a traditional region of interest (ROI) analysis on z-scoresfor nonword repetition, picture naming, and sentence production. As hypothesisedabove, left hemispheric regions including the IFG (pars trangularis and opercularis),posterior and middle STG, supramarginal and angular gyri, and insula were pre-dicted to be involved in these three tasks. Considering the fine regional structurereported in the previous literature (Amunts et al., 1999) each of these areas ofinterest, except for the anterior insula, depicted in the relatively coarse PickAtlas(Maldjian, Laurienti, Kraft, & Burdette, 2003) was further divided into two subregions, as shown in Figure 2. The averaged z-scores across all voxels in all ROIswere calculated for each task. Since the main purpose of this analysis is to identify thelesion locations specifically correlated with impairment on language tasks, a

LESION ANALYSIS OF APHASIA 7

Dow

nloa

ded

by [

Dr

Yas

mee

n Fa

roqi

-Sha

h] a

t 08:

36 1

9 N

ovem

ber

2013

significant threshold of z = 1.65 (p < .05 for one-sided test) was utilised. The lack ofcorrection for multiple comparisons across voxels is intrinsically avoided in this ROIanalysis, which here serves as an alternative to the voxel-based analysis for purposesof confirmation.

RESULTS

Behavioural measures

A wide range of performance was observed for all three production measures indicatingthat the participants were a heterogeneous group, which is desirable when attemptingcorrelations between behavioural measures and neuroanatomic lesions. The meanaccuracy of picture naming was 63.7% (SD = 36.8; range: 0–100%), the mean nonwordrepetition score was 52.7% (SD = 36.5; range: 0% to 100%), and the mean accuracy ofsentence production was 21.8% (SD = 21.4; range: 0–69%). All three scores werecorrelated with each other (nonword repetition and picture naming: Spearmanr = .57, p < .01; nonword repetition and sentence production (Spearman r = .48,p < .01; and sentence production and picture naming: Spearman r = .56, p < .01).Although the behavioural scores were correlated, the lesions for the three behaviourswere mostly unique and non-overlapping (below).

Lesion analyses

In the following sections, lesions unique to individual measures are presented first.This is followed by lesions for two overlapping measures, and finally lesions commonto all three language measures. The z-values and regions are summarised in Table 2and lesion maps are shown in Figure 2. Selected axial images of the conjunctionanalyses are provided in Supplementary Figures S2 and S3.

Nonword repetition deficit. This analysis identified a cluster in the inferior frontallobe that spanned the pars opercularis (BA 44), pars triangularis of the IFG (BA 45),and the Rolandic operculum (BA 44/6). A small parietal cluster included the anteriorportion of the supramarginal gyrus (SMG, BA 40) that extended into the STG (BA22/42) and postcentral gyrus (SII, BA 43).2

Sentence production deficit. As shown in Table 2 and Figure 1, an extensive lesioncluster was associated with impairment of sentence production, including the leftIFG, STG, SMG, insula, and BG. There was a significant involvement of the IFG, ingeneral posterior and dorsal to the regions associated with nonword repetition deficit,extending from the pars orbitalis (BA 47), pars triangularis (BA 45), pars opercularis(BA 44), and the Rolandic operculum (BA 44/6) and upwards into the middle frontalgyrus. The precentral gyrus in the vicinity of the dorsal and ventral lateral premotorcortex was also involved. The STG lesion cluster extended from the anterior STG,included Heschl’s gyrus and into the dorsal SMG. The SMG involvement wasposterior to the cluster associated with nonword repetition impairment.Subcortically, significant portions of the putamen and insula were identified. The

2 The overall cluster size for SMG was small relative to other lesion clusters, and therefore one cannotrule out the possibility of this being a false positive finding, given that correction for multiple comparisonswas not used in this study.

8 FAROQI-SHAH ET AL.

Dow

nloa

ded

by [

Dr

Yas

mee

n Fa

roqi

-Sha

h] a

t 08:

36 1

9 N

ovem

ber

2013

TABLE2

Summary

oflefthemisphere

lesionsbyco

ntrast

andregionofinterest

Region

NWR

–

(SP,PN)

PN

–

(NWR,SP)

SP–(N

WR,PN)

(NWR

+SP)–PN

(NWR

+PN)–SP

(SP+PN)–

NWR

SP+PN

+NWR

Fron

tal

IFG

pars

orbitalis

42,22

,–6

48,20

,–10

IFG

pars

triang

ularis

52,26,4

46,24,10

42,24,4

IFG

pars

opercularis

58,16,6

42,14,8

60,8,

646,10,4

Rolan

dicop

erculum

62,2,

654,–2,

850

,–2,

844

,–8,

10Precentralgy

rus

46,0,

24MFG

32,26

,50

Tem

poral

Planu

mtempo

rale

46,–46

,20

60,–24

,16

Heschlgy

rus

40,–22

,12

STG

ant.+temp.

pole

60,–4,

650

,14

,–2

STG

post.

STS

52,–30

,8

MTG

56,–48

,–22

Parietal

Postcentral

gyrus

62,–8,

1660

,–10

,14

48,–22

,28

Supram

argina

lgy

rus

62,–42

,26

56,–46

,28

48,–30

,30

56,–46

,34

48,–36

,24

50,–24

,24

Ang

ular

gyrus

46,–48

,30

52,–24

,40

54,–62

,36

TPO

Insula

Agran

ular

38,6,

–12

Dysgran

ular

46,8,

–2

40,–2,

–2

42,6,

6Granu

lar

40,–8,

6

Basal

gang

liaPutam

en32,6,

–4

28,10

,8

Inferior

fron

talg

yrus

=IF

G;m

edialfrontal

gyrus=MFG;sup

eriorfron

talg

yrus

=SF

G;sup

eriortempo

ralg

yrus

=ST

G;sup

eriortempo

ralsulcus=ST

S;middletempo

ral

gyrus=MTG;inferiortempo

ralg

yrus

=IT

G.T

hestereotacticcoordina

tesrepresentthelocalm

axim

ain

each

region

.The

firstthree

columns

representlesions

unique

toeach

measure:NWR—

nonw

ordrepetition

,SP

-sentenceprod

uction

,PN—

picturena

ming.

The

four

columns

ontherigh

trepresentlesion

sof

theconjun

ctionan

alyses.

LESION ANALYSIS OF APHASIA 9

Dow

nloa

ded

by [

Dr

Yas

mee

n Fa

roqi

-Sha

h] a

t 08:

36 1

9 N

ovem

ber

2013

insular lesions that were unique to sentence production deficits were widespread,spanning granular, dysgranular, and agranular regions; there was also white matterinvolvement in the proximity of the insula.

Picture naming deficit. These lesions were located in a sizeable portion of posteriortemporo-parietal regions, including the STG, MTG, and posterior portion of the PT,extending into the IPL including SMG-angular gyrus (AG) and the post-centralgyrus (PoCG; see Figure 1 and Table 2). The region of the SMG involved wasposterior to the portions associated with nonword and sentence production impair-ments. The MTG and AG were uniquely associated with picture naming deficit, andnot lesioned for nonword repetition or sentence production. No frontal lesions wereidentified.

Conjunction of nonword repetition and sentence production deficits. Lesions identi-fied for combined nonword repetition and sentence production deficits included theIFG’s pars opercularis (BA 44) and triangularis (BA 45), extending caudally until theRolandic operculum (see Table 2 and Supplementary Figure S2). Another prominentlesion extended along the anterior portion of STG ending posteriorly at Heschl’sgyrus. A significant lesion of the granular and dysgranular portions of the insula wasidentified, extending into the claustrum. Overall, these lesions were located in transi-tion zones bounded anteriorly and posteriorly by lesions unique to nonword repeti-tion and sentence production deficits, respectively.

Conjunction of sentence production and picture naming deficits. This conjunctionanalysis identified three lesion clusters which were smaller than those for the

Pic NamNonWord Rep Sent Prod

Figure 1. Axial images showing lesion maps for the various production impairments: red = nonwordrepetition (NonWordRep), blue = sentence production (SentProd), yellow = picture naming (PicNam). Inall coloured voxels, p-values exceeded a corrected significance level of .05 (uncorrected z-scores exceeding1.96). An anterior (nonword repetition and sentence production) to posterior (picture naming) gradient oflesions is evident. [To view this figure in colour, please see the online version of this journal].

10 FAROQI-SHAH ET AL.

Dow

nloa

ded

by [

Dr

Yas

mee

n Fa

roqi

-Sha

h] a

t 08:

36 1

9 N

ovem

ber

2013

sentence-nonword repetition overlap: a part of SMG (bordering the STG) that was atransition zone between unique lesions for sentence production rostrally and forpicture naming caudally. In addition, the mid STG–STS, and the posterior dysgra-nular insula and precentral gyrus extending into the Rolandic operculum wereidentified (Figure 1 and Supplementary Figure S2).

Conjunction of picture naming and nonword deficits. This comparison identifiedonly a single restricted cluster of voxels in the SMG (see Table 2 and SupplementaryFigure S3). Hence, although these two measures were highly correlated behaviourally,their lesions were mostly non-overlapping. Picture-based lexical retrieval may havelittle in common with nonword repetition, the only exception being sublexical storageprior to articulatory planning (phonological output buffer), and this process has beenassociated with the SMG (Buchsbaum & D’Esposito, 2008; Graves et al., 2008).

Conjunction of all three production deficits. The overlap between nonword repeti-tion, sentence production, and picture naming deficits centred in the PT and extendedinto the SMG, bordering on the parietal operculum (see Supplementary Figure S3).Prior studies have identified impaired repetition seen in conduction aphasia as theprimary symptom following left PT lesions (Damasio & Damasio, 1980; Hickok &Poeppel, 2007). Our findings extend the symptoms to include a combination ofpicture naming and sentence production deficits. There was no lesion overlap inthe frontal lobe.

ROI analysis for each production deficit

Using a relatively stringent ROI analysis confined to a limited set of perisylvianlanguage areas (illustrated in Figure 2), we found that lesions within frontal, tem-poral, and insular cortices are broadly associated with deficits in sentence production;lesions of the posterior STG and angular gyrus impairments are associated withpicture naming; and impairments in nonword repetition are selectively related tolesions of the pars triangularis in the IFG. Results of the ROI analysis, along withaverage regional z-scores are given in Supplementary materials (Table 4). Theseresults are consistent with those derived using the voxel-wise analysis, reportedabove.

DISCUSSION

This study conducted whole-brain and ROI analyses of three production deficits inpersons with post-stroke aphasia. The results show that sentence production andnonword repetition deficits were more likely to be associated with left anteriorperisylvian lesions, while picture naming deficits were associated with posteriorperisylvian lesions. The insula showed a distribution of lesions that was similar tothis anterior–posterior perisylvian trend. While most of the lesions appeared to be, ona voxel by voxel basis, selectively associated with individual linguistic deficits, thelesions commonly interdigitated in an overlapping montage within the same fiveanatomical regions: inferior frontal, inferior parietal, superior/middle temporal,insula, and the BG. In the following section, we will briefly discuss the implicationsof lesion patterns observed in these five regions of interest.

LESION ANALYSIS OF APHASIA 11

Dow

nloa

ded

by [

Dr

Yas

mee

n Fa

roqi

-Sha

h] a

t 08:

36 1

9 N

ovem

ber

2013

Inferior frontal gyrus

We found left IFG lesions were most extensive for sentence production deficits,followed by lesions for nonword repetition deficits and conjunction of sentence-plus-nonword repetition deficits. These left IFG lesions are consistent with priorfindings for syntactic production deficits (Borovsky et al., 2007; Vanier & Caplan,1990) and neuroimaging studies for syntactic and phonological processing (syntax:Blank et al., 2002; Braun, Guillemin, Hosey, & Varga, 2001; Heim et al., 2002;Indefrey, Brown, Hellwig, Amunts, & Herzog, 2001; phonology: Baldo et al., 2006;Heim & Friederici, 2003; Poldrack et al., 1999).

Along the rostro-ventral to caudo-dorsal axis, there was a graded progressionfrom lesions associated with deficits in nonword repetition (BA 45) to sentence-

Ventral SMG

Dorsal SMG

Ventral AG

Dorsal AG

Ventral post STG

Dorsal post STG

Ventral mid STG

Dorsal mid STG

Rolandic Op. BA 6

Ventral BA 44

Dorsal BA 44

Ventral BA 45

Dorsal BA 45

Insula

X = –56

X = –49

X = –42

Figure 2. Selected sagittal images showing segmentation of regions of interests in the left hemisphere (MNIspace). Inferior frontal gyrus pars opercularis = BA44, inferior frontal gyrus pars triangularis = BA45,Rolandic operculum = BA6, superior temporal gyrus = STG, supramarginal gyrus = SMG, angulargyrus = AG. [To view this figure in colour, please see the online version of this journal.]

12 FAROQI-SHAH ET AL.

Dow

nloa

ded

by [

Dr

Yas

mee

n Fa

roqi

-Sha

h] a

t 08:

36 1

9 N

ovem

ber

2013

plus-nonword repetition deficits (BA 45/44) to sentence production deficits alone (BA44/6) (Supplementary Figure S2). This is consistent with proposals that IFG iscytoarchitectonically heterogeneous and multifunctional with subregions that arespecialised for phonological, semantic, and syntactic processing (Bookheimer, 2002;Poldrack et al., 1999; Vigneau et al., 2006; Willems & Hagoort, 2007). There are twopossible interpretations our finding of left IFG lesions for sentence production andnonword repetition, but not for picture naming deficits. One is that the left IFG isinvolved in rule-based concatenation and integration of linguistic units (Hagoort,2005; Ullman, 2006) is compatible with. An alternate interpretation of left IFGlesions is that it is engaged in computationally demanding tasks, and hence asso-ciated with sentence production and repetition deficits.

Inferior parietal region (IPL), including SMG and AG

Extensive lesions of the IPL (from the SII to SMG and AG) were associated withpicture naming deficits with smaller lesions for conjunction maps involving picturenaming and individually for the other two production measures (SupplementaryFigure S2). Other lesion studies have also identified AG extending into the mid-posterior MTG for noun naming deficits (Cloutman et al., 2009; Daniele et al., 1994;Dronkers, Wilkins, van Valin, Redfern, & Jaeger, 2004; Luzzatti, Aggujaro, &Crepaldi, 2006; Miceli, Silveri, Nocentini, & Caramazza, 1988; Piras & Marangolo,2007; Shelton & Caramazza, 1999; Tranel, Adolphs, Damasio, & Damasio, 2001).

There was a graded progression from lesions associated with deficits in nonwordrepetition (BA 43, BA 40) and sentence production (dorsal BA 40) located morerostro-dorsally to more caudal lesions associated with picture naming deficits (BA 39/40, extending into BA22/21) (Supplementary Figure S2). The IPL is associated withverbal working memory circuits (Vigneau et al., 2006), which may be tapped by allthree production tasks and could explain this rostral to caudal distribution of lesions.The findings suggest that the IPL, like the IFG, is a cytoarchitectonically diverse andmultifunctional region. It is involved in semantic processing (AG in conjunction withMTG), auditory-motor integration (SMG), and verbal working memory circuits(SMG, AG) (Binder et al., 1997; Buchsbaum & D’Esposito, 2008; Caspers et al.,2006; Damasio et al., 1996; Graves et al., 2008; Hickok & Poeppel, 2007; Wise et al.,2001; see review by Indefrey, 2011). It should be noted that the parieto-temporalboundary, especially the SMG-PT boundary, is obscure (Démonet, Thierry, &Cardebat, 2005; Graves et al., 2008; Hickok & Poeppel, 2007; Shalom & Poeppel,2008). Hence, IPL lesions must be considered in conjunction with postero-superiortemporal lesions (see next paragraph).

Superior and middle temporal lobe, including PT,3 STG, and MTG

The present study revealed three unique left temporal lesions for specific productionimpairments, which followed a similar anterior–posterior gradient to that describedpreviously: anterior-mid STG lesions for sentence production and nonword repetition

3 The PT is a triangular region in the Sylvian fissure, bounded anteriorly by the Heschls gyri andcontinuing posteriorly into the parieto-temporal operculum and SMG (Griffiths & Warren, 2002;Shapleske, Rossel, Woodruff, & David, 1999). The PT is considered by some researchers to be part ofWernicke’s area (Binder, Frost, Hammeke, Rao, & Cox, 1996; Wise et al., 2001).

LESION ANALYSIS OF APHASIA 13

Dow

nloa

ded

by [

Dr

Yas

mee

n Fa

roqi

-Sha

h] a

t 08:

36 1

9 N

ovem

ber

2013

deficits, mid STG/STS lesions for sentence production and picture naming deficits,and mid-posterior MTG lesions were associated with picture naming deficits. Theanterior-mid STG lesions for sentence production deficits are consistent with priorneuroimaging findings for syntactic comprehension (e.g., Embick, Marantz,Miyashita, O’Neill, & Sakai, 2000; Newman, Just, Keller, Roth, & Carpenter,2003). The middle and posterior temporal lesions for picture naming deficits agreewith this region’s association with lexical retrieval in functional neuroimaging(reviewed by Binder & Desai, 2011; Indefrey, 2011). The association between lefttemporo-parietal cortex lesions and repetition deficits could be due to two underlyingimpairments: phonological and auditory verbal short-term memory. For example,Baldo et al. (2012) VLSM study found left temporo-parietal lesions for both repeti-tion and auditory verbal short-term memory deficits. The behavioural data frompresent study were insufficient to distinguish between these two sources of deficits.

Posterior PT lesions were associated with impairment of all three productionmeasures. The posterior part of left PT (referred as Spt: Sylvian fissure at theparieto-temporal junction), extending into the SMG, is thought to be a heteromodalsensory area with auditory, visual, and somatosensory inputs (Booth et al., 2006;Hickok, Okada, & Serences, 2009; Pa & Hickok, 2008; see also Griffiths & Warren,2002). It is thought that the Spt is cytoarchitectonically similar to other sensory-motor regions (such as those in the posterior parietal lobe). Hence, this region is wellsuited for integrating phonological (SMG) and semantic (MTG-AG) aspects of wordretrieval (Hickok & Poeppel, 2007; Price, 2000; Price, Moore, Humphreys, & Wise,1997). Although most authors have predicted PT (or Spt) lesions to affect repetitiononly, our findings indicate an impact on picture naming as well as sentenceproduction.

Insula

In the present study, lesions of the insula were primarily associated with sentenceproduction deficits, and to a smaller extent, for conjunction maps of sentenceproduction with picture naming and nonword repetition deficits. Lesions of the insulahave been implicated for syntactic decline in primary progressive aphasia (Nestoret al., 2003) and a variety of speech-language deficits, such as, mutism, oral apraxia,conduction aphasia, Broca’s aphasia, and auditory agnosia (Bates et al., 2003;Borovsky et al., 2007; Dronkers, 1996; Nestor et al., 2003; Wise, Greene, Buchel,& Scott, 1999; reviewed in Ardila, 1999). There are two plausible accounts of theinsula for language production. First, given its intrasylvian location and presence ofnumerous efferent and afferent synapses, the insula may serve to connect anteriorand posterior perisylvian language areas (Augustine, 1996; Bonilha & Fridriksson,2009; Flynn, Benson, & Ardila, 1999; Galaburda & Pandya, 1983). Second, theinsula may be functionally fractionated for specific linguistic and non-linguisticfunctions. Support for this comes from hemispheric differences and cytoarchitectonicdifferences between posterior (resembling sensorimotor cortex) and anterior (resem-bling frontal association cortex) regions of insula (Ackermann & Riecker, 2004;Bamiou, Musiek, & Luxon, 2003; Craig, 2009; Flynn et al., 1999; Mutschler et al.,2009). These two explanations need to be validated with further research in neuro-logically healthy adults.

14 FAROQI-SHAH ET AL.

Dow

nloa

ded

by [

Dr

Yas

mee

n Fa

roqi

-Sha

h] a

t 08:

36 1

9 N

ovem

ber

2013

Basal ganglia

Lesions of the BG (predominantly the putamen) were associated with sentenceproduction deficits. There are multiple cortical-BG circuits between the frontallobes and BG which are assumed to contribute to speech-language behaviour(Middleton & Strick, 2000; Ullman, 2006). Our lesion findings are consistent withother evidence that both IFG and BG patient groups exhibit syntactic processing andproduction deficits (Bastiaanse & Leenders, 2009; Friederici & Kotz, 2003; Frisch,Kotz, von Cramon, & Friederici, 2003; Kotz, Schwartze, & Schmidt-Kassow, 2009;Ullman, Corkin, Coppola, & Hickok, 1997). Lieberman (2002, 2007) proposed thatthe BG act as a sequencing engine that aligns various units, including phonemes toform words and words to form sentences (also Ullman, 2006).

CONCLUSIONS

Before presenting the conclusions of this study, it is imperative to consider thecaveats of lesion mapping in patients with chronic conditions (Ridgeway et al.,2008). One criticism is that chronic patients are likely to have suffered from largerlesions because their deficits have continued beyond the spontaneous recovery phase(Hillis et al., 2004). However, there was a wide range of lesion volumes in the presentstudy, and some participants had relatively mild behavioural deficits. It is alsopossible that the lesioned voxels are in a brain region highly susceptible to ischemiaand are unrelated to the language deficit(s) (Dronkers & Ogar, 2004; Hillis et al.,2004).4 However in the present study, the occurrence of lesions in various perisylvianregions was comparable (see Table 1). An additional point is that the lesion mapsspecifically reflect the behavioural task used and not general semantic, phonological,or syntactic processes, just as activation patterns for functional neuroimaging data.Finally, it should be noted that the small number of subjects did not permit formalmultiple comparison correction of the VLSM analyses. While these general findingswere supported by relatively stringent ROI analyses, they should perhaps be con-sidered preliminary.

In conclusion, the primary finding was that there were unique, multiple lesions foreach language task. Most voxels were selectively associated with individual psycho-linguistic deficits, and a smaller number of voxels interdigitated the unique lesions forcombined deficits. This mosaic-like lesion-deficit pattern is consistent with the ideathat the functional fractionation of the human brain follows a many (functions)-to-many (networks) scheme (Blank et al., 2002; Mesulam, 1998; Roland & Zilles, 1998;Vigneau et al., 2006). Second, the frontal, inferior parietal, temporal, insular, andsubcortical lesion locations were not only consistent with prior functional neuroima-ging and lesion studies of production, but were also remarkably similar to neuralcorrelates of language processing (Vigneau et al., 2006). A few less frequentlyreported, but nevertheless unsurprising neuroanatomical associations were a centralSylvian region (posterior PT, posterior insula, and SMG) for all three productionmeasures combined, SMG for sentence production deficits, and anterior STG for theconjunction map of nonword repetition and sentence production deficits. Third, therewas an antero-posterior gradient in the frontal, IPL, temporal, and intrasylvian

4 For example, the insula is more susceptible to middle cerebral artery strokes (Ay, Arsava,Koroshetz, & Sorensen, 2008). But this was not the case in our patient sample (see Table 2).

LESION ANALYSIS OF APHASIA 15

Dow

nloa

ded

by [

Dr

Yas

mee

n Fa

roqi

-Sha

h] a

t 08:

36 1

9 N

ovem

ber

2013

regions: proceeding from anterior lesions for phonological and sentence productiondeficits to posterior lesions for lexical deficit. There were also deficit specific subdivi-sions within each of these regions. Recent neuroanatomical models of language(processing) reconcile this multifunctionality by attributing (sometimes domain gen-eral) cognitive processes to each region, such as IFG for rule-based combinatorialoperations, temporal cortex for storage/retrieval, IPL for sublexical analysis/synth-esis, posterior PT for vocal tract related auditory-motor correspondence, insula formotor planning, and BG for enabling cortical connections related to sequencing/retrieval (Bookheimer, 2002; Grodzinsky & Friederici, 2006; Hagoort, 2005; Shalom& Poeppel, 2008; Ullman, 2001, 2006). Our findings signify that such cognitiveprocess-based neuroanatomical models may also be applicable to language encodingfor production. Further research using more fine-grained approaches such as diffu-sion tensor imaging tractography will help elucidate neuroanatomical models forlanguage production.

Supplementary Material

Supplementary content is available via the ‘Supplementary’ tab on the article’s onlinepage (http://dx.doi.org/10.1080/02687038.2013.853023).

Manuscript received 10 June 2013Manuscript accepted 3 October 2013

First published online 19 November 2013

REFERENCES

Ackermann, H., & Riecker, A. (2004). The contribution of the insula to motor aspects of speech produc-tion: A review and a hypothesis. Brain and Language, 89, 320–328.

Amunts, K., Schleicher, A., Bürgel, U., Mohlberg, H., Uylings, H. B. M., & Zilles, K., (1999). Broca’sregion revisited: Cytoarchitecture and intersubject variability. The Journal of Comparative Neurology,412, 319–341.

Ardila, A. (1999). The role of insula in language: An unsettled question. Aphasiology, 13, 79–87.Augustine, J. (1996). Circuitry and functional aspects of the insular lobe in primates including humans.

Brain Research Reviews, 22, 229–244.Ay, H., Arsava, E. M., Koroshetz, W. J., & Sorensen, A. G. (2008). Middle cerebral artery infarcts

encompassing the insula are more prone to growth. Stroke, 39, 373–378.Baldo, J. V., Katseff, S., & Dronkers, N. F. (2012). Brain regions underlying repetition and auditory-verbal

short-term memory deficits in aphasia: Evidence from voxel-based lesion symptom mapping.Aphasiology, 26, 338–354.

Baldo, J. V., Schwartz, S., Wilkins, D., & Dronkers, N. F. (2006). Role of frontal versus temporal cortex inverbal fluency as revealed by voxel-based lesion symptom mapping. Journal of the InternationalNeuropsychological Society, 12, 896–900.

Bamiou, D. E., Musiek, F. E., & Luxon, L. M. (2003). The insula (island of Reil) and its role in auditoryprocessing: Literature review. Brain Research Reviews, 42, 143–154.

Bastiaanse, R., & Leenders, K. L. (2009). Language and Parkinson’s disease. Cortex, 45, 912–914.Bates, E., Wilson, S. M., Saygin, A. P., Dick, F., Sereno, M. I., Knight, R., & Dronkers, N. F. (2003).

Vowel-based lesion symptom mapping. Nature Neuroscience, 6, 448–450.Bernal, B., & Ardila, A. (2009). The role of arcuate fasciculus in conduction aphasia. Brain, 132,

2309–2316.Binder, J., & Desai, R. (2011). The neurobiology of semantic memory. Trends in Cognitive Sciences, 15,

527–536.Binder, J. R., Frost, J. A., Hammeke, T. A., Cox, R. W., Rao, S. M., & Prieto, T. (1997). Human

brain language areas identified by functional magnetic resonance imaging. Journal of Neuroscience,17, 353–362.

16 FAROQI-SHAH ET AL.

Dow

nloa

ded

by [

Dr

Yas

mee

n Fa

roqi

-Sha

h] a

t 08:

36 1

9 N

ovem

ber

2013

Binder, J. R., Frost, J. A., Hammeke, T. A., Rao, S., & Cox, B. (1996). Function of the left planumtemporale in auditory and linguistic processing. Brain, 119, 1239–1247.

Blank, S. C., Scott, S. K., & Wise, R. J. S. (2002). Speech production: Wernicke, Broca, and beyond. Brain,125, 1829–1838.

Bonilha, L., & Fridriksson, J. (2009). Subcortical damage and white matter disconnected associated withnon-fluent speech. Brain, 132, 1–2.

Bookheimer, S. (2002). Functional MRI of language: New approaches to understanding the corticalorganization of semantic processing. Annual Review of Neuroscience, 25, 151–188.

Booth, J. R., Lu, D., Burman, D. D., Chou, T.-L., Jin, Z., Peng, D.-L., … Liu, L. (2006). Specialization ofphonological and semantic processing in Chinese word reading. Brain Research, 1071, 197–207.

Borovsky, A., Saygin, A. P., Bates, E., & Dronkers, N. (2007). Lesion correlates of conversational speechproduction deficits. Neuropsychologia, 45, 2525–2533.

Braun, A. R., Guillemin, A., Hosey, L., & Varga, M. (2001). The neural organization of discourse: AnH2O15 PET study of narrative production in English and American sign language. Brain, 124,2028–2044.

Buchsbaum, B., & D‘Esposito, M. (2008). The search for the phonological store: From loop to convolu-tion. Journal of Cognitive Neuroscience, 205, 762–778.

Caplan, D., Gow, D., & Markis, N. (1995). Analysis of lesions by MRI in stroke patients with acoustic-phonetic deficits. Neurology, 45, 293–298.

Caplan, D., Hildebrandt, N., & Makris, N. (1996). Location of lesions in stroke patients with deficits insyntactic processing in sentence comprehension. Brain, 119, 933–949.

Caspers, S., Geyer, S., Schleiche, R. A., Mohlberg, H., Amunts, K., & Zilles, K. (2006). The humaninferior parietal cortex: Cytoarchitectonic parcellation and interindividual variability. NeuroImage, 33,430–448.

Cloutman, L., Gottesman, R., Chaudhry, P., Davis, C., Kleinman, J. T., Pawlak, M., … Hillis, A. E.(2009). Where (in the brain) do semantic errors come from? Cortex, 45, 641–649.

Craig, A. (2009). How do you feel now? The anterior insula and human awareness. Nature Reviews.Neuroscience, 10, 59–70.

Dabul, B. L. (2000). Apraxia battery for adults (2nd ed.). Austin, TX: Pro-Ed.Damasio, H., & Damasio, A. R. (1980). The anatomical basis of conduction aphasia. Brain, 103, 337–350.Damasio, H., Grabowski, T. J., Tranel, D., Hichwa, R. D., & Damasio, A. R. (1996). A neural basis for

lexical retrieval. Nature, 380, 499–505.Daniele, A., Giustolisi, L., Silveri, M. C., Colosimo, C., & Gainotti, G. (1994). Evidence for a possible

neuroanatomical basis for lexical processing of nouns and verbs. Neuropsychologia, 32, 1325–1341.Démonet, J. F., Thierry, G., & Cardebat, D. (2005). Renewal of the neurophysiology of language:

Functional neuroimaging. Psychological Review, 85, 49–95.Dick, F., Saygin, A. P., Galati, G., Pitzalis, S., Bentrovato, S., D‘Amico, S., … Pizzamiglio, L. (2007).

What is involved and what is necessary for complex linguistic and nonlinguistic auditory proces-sing: Evidence from functional magnetic resonance imaging and lesion data. Journal of CognitiveNeuroscience, 19, 799–816.

Dronkers, N., & Ogar, J. (2004). Brain areas involved in speech production. Brain, 127, 1461–1462.Dronkers, N. F. (1996). A new brain region for coordinating speech articulation. Nature, 384, 159–161.Dronkers, N. F., Wilkins, D. P., van Valin Jr, R. D., Redfern, B. B., & Jaeger, J. J. (2004). Lesion analysis

of the brain areas involved in language comprehension. Cognition, 92, 145–177.Duffy, J. (2005). Motor speech disorders: Substrates, differential diagnosis, and management. San Louis,

MO: Mosby.Embick, D., Marantz, A., Miyashita, Y., O’Neil, W., & Sakai, K. L. (2000). A syntactic specialization for

Broca’s area. Proceedings of the National Academy of Sciences, 97, 6150–6154.Flynn, F. G., Benson, D. F., & Ardila, A. (1999). Anatomy of the insula: Functional and clinical

correlates. Aphasiology, 13, 55–78.Fridriksson, J., Kjartansson, O., Morgan, P., Haukur, H., Magnusdottir, S., Bonilha, L., & Rorden, C.

(2010). Impaired speech repetition and left parietal lobe damage. The Journal of Neuroscience, 30,11057–11061.

Friederici, A., & Kotz, S. (2003). The brain basis of syntactic processes. NeuroImage, 20, S8–S17.Frisch, S., Kotz, S. A., von Cramon, D. Y., & Friederici, A. D. (2003). Why the P600 is not just a P300:

The role of the basal ganglia. Clinical Neurophysiology, 114, 336–340.Galaburda, A. M., & Pandya, D. N. (1983). The intrinsic architectonic and connectional organization of

the superior temporal regions of the rhesus monkey. Journal of Comparative Neurology, 221, 169–184.

LESION ANALYSIS OF APHASIA 17

Dow

nloa

ded

by [

Dr

Yas

mee

n Fa

roqi

-Sha

h] a

t 08:

36 1

9 N

ovem

ber

2013

Geschwind, N. (1972). Language and the brain. Scientific American, 226, 76–83.Graves, W., Grabowski, T. J., Mehta, S., & Gupta, P. (2008). The left posterior superior temporal

gyrus participates specifically in accessing lexical phonology. Journal of Cognitive Neuroscience, 20,1698–1710.

Griffiths, T. D., & Warren, J. D. (2002). The planum temporale as a computational hub. Trends inNeurosciences, 26, 348–353.

Grodzinsky, Y., & Friederici, A. (2006). Neuroimaging of syntax and syntactic processing. Current Opinionin Neurobiology, 16, 240–246.

Hagoort, P. (2005). On broca, brain and binding: A new framework. Trends in Cognitive Science, 9,416–423.

Hagoort, P., Indefrey, P., Brown, C., Herzog, H., Steinmetz, H., & Seitz, Rd. J. (1999). The neuralcircuitry involved in the reading of German words and pseudowords: A PET study. Journal ofCognitive Neuroscience, 11, 383.

Heim, S., & Friederici, A. D. (2003). Phonological processing in language production: Time course of brainactivity. NeuroReport, 14, 2031–2033.

Heim, S., Opitz, B., & Friederici, A. D. (2002). Broca’s area in the human brain is involved in the selectionof grammatical gender for language production: Evidence from event related functional magneticresonance imaging. Neuroscience Letters, 328, 101–104.

Herbster, A. N., Mintun, M. A., Nebes, R. D., & Becker, J. T. (1997). Regional cerebral blood flow duringword and nonword reading. Human Brain Mapping, 5, 84–92.

Hickok, G., Okada, K., & Serences, J. T. (2009). Area Spt in the human planum temporale supportssensory-motor integration for speech processing. Journal of Neurophysiology, 101, 2725–2732.

Hickok, G., & Poeppel, D. (2007). The cortical organization of speech processing. Nature Neuroscience, 6,393–402.

Hillis, A. E., Work, M., Barker, P. B., Jacobs, M. A., Breese, E. L., & Maurer, K. (2004). Reexamining thebrain regions crucial for orchestrating speech articulation. Brain, 127, 1479–1487.

Indefrey, P. (2011). The spatial and temporal signatures of word production components: A critical update.Frontiers in Psychology, 2(255), 1–16.

Indefrey, P., Brown, C. M., Hellwig, F., Amunts, K., & Herzog, H. (2001). A neural correlate ofsyntactic encoding during speech production. Proceedings of the National Academy of Sciences,USA, 98, 5933–5936.

Indefrey, P., Hellwig, F., Herzog, H., Seitz, Rd. J., & Hagoort, P. (2004). Neural responses to theproduction and comprehension of syntax in identical utterances. Brain and Language, 89, 312.

Indefrey, P., & Levelt, W. J. M. (2004). The spatial and temporal signatures of word productioncomponents. Cognition, 92, 101–144.

Kay, J., Coltheart, M., & Lesser, R. (1992). Psycholinguistic assessment of language processing in aphasia(PALPA). Philadelphia, PA: Psychology Press.

Kertesz, A. (1982). Western aphasia battery. New York, NY: Grune Stratton.Kotz, S. A., Schwartze, M., & Schmidt-Kassow, M. (2009). Non-motor basal ganglia functions: A

review and proposal for a model of sensory predictability in auditory language perception. Cortex,45, 982–990.

Levelt, W. (1999). Producing spoken language: A blueprint of the speaker. In C. M. Brown & P. Hagoort(Eds.), The neurocognition of language (pp. 83–122). New York, NY: Oxford University Press.

Lieberman, P. (2002). On the nature and evolution of the neural bases of human language. AmericanJournal of Physical Anthropology, 45, 36–62.

Lieberman, P. (2007). The evolution of human speech: Its anatomical and neural bases. CurrentAnthropology, 48, 584–596.

Luzzatti, C., Aggujaro, S., & Crepaldi, D. (2006). Verb-noun double dissociation in aphasia: Theoreticaland neuroanatomical foundations. Cortex, 42, 875–883.

Mai, J. K., Paxinos, G., & Voss, T. (2008). Atlas of the human brain (3rd ed.). London: Academic Press.Maldjian, J. A., Laurienti, P. J., Kraft, R. A., & Burdette, J. H. (2003). An automated method for

neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets. NeuroImage, 19,1233–1239.

McGettigan, C., Warren, J. E., Eisner, F., Marshall, C. R., Shanmugalingam, P., & Scott, S. K. (2011).Neural correlates of sublexical processing in phonological working memory. Journal of CognitiveNeuroscience, 23, 961–977.

18 FAROQI-SHAH ET AL.

Dow

nloa

ded

by [

Dr

Yas

mee

n Fa

roqi

-Sha

h] a

t 08:

36 1

9 N

ovem

ber

2013

McNeil, M. R., Doyle, P. J., Wambaugh, J., Nadeau, S. E., Gonzalez Rothi, L. J., & Crosson, B. (2000).Apraxia of speech: A treatable disorder of motor planning and programming. New York, NY: GuilfordPress.

Mesulam, M. (1998). From sensation to cognition. Brain, 121, 1013–1052.Miceli, G., Silveri, M. C., Nocentini, U., & Caramazza, A. (1988). Patterns of dissociation in comprehen-

sion and production of nouns and verbs. Aphasiology, 2, 351–358.Middleton, F. A., & Strick, P. L. (2000). Basal ganglia output and cognition: Evidence from anatomical,

behavioral, and clinical studies. Brain and Cognition, 42, 183–200.Mutschler, I., Wieckohorst, B., Kowalevski, S., Derix, J., Wentlandt, J., Schulze-Bonhage, A., & Ball, T.

(2009). Functional organization of the human anterior insular cortex. Neuroscience Letters, 457, 66–70.Nestor, P. J., Graham, N. L., Fryer, T. D., Williams, G. B., Patterson, K., & Hodges, J. R. (2003).

Progressive non-fluent aphasia is associated with hypometabolism centered on the left anterior insula.Brain, 126, 2406–2418.

Newman, S. D., Just, M. A., Keller, T. A., Roth, J., & Carpenter, P. A. (2003). Differential effects ofsyntactic and semantic processing on the subregions of broca’s area. Brain Research Cognitive BrainResearch, 16, 297–307.

Pa, J., & Hickok, G. (2008). A parietal-temporal sensory-motor integration area for the human vocal tract:Evidence from an fMRI study of skilled musicians. Neuropsychologia, 46, 362–368.

Piras, F., & Marangolo, P. (2007). Noun-verb naming in aphasia: A voxel-based lesion-symptom mappingstudy. NeuroReport, 18, 1455–1458.

Poldrack, R., Wagner, A. D., Prull, M. W., Desmond, J. E., Glover, G. H., & Gabrieli, J. D. E. (1999).Functional specialization for semantic and phonological processing in the left inferior prefrontal cortex.NeuroImage, 10, 15–35.

Price, C. J. (2000). The anatomy of language: Contributions from functional neuroimaging. Journal ofAnatomy, 197, 335–359.

Price, C. J., Moore, C. J., Humphreys, G. W., & Wise, R. J. S. (1997). Segregating semantic fromphonological processes during reading. Journal of Cognitive Neuroscience, 9, 727–733.

Ridgeway, G. R., Henley, S., Rohrer, J., Scahill, R., Warren, J. D., & Fox, N. (2008). Ten simple rules forreporting voxel-based morphometry studies. NeuroImage, 40, 1429–1435.

Roland, P. E., & Zilles, K. (1998). Structural divisions and functional fields in the human cerebral cortex.Brain Research Reviews, 26, 87–105.

Saygin, A. P., Dick, F., Wilson, S. W., Dronkers, N. F., & Bates, E. (2003). Neural resources forprocessing language and environmental sounds: Evidence from aphasia. Brain, 126, 928–945.

Saygin, A. P., Wilson, S. M., Dronkers, N. F., & Bates, E. (2004). Action comprehension in aphasia:Linguistic and non-linguistic deficits and their lesion correlates. Neuropsychologia, 42, 1788.

Schwartz, M. F., Kimberg, D. Y., Walker, G. M., Fasiyetan, O., Brecher, A., Dell, G. S., & Coslett, B.(2009). Anterior temporal involvement in semantic word retrieval: Voxel based lesion symptom map-ping evidence from aphasia. Brain, 132, 3411–3427.

Shalom, D. B., & Poeppel, D. (2008). Functional anatomic models of language: Assembling the pieces. TheNeuroscientist, 14, 119–127.

Shapleske, J., Rossel, S. L., Woodruff, P. W. R., & David, A. (1999). The planum temporale: A systematic,quantitative review of its structural, functional and clinical significance. Brain Research Reviews, 29,26–49.

Shelton, J., & Caramazza, A. (1999). Deficits in lexical and semantic processing: Implications for models ofnormal language. Psychonomic Bulletin Review, 6, 5–27.

Solomon, J., Raymont, V., Braun, A., Butman, J. A., & Grafman, J. (2007). User-friendly software for theAnalysis of Brain Lesions (ABLe). Computer Methods and Programs in Biomedicine, 86, 245–254.

Swaab, T., Brown, C., & Hagoort, P. (1997). Spoken sentence comprehension in aphasia: Event relatedpotential evidence for a lexical integration deficit. Journal of Cognitive Neuroscience, 9, 39–66.

Talairach, J., & Tournoux, P. (1988). Co-planar stereotaxic atlas of the human brain: 3-D proportionalsystem: An approach to cerebral imaging. New York, NY: Thieme Medical.

Tranel, D. (2006). Impaired naming of unique landmarks is associated with left temporal polar damage.Neuropsychology, 20, 1–10.

Tranel, D., Adolphs, R., Damasio, H., & Damasio, A. R. (2001). A neural basis for the retrieval of wordsfor actions. Cognitive Neuropsychology, 18, 655–674.

Tzourio-Mazoyer, N., Landeau, B., Papthanassiou, F., Crivello, F., Etard, N., Delcroix, N., … Joliot, M.(2002). Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcel-lation of the MNI MRI single-subject brain. NeuroImage, 15, 273–289.

LESION ANALYSIS OF APHASIA 19

Dow

nloa

ded

by [

Dr

Yas

mee

n Fa

roqi

-Sha

h] a

t 08:

36 1

9 N

ovem

ber

2013

Ullman, M. T. (2001). The neural basis of lexicon and grammar in first and second language: Thedeclarative/procedural model. Bilingualism: Language and Cognition, 4, 105–122.

Ullman, M. T. (2006). Is Broca’s area part of a basal ganglia thalamocortical circuit? Cortex, 42, 480–485.Ullman, M. T., Corkin, S., Coppola, M., & Hickok, G. (1997). A neural dissociation within language:

Evidence that the mental dictionary is part of declarative memory, and that grammatical rules areprocessed by the procedural system. Journal of Cognitive Neuroscience, 9, 266–276.

Vanier, M., & Caplan, D. (1990). CT-scan correlates of agrammatism. In L. Menn & L. K. Obler (Eds.),Agrammatic aphasia: A cross-language narrative sourcebook. Amsterdam: John Benjamins PublishingCompany.

Vigneau, M., Beaucousin, V., Hervé, P. Y., Duffau, H., Crivello, F., Houdé, O., … Tzourio-Mazoyer, N.(2006). Meta-analyzing left hemisphere language areas: Phonology, semantics, and sentence processing.NeuroImage, 30, 1414–1432.

Willems, R. M., & Hagoort, P. (2007). Neural evidence for the interplay between language, gesture, andaction: A review. Brain and Language, 101, 287–289.

Willmes, K., & Poeck, K. (1993). To what extent can aphasic syndromes be localized? Brain, 116,1527–1540.

Wise, R., Greene, J., Buchel, C., & Scott, S. K. (1999). Brain regions involved in articulation. Lancet, 353,1057–1061.

Wise, R. J. S., Scott, S. K., Blank, S. C., Mummery, C. J., Murphy, K., & Warburton, E. A. (2001).Separate neural sub-systems within ‘Wernicke“s area”. Brain, 124, 83–95.

Woods, R. P., Grafton, S. T., Watson, J. D., Sicotte, N. L., & Maziotta, J. D. (1998). Automated imageregistration: II intersubject validation of linear and nonlinear models. Journal of Computer AssistedTomography, 22, 153–165.

20 FAROQI-SHAH ET AL.

Dow

nloa

ded

by [

Dr

Yas

mee

n Fa

roqi

-Sha

h] a

t 08:

36 1

9 N

ovem

ber

2013