Language organization in patients with early and lateleft-hemisphere lesion: a pet study

\ PERGAMON

Neuropsychologia 26 "0888# 434Ð446

Language organization in patients with early and late left!hemisphere lesion] a PET study R[!A[ Mullera\e\\ R[D[ Rothermela\b\ M[E[ Behena\ O[ Muzika\ P[K[ Chakrabortyc\ H[T[ Chugania\c\d a

Department of Pediatrics\ Wayne State University Medical Center\ Detroit\ MI\ USA Department of Psychiatry\ Wayne State University Medical Center\ Detroit\ MI\ USA c Department of Radiolo`y\ Wayne State University Medical Center\ Detroit\ MI\ USA d Department of Neurolo`y\ Wayne State University Medical Center\ Detroit\ MI\ USA e Department of Co`nitive Science\ University of California\ San Die`o\ CA\ USA

b

Received 4 February 0887^ accepted 5 August 0887

Abstract Functional neuroimaging studies have shown enhanced right!hemisphere language activations in adults with left!hemisphere damage[ We hypothesized that this e}ect would be stronger in patients with lesion occurring early in development[ Using ð04OŁ!water PET\ we studied eight normal adults and 12 patients with unilateral left lesion during rest\ listening to sentences\ and sentence repetition[ Thirteen patients had lesions with early onset "³4 years# and ten had lesions with late onset "×19 years#[ For listening to sentences\ frontotemporal blood ~ow increases were signi_cantly stronger in the left than in the right hemisphere in normal adults[ This normal asymmetry was reduced in patients with late lesion and reversed in those with early lesion[ For sentence repetition\ analogous group di}erences were signi_cant for the basal ganglia\ but failed to reach signi_cance for the "pre#motor and insular regions[ We conclude that left lesion leads to alterations in the asymmetry of language activations "in and beyond the perisylvian areas#[ In addition\ rightward shifts of language activation tend to be stronger as a consequence of early "as compared to late# lesion[ Finally\ postlesional reorganization appears to re~ect a coexistence of {additive| and {subtractive| e}ects\ i[e[\ activation in some regions that are not normally involved in language processing and lack of activation in other "undamaged# regions that are normally activated by language tasks[ Þ 0888 Elsevier Science Ltd[ All rights reserved[ Keywords] Language^ Brain damage^ Development^ Plasticity^ Functional mapping^ Cerebral blood ~ow^ Positron emission tomography

0[ Introduction The mammalian brain is characterized by considerable normal and lesion!induced plasticity\ especially during maturation ð0Ð3Ł[ In nonhuman animals\ enriched environment has been shown to have positive impact on cortical thickness and synaptic density ð4\ 5Ł[ Human studies suggest considerable epigenetic in~uences on brain morphology ð6\ 7Ł as well as experiential and skill!related e}ects on the size ð8Ð00Ł and dendritic architecture ð01Ł of sensorimotor\ association\ and lan! guage cortices[

 Corresponding author] Ralph!Axel Muller\ Children|s Hospital Research Center\ 7009 La Jolla Shores Dr[ No[ 199\ San Diego\ CA 81926\ USA[ Fax] ¦0 508!440!6820^ e!mail] amuellerÝcogsci[ucsd[edu

Clinical studies demonstrate that\ as a rule of thumb\ compensatory reorganization is greater when brain injury occurs during maturation as compared to damage acquired in adulthood "for nonhuman animal data\ see Refs ð02Ð04Ł#\ even though this may not apply to prenatal and early postnatal lesions ð05Ð07Ł or to early neurodevelopmental disturbances ð08Ł[ Early absence of stimulation from one sensory modality may lead to an expansion of the cortical representation of intact sensory modalities[ Such cross!modal plasticity has been observed in studies showing tactile and auditory processing in the occipital cortex of early blind subjects ð19Ð12Ł and enhanced visual processing in the temporal lobe of early deaf subjects ð13\ 14Ł[ Early left hemi! spherectomy does not typically result in persistent severe dysphasia ð15Ð17Ł\ even though it remains unsettled whether there is some degree of long!term language impairment ð18Ð21Ł[ This contrasts with the typically sev! ere and persistent language de_cits following extensive

9917Ð2821:88:, ! see front matter Þ 0888 Elsevier Science Ltd[ All rights reserved PII] S 9 9 1 7 Ð 2 8 2 1 " 8 7 # 9 9 0 9 8 Ð 1

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left!hemisphere lesion in adulthood[ Middle cerebral artery infarct\ for instance\ is likely to result in persistent aphasia ð22Ð24Ł[ Findings from various clinical and experimental paradigms thus seem incompatible with the notion of language being {hard!wired| into the left perisylvian cortex "cf Ref[ ð25Ł#[ Instead they suggest remarkable developmental plasticity in the context of structural brain damage or lack of environmental stimu! lation ð26Ł[ Task!related functional neuroimaging in lesion pat! ients has so far been almost exclusively performed in adults[ Recovery from aphasia in adults with left!hemi! sphere lesion is associated with greater than normal lan! guage activation in the right hemisphere ð27\ 28Ł\ in regions homologous to the usual perisylvian language areas ð39Ð32Ł[ In view of the especially pronounced matu! rational plasticity discussed above\ the potential for inter! hemispheric reorganization may be expected to be even stronger after early lesion[ In previous studies examining e}ects of early unilateral brain damage ð33\ 34Ł\ we did indeed observe considerable {right!hemisphere shifts| of language!related activations in children and adolescents with left lesion[ The present study directly compares pat! ients with early and late!onset lesion[ We hypothesized that patients with early left lesion would show greater rightward asymmetry in perisylvian language activations than adults with late lesion[ A second issue addressed in our study concerns sub! cortical involvement in language processing as dem! onstrated by lesion and functional imaging studies "for review see Ref[ ð35Ł#[ Language de_cits have been found in patients with injury to the thalamus and the basal ganglia\ especially of the dominant left hemisphere ð36Ð 40Ł[ Predominantly left!sided activation in the thalamus and basal ganglia have also been reported in functional imaging studies with normal adults performing word rep! etition ð41Ł and generation ð42Ł\ as well as semantic and phonological working memory tasks ð43Ł[ We therefore also examined subcortical activations\ focusing on the basal ganglia "since the thalamus did not show lat! eralizing activation in normal control subjects for the language conditions applied#[ We hypothesized that the potential for interhemispheric cortical reorganization "especially after early lesion# would be re~ected in anal! ogous interhemispheric reorganization in the basal gang! lia\ and thus in reversed functional asymmetry as compared to normal adults[ To our knowledge\ this is the _rst functional neuro! imaging study directly comparing language!related brain activations in patient groups with early versus late lesion[ The goals of our study were therefore mainly exploratory\ especially in view of the scarcity of clinical functional neuroimaging data for language in children and ado! lescents "for some preliminary and single!case studies\ see Refs ð44Ð48Ł# and the almost complete lack of age! matched normative data "cf ð59Ł#[

1[ Method 1[0[ Subjects Twenty!three patients and eight normal adults were included in the study[ All patients had unilateral struc! tural and:or functional lesion in or in the vicinity of the left perisylvian cortex\ as determined by MRI and 1! deoxy!1ð07FŁ~uoro!D!glucose "FDG# PET "for methods\ see Ref[ ð50Ł#[ Functional mapping of language by means of ð04OŁ!water PET was performed in preparation for possible resective brain surgery for the treatment of intractable epilepsy and:or neoplastic disease "Table 0#[ The bene_ts from these studies for surgical decision!mak! ing and planning ð34\ 46Ł clearly outweighed possible risks through radioisotope exposure\ which*according to a recent review ð51Ł*is probably negligible even in pedi! atric applications[ Patients were assigned to two groups according to age at lesion onset[ The _rst group "EL  early lesion# consisted on 02 patients with age at _rst risk under _ve years[ Age at _rst risk was determined by the earliest event indicating brain damage ð52\ 53Ł[ The second group "LL  late lesion# was formed by 09 adults with _rst risk in the third decade of life or later[ All patients except three "LL1\ LL2\ LL09# had seizures\ and all except one "LL1# received antiepileptic medication at the time of study "as listed in Table 0#[ For ethical reasons\ ð04OŁ!water PET control data for healthy children and adolescents were unavailable[ A nor! mal adult "NA# comparison group consisting of three women and _ve men "age range] 12Ð28 years^ mean] 18[2 years# was therefore included[ None of the adult com! parison subjects had a history of neurologic or psychiatric disease[ One left!handed female subject was included in view of the fact that _ve patients in the EL group and two patients in the LL group had a family history of sinistrality and the occurrence of atypical handedness in the patient groups was therefore probably not exclusively lesion!induced[ 1[1[ PET study In ð04OŁ!water PET\ tracer uptake is closely related to regional cerebral blood ~ow "rCBF#\ which is in turn linked to localized cerebral activation in response to sen! sory stimulation and cognitive tasks ð54Ð56Ł[ PET scans were performed on a Siemens EXACT HR scanner "Knoxville\ TN# with an axial _eld!of!view of 04 cm[ The reconstructed image resolution obtained in the study was 4[429[24 mm in!plane and 5[929[38 mm in axial direc! tion "full!width at half maximum^ reconstruction par! ameters] Shepp _lter with 9[2 cycles:pixel cuto} frequency#[ A {scout scan| was performed for con! _rmation of optimal head position and determination of the delay between injection in the antecubital vein and tracer arrival in the brain[ This was followed by an exter!

Table 0 Patient information Lesion localizationa Patient

Age

Sex

Hand preference

on MRI

on FDG PET

Diagnosis:etiology

Age at 0st risk "years^ months#

Antiepileptic medication

Frontal Temporo!parietal Temporo!occipital Di}use Frontal Temporo!parietal Di}use Di}use Di}use Temporo!parietal Temporal Di}use Temporal

Epilepsy Epilepsy Left carotid hypoplasia\ left temporal pachygyria Epilepsy Epilepsy Epilepsy SturgeÐWeber syndrome Epilepsy Arteriovenous malformation\ stroke Epilepsy\ tumor Epilepsy Perinatal ischemia Epilepsy

1^ 9 2^ 5 cg 9^ 2 cg 3^ 9 cg 0^ 5 cg 0^ 5 pn pn 9^ 8

PHT\ VPA PHT CBZ\ FBM PHT CBZ\ FBM\ VPA CBZ\ VPA CBZ CBZ CBZ\ GBP CBZ GBP\ VPA CBZ\ GBP\ VPA VPA

Frontal Frontal Temporal Temporo!parietal Parietal Fronto!temporo!parietal Di}use Fronto!parietal Frontal Parietal

Epilepsy Astrocytoma Astrocytoma Tumor Glioblastoma Astrocytoma Glioblastoma Astrocytoma Astrocytoma Tumor

10^ 9 29^ 9 20^ 9 11^ 9 20^ 9 39^ 9 33^ 9 40^ 9 42^ 9 59^ 9

PHT none PHT CBZ\ PHT PB\ PHT CBT GBP\ PHT PHT PHT\ CBZ PHT

EARLY LESION GROUP "_rst risk ³ 4 years# 5 5 6 7 7 8 00 03 04 04 04 05 22 01[4

m m f m f m m m f f m m m

R:M L L R R R L L L R R R L

Normal Normal Temporal Parieto!occipital Normal Normal Hemiatrophy Temporal Sylvian:hemiatrophy Mesiotemporal Temporo!parietal Temporo!occipital Temporal

LATE LESION GROUP "_rst risk ×19 years# LL0 LL1 LL2 LL3 LL4 LL5 LL6 LL7 LL8 LL09 Mean

17 20 22 22 39 30 36 42 45 50 31[2

m m f m m m f m m m

R R R R L L R M M R

Frontal Frontal Posterior temporal Temporal Parietal Fronto!parietal Parietal Fronto!parietal Fronto!parietal Parietal\ insular

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EL0 EL1 EL2 EL3 EL4 EL5 EL6 EL7 EL8 EL09 EL00 EL01 EL02 Mean

a

All lesions are lateralized to the left hemisphere[ Lesions were identi_ed through visual inspection by a radiologist[ Abbreviations] L  left^ M  mixed^ R  right^ CBZ  carbamazepine^ CNZ  clonazepam^ FBM  felbamate^ GBP  gabapentin^ LMT  lamotrigine^ PB  phenobarbitol^ PHT  phenytoin^ VPA  valproate[

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nal 57Ga line source transmission scan for attenuation correction[ For each activation scan\ the radioisotope dose for patients under age 07 years was 9[246 mCi per kg ð57Ł\ with a maximum dose of 14 mCi[ All adult subjects received this maximum dose[ The ð04OŁ!water dose diluted in 2Ð5 ml of saline "adjusted for patient weight# was administered as a slow bolus over 19 s using a volumetric pump via a peripheral intravenous line[ Time between injection and the start of a static 59 s scan was individually determined according to the delay observed in the scout scan[ The stimulation extended over 49 s\ starting 19 s before each activation scan[ An interval of −09 min between scans ensured almost complete decay of oxygen! 04 "physical half!life 012 s#[ Three di}erent conditions were analyzed in this study] "0# Rest "with minimal white noise from fans#^ "1# Listening to 09 short sentences "such as] {{The game was very interesting||^ {{They go to school together||#\ played through earphones from a high!_delity tape recorder^ and "2# Listening and immediate repetition of eight sentences of the same type as used for condition "1#[ Inter! stimulus intervals in this condition were slightly longer\ to allow time for repetition[ Patients were instructed to keep their eyes closed under a black eye mask during all scans[ The experimental conditions were selected in view of the clinical goals of presurgical evaluation and were thus intended to be comprehensive "incorporating several linguistic domains# and simple "i[e[\ appropriate for low! functioning patients#[ Passive stimulation with complex verbal material "rather than single words# has been shown to be associated with left!dominant activations in tem! poral and frontal regions in normal adults ð58Ð60Ł\ pre! sumably re~ecting automatic lexicosemantic activation "cf ð61Ł#[ The subjects in our study were instructed to attend to and {try to understand| the stimulus sentences[ Sentence repetition was chosen as a maximally cir! cumscribed and easy output task[ Word generation\ as successfully applied in studies with normal adults "e[g[\ Ref[ ð62Ł#\ was not expected to be reliably performed by low!functioning children "see Discussion#[ Each condition was scanned twice in each patient\ with counterbalanced order of repeat scans[ Di}erent sets of stimuli were used for repeat scans[ However\ due to lim! ited patient cooperation\ only one scan could be used for listening to sentences in patients EL2 and EL7\ and for the resting condition in patient LL4[ All subjects per! formed the repetition task without errors\ except for cases EL5\ EL7\ and EL09\ who made errors on three or less out of 05 items[ One patient "EL6# did not repeat sen! tences from tape\ but expressive speech "word repetition and yes:no responses# could instead be elicited in response to utterances from his mother\ following a format com! parable to condition "2#[

1[2[ Data analysis Forty!seven cross!sectional image planes were recon! structed for each scan[ The reconstructed images con! tained 017×017 pixels\ each measuring 0[62×0[62 mm\ with a plane separation of 2[014 mm[ The volume was analyzed using automated software ð63\ 64Ł\ incor! porating motion correction\ pixel value normalization\ realignment to automatically detected anterior!posterior commissure line\ image subtraction "stimulation minus control#\ and statistical parametric mapping based on smoothness estimation ð65Ł and a pooled!variance t"Z#! statistic model ð66Ł[ Image subtractions isolate rCBF changes for task:stimulation as compared to control con! ditions[ Two subtractions "comparisons# were performed] listening to sentences minus rest "{language perception|# and repeating sentences minus listening "{sentence rep! etition|#[ Comparisons were based on normalized data\ with pixel values for all scans being reset to a standard range "9Ð0999#[ Common applications of the ð04OŁ!water PET technique do not permit quanti_cation of absolute blood ~ow rates[ Therefore\ any use of the terms {activation| and {deactivation| only refers to relative increases and decreases in radioisotope counts within a given region\ which in turn re~ect rCBF changes[ Furthermore\ ð04OŁ! water PET data do not allow a clear distinction between regional neuronal activations that are indispensable for a given cognitive process and those that are only faci! litative[ This is re~ected in the _ndings in many PET language studies of activations in regions not usually associated with aphasia when damaged ð62\ 67\ 68Ł[ 1[3[ Regions of interest "ROIs# For descriptive purposes\ 37 ROIs "Table 2# were ident! i_ed on summed resting blood ~ow images and on volu! metric MRI\ coregistered by means of semiautomated software ð79Ł[ Due to the occurrence of extensive struc! tural lesions in both patient groups\ nonlinear warping to Talairach space ð70Ł was deemed inappropriate and group!wise statistical parametric mapping was therefore not performed "except for illustration purposes in the normal adult group^ see Fig[ 1C#[ Instead\ ROIs were identi_ed in each patient separately in order to correct for lesion!induced structural variation[ Each ROI was drawn on at least two separate image planes in order to increase the number of pixels included in the computation of mean CBF changes within a given ROI[ All neocortical ROIs were de_ned in terms of Brodmann areas "see Table 2#[ Mean changes were computed for each ROI and pati! ent[ 1[4[ Statistical group comparisons Considering limitations of statistical power and the necessity of restricting the number of regional compari!

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sons\ only a few composite ROIs that showed left!domi! nant activation in normal adults were analyzed statistically] a frontotemporal ROI "consisting of the inferior frontal\ superior and middle temporal ROIs#\ a motor speech ROI "consisting of the rolandic\ premotor\ and insular ROIs#\ a cortical hemispheric ROI "consisting of all cerebral cortical ROIs listed in Table 2#\ and the basal `an`lia "caudate and lentiform nuclei#[ Asymmetry scores were calculated for each subject as the mean blood ~ow change in a given left!hemisphere ROI minus the change in the homotopic right!hemisphere ROI[ Asym! metry scores were not further normalized since they were based on normalized rCBF data[ The frontotemporal ROI was analyzed for our {lan! guage perception| subtraction "which predominantly acti! vates this ROI in the left hemisphere in normal adults ð60Ł#\ as was the cortical hemispheric ROI[ The motor speech ROI "incorporating regions previously found to activate during word repetition ð41\ 62Ł# and the basal ganglia were analyzed for sentence repetition[ The thala! mus was not included in the statistical analyses since it did not show lateralizing activation on either subtraction in the normal adults[ Planned comparisons were per! formed by means of linear contrasts "ANOVA with pooled variance estimate# for expected group di}erences "NA × LL × EL for left!hemispheric ROIs and asym! metry scores^ EL × LL × NA for right!hemispheric ROIs#[ Expected di}erences in left! vs right!hemispheric ROI activations were additionally evaluated by means of paired one!tailed t!tests in order to establish signi_cance of regional hemispheric dominance within groups[

2[ Results 2[0[ Composite regions of interest In view of the signi_cant age di}erences between the two patient groups\ it was necessary to rule out possible confounding e}ects of chronological age[ For language perception\ chronological age was signi_cantly correlated with blood ~ow dependent variables in the left fronto! temporal ROI "r  9[25^ P  9[936#\ with further mar! ginally signi_cant correlations for the right cortical hemi! spheric ROI "r  9[21^ P  9[97# and for cortical hemispheric asymmetry scores "r  9[22^ P  9[95#[ For repetition\ a marginally signi_cant correlation was found for the right motor speech ROI "r  −9[29^ P  9[987#[ Because all these correlations indicate potential con! founds with the predicted lesion!induced e}ects\ one!way analyses of covariance were additionally performed for these ROIs\ covarying for chronological age[ The patient groups also di}ered signi_cantly in terms of time since lesion onset "_rst risk^ see Table 0#[ However\ there were no signi_cant correlations between blood ~ow measures and time since lesion onset for any of the ROIs "all correlations P × 9[04#[ Therefore\ this variable did not qualify as a covariate in this study[ As predicted\ asymmetry scores for language per! ception in the frontotemporal composite ROI were high! est in the NA\ reduced in the LL\ and lowest in the EL group "Fig[ 0#[ The linear contrast "NA × LL × EL# was highly signi_cant "T  2[06^ P  9[993#[ Mean rCBF changes were left!dominant in the comparison group

 Y

Fig[ 0[ Asymmetry scores per region of interest\ group\ and task condition "means\ standard error#[  P ³ 9[994^  P ³ 9[90^ P ³ 9[90 "P  9[03 after covarying for chronological age#[

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Fig[ 1[ Typical examples from patients in the early "A# and late "B# lesion onset groups\ showing regions of rCBF increase "×00)^ P ³ 9[990 "uncorr[## for language perception superimposed onto coregistered volumetric MRI[ "A# Bilateral temporal activations in patient EL4\ an eight!year old girl with seizure onset at 00 months of age[ Activation is slightly stronger and more extensive in the right hemisphere "mean activation in the frontotemporal ROI] left 2[3)\ right 4[1)#^ "B# Bilateral temporal and left inferior frontal activations in patient LL0\ a 17!year old man with _rst risk at 10 years of age "mean frontotemporal activation] left 2[2)\ right 2[6)#^ "C# activations "×7)^ P ³ 9[990 "uncorr[## for the normal adult group superimposed onto composite standard MRI\ showing more extensive frontotemporal activations in the left than in the right hemisphere[ Due to greater statistical power in the group analysis for normal adults\ more extensive regions exceed the signi_cance threshold even though the magnitude of percent rCBF changes is slightly lower than in the individual studies shown in "A# and "B#[

"P  9[911#\ bilateral in the LL group\ and right!domi! nant in EL group "P  9[907^ Fig[ 1#[ The same linear contrast "NA × LL × EL# revealed signi_cant group di}erences for the left frontotemporal ROI alone "T  3[73^ P ³ 9[9994^ Table 1#[ When covarying for chronological age\ this contrast remained signi_cant "F"1\29#  7[12^ P  9[991#[ The expected inverse linear contrast "EL × LL × NA# for the right frontotemporal

ROI was\ however\ not signi_cant "P  9[312#[ With respect to cortical hemispheric ROIs\ similar group di}erences were seen[ Activations were left!dominant in the NA group "P  9[911#\ bilateral in the LL group\ and right!dominant in the EL group "P  9[915#[ The expected linear contrast "NA × LL × EL# was signi_cant for left!hemispheric blood ~ow changes "T  2[65^ P  9[990# and for asymmetry scores "T  1[66^

Table 1 Mean blood ~ow changes "in )# per task condition\ group\ and composite ROI Group Region of interest

Brodmann areas: regions included

Language Perception "Listening to sentences compared to rest# Frontotemporal 33Ð34\ 36 "posterior part#\ 10Ð11\ 30Ð31 Cortical hemisphere All cortical ROIs

Sentence Repetition "Repeating sentences compared to listening# Motor speech 0Ð4\ 5 "middle and inf[ part#\ 32\ insula Basal ganglia Caudate and lentiform nuclei  P ³ 9[994^  P ³ 9[94^ n[s[  not signi_cant[

Hemisphere

EL

LL

NA

Group di}erences

L R L R

0[1 2[5 −9[7 9[3

2[3 2[3 −9[0 −9[4

4[5 1[5 0[2 −9[5

NA × LL × EL n[s[ NA × LL × EL n[s[

L R L R

0[9 1[1 −9[7 9[1

9[3 9[6 0[2 1[9

0[3 0[0 2[9 −9[6

n[s[ n[s[ NA × LL × EL n[s[

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P  9[90#[ However\ on ANCOVA with chronological age as covariate the group di}erence for hemispheric asymmetry scores failed to reach signi_cance "main group e}ect] F"1\29#  1[01\ P  9[03#[ The expected inverse linear contrast "EL × LL × NA# for the right hemi! spheric cortical ROI was not signi_cant "P  9[145#[ For sentence repetition\ the expected group di}er! ences of asymmetry scores in the motor speech ROI "NA × LL × EL#\ although evident on inspection of group means\ did not reach signi_cance "P  9[083^ Fig[ 0#[ Group di}erences in the left! and right!hemisphere motor speech ROIs were small except for somewhat enhanced activation in the right motor speech ROI for the EL group "Table 1#[ With respect to the basal ganglia\ on the other hand\ the predicted group di}erences "NA × LL × EL# were found for the left!hemisphere ROI "T  1[58^ P  9[901# and for asymmetry scores "T1[42^ P9[906#[ Activation in the right basal ganglia was greater in the LL than in the NA group\ but this di}erence was not signi_cant[ 2[1[ Single regions of interest For more complete qualitative presentation of the data\ mean rCBF changes for all ROIs are listed in Table 2[ For language perception\ several right!hemisphere regions showed group di}erences "EL × LL# compatible with our general hypothesis of greater interhemispheric plasticity after early than after late lesion[ These were the prefrontal\ superior temporal\ and inferior parietal regions\ the angular and cingulate gyri\ and the precu! neus[ For all of these right!hemisphere ROIs except the superior temporal\ the pattern of group di}erences in rCBF change was EL × LL × NA[ In the left hemi! sphere\ we found a complementary e}ect of greater acti! vation in normal adults compared to the lesion groups[ This was observed in the orbito! and inferior frontal ROIs\ the supplementary motor\ premotor\ and cingulate regions\ as well as in all _ve temporal ROIs and in the lentiform nucleus[ Most of these left!hemisphere ROIs showed the expected pattern NA × LL × EL[ For sentence repetition\ reduced deactivation or enhanced activation in frontal and parietal ROIs was found in the EL group\ in comparison with the two other groups[ Greater mean activation in the normal adults than in the lesion groups was seen in the right middle temporal\ posterior cingulate\ and inferior parietal ROIs[ The right caudate nucleus and thalamus showed greater activation in the LL group than in both other groups[ 3[ Discussion In view of the evidence for pronounced postlesional brain plasticity in children\ we expected language acti! vations to shift more strongly towards the right hemi!

440

sphere in patients with early "as compared to late# left lesion[ This expectation was partly supported by our data[ Activations for language perception "listening to sentences minus rest# were left!dominant in normal adults\ bilateral in the late lesion patients\ and right! dominant in the early lesion group "Figs 0 and 1#[ The expected group di}erences for left!hemispheric activation and for asymmetry scores "NA × LL × EL# were highly signi_cant in a region including the inferior frontal and superior and middle temporal gyri[ On the other hand\ expected complementary group di}erences for the right frontotemporal ROI "EL × LL × NA# were less pro! nounced and not signi_cant[ This suggests that while damage involving the left perisylvian cortex can enhance the language participation of homotopic right!hemi! sphere regions\ additional regions outside the perisylvian cortex may assume language functions\ especially in case of early damage[ Qualitative inspection of the data showed such enhanced right!hemispheric activation "or reduced deactivation#\ especially in the EL group\ for the prefrontal\ inferior temporal\ cingulate\ and several parietal ROIs "Table 2#[ However\ the verbal listening condition applied in our study did not allow us to deter! mine precisely to what extent the group di}erences in asymmetry were related to verbal perception\ on the one hand\ and to semantic functions\ on the other[ Activations for sentence repetition\ when compared to passive listening to sentences\ showed little asymmetry in the normal adults for a cortical region consisting of the premotor\ rolandic\ and insular areas[ Even though the expected group di}erences for asymmetry scores "NA × LL × EL# were seen in this region\ they did not reach signi_cance[ The repetition task had been chosen for presurgical mapping of motor speech functions because it could be performed even by very young and low!functioning patients ð34Ł[ In previous imaging stud! ies\ perisylvian activations for verbal repetition tasks have been reported in part as bilateral ð62Ł and in part as left!dominant ð71Ł[ Two studies found inferior frontal activation for word repetition predominantly in the left hemisphere ð41\ 72Ł[ However\ all of these studies used single!word tasks and the control conditions in two stud! ies ð71\ 72Ł were di}erent from the one applied here[ In our normal subjects\ the right premotor region was deactivated for the subtracted control condition "listening to sentences# and relatively enhanced for repetition[ This may explain the lack of robust leftward asymmetry for repetition in our study[ As mentioned above\ PET data for healthy children and adolescents are not available for ethical reasons[ Studies on children with congenital or very early post! natal lesion reviewed by Bates and colleagues ð73\ 74Ł suggest that the brain organization for language during acquisition di}ers from the typical adult pattern\ both in terms of regional specializations and of functional asymmetries[ This could imply that our _ndings in part

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Table 2 Mean blood ~ow changes "in )# per task condition\ group\ and region Listening to sentences

Sentence repetition

Anatomical region

Brodmann areas

Hemisphere

EL

LL

NA

EL

LL

NA

Prefrontal

8Ð09\ 35

L R

¦0[1 ¦1[9

¦0[1 ¦9[3

¦9[4 −9[0

−0[0 −9[5

−9[6 ¦9[2

−1[7 9[9

Orbitofrontal

00\ 01

L R

−0[0 ¦9[1

¦9[3 −0[6

¦1[1 ¦1[7

−9[5 −0[9

−2[4 −0[5

−4[9 −1[2

Supplementary motor area

5 "superior:mesial#

L R

−1[9 ¦9[0

−9[5 ¦9[2

¦9[6 ¦9[6

¦9[7 ¦0[3

¦0[6 ¦0[9

−0[3 −9[0

Anterior cingulate

13\ 21

L R

−0[7 ¦9[9

−1[2 −0[2

¦9[8 −2[4

¦0[2 −9[3

¦9[3 −9[3

−1[1 ¦0[9

Inferior frontal

33Ð34\ 36 "posterior#

L R

¦0[1 ¦1[8

¦1[5 ¦1[5

¦2[4 ¦0[0

¦9[0 ¦0[8

−0[4 −0[5

−3[3 −0[5

Premotor

5 "middle:inferior#

L R

−9[8 −0[7

−0[0 −1[0

¦1[0 −2[9

¦0[7 ¦3[0

¦9[7 ¦2[0

¦1[7 ¦4[6

Rolandic

0Ð4\ 32

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Insula Superior temporal

11\ 30Ð31

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Middle temporal

10

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Anterior temporal

27

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Inferior temporal

19

L R

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Mesiotemporal

16Ð17\ 23Ð26 "medial portion# hippocampus\ amygdala

L R

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Posterior:retro!splenial cingulate

12\ 15\ 18Ð20

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39

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28

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6 "anterior#

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Precuneus

6 "posterior#

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L R

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L R

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Midbrain

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Pons Vermis Cerebellar hemispheres

L R

R[!A[ Muller et al[ : Neuropsycholo`ia 26 "0888# 434Ð446

re~ect normal developmental schedules[ However\ the data reported by Bates and colleagues apply to infants and toddlers up to 33 months of age\ whereas our early lesion patients were six years and older[ There have been only very few functional mapping studies of language in children using functional MRI ð46Ł "for review\ see Ref[ ð59Ł#[ The studies by Casey and colleagues ð75\ 76Ł apply! ing letter stimuli in working memory tasks are not directly relevant to the functional asymmetry of language[ To our knowledge\ only one preliminary study with healthy children ð77Ł has reported _ndings for age groups and language tasks related to those used in our study[ In this study\ consistent left dominance was found in right! handed children from age seven years onwards\ even though this asymmetry was more pronounced in ado! lescents and in adults[ Since many of our early lesion subjects were children\ developmental factors of increas! ing hemispheric specialization could have contributed to the _ndings[ On the other hand\ rCBF was not sig! ni_cantly correlated with age on most of our compari! sons\ and our major _nding for the frontotemporal region was signi_cant even after covarying for chronological age[ We also examined e}ects of left!hemisphere damage on subcortical language activations for sentence repetition[ Since thalamic activations did not lateralize in our normal adult group\ we focussed on the basal ganglia\ expecting possibly enhanced speech participation in the contra! lesional hemisphere[ Leftward asymmetry of activations found in the normal adults was indeed signi_cantly reduced or reversed in both lesion groups[ In a recent review\ Nadeau and Crosson ð35Ł conclude that sub! cortical aphasia is typically related to involvement of the left thalamus\ whereas {{the basal ganglia have very little to do with language function|| "ibid[]276#[ This conclusion appears too strong in view of clinical studies reporting linguistic\ especially semantic\ involvement of the basal ganglia ð36\ 38\ 78\ 89Ł[ Left!dominant activation in the basal ganglia for sentence repetition in normal adults is probably due to motor speech components "rather than lexicosemantic processing\ which appears to involve the left thalamus ð43\ 80Ł#[ The role of the basal ganglia in movement has been described as relating to preparation\ monitoring\ and optimization ð81Ł and analogous involve! ment in speech is likely ð49\ 82Ł[ The leftward asymmetry of activations in the basal ganglia observed in our normal adults is consistent with previous imaging studies ð41\ 83Ł[ It suggests that subcortical motor activations\ when linked to language processing\ tend to lateralize to the side of cortical language dominance[ This corresponds to reports of language de_cits following damage to the basal ganglia of the language!dominant hemisphere ð40\ 84Ł[ Our _ndings further suggest that postlesional reorganiza! tion of language is not restricted to the neocortex\ but also a}ects the subcortex[ However similar to our obser! vations for cortical ROIs\ our _nding for the basal ganglia

442

predominantly re~ected reduced activations in the left hemisphere in the patients "especially those with early lesion#[ Greater than normal activation in the right basal ganglia was seen only in the late lesion patients and this di}erence did not reach signi_cance[ Both the _ndings in the frontotemporal ROI for lan! guage perception and in the basal ganglia for sentence repetition suggest that reorganizational events after left perisylvian lesion cannot be captured exclusively in terms of compensatory plasticity and functional reallocation[ While we did _nd greater than normal activations in many frontal\ temporal\ and parietal ROIs of the right hemisphere\ especially in the early lesion group\ these enhanced homotopic activations in the contralesional hemisphere did generally not outweigh the reduced lan! guage participation of the lesional left perisylvian cortex[ As discussed in a recent study comparing the e}ects of early left versus right!hemisphere lesion on language acti! vations ð33Ł\ postlesional events appear to involve a com! bination of additive and subtractive e}ects[ This implies that some regions that are not normally involved in a given function will become involved\ while other regions that are normally involved will show reduced partici! pation\ even though they are not directly a}ected by structural damage[ The notion of {subtractive| post! lesional e}ects is akin to the concept of diaschisis ð85\86Ł\ which can be de_ned as a "usually reversible# {{functional {shock| or deactivation of intact brain regions remote from but connected to the area of primary injury|| "Ref[ ð86Ł] p[ 706f#[ FDG PET studies have demonstrated glu! cose hypometabolism in regions far removed from struc! tural lesions ð87Ł\ a typical example being crossed cerebellar diaschisis following cerebral cortical injury ð88Ð091Ł[ Our _ndings suggest that in some instances structural damage may a}ect distal regions\ not only in terms of resting metabolism\ but also in terms of func! tional activation "rCBF increase# during cognitive and sensorimotor challenge[ This implies that enhanced plas! ticity during brain maturation may involve both an increased potential for "presumably compensatory# re! organization and increased vulnerability[ Our _ndings could be related to neuropsychological data suggesting greater long!term de_cits in patients with congenital and early postnatal unilateral lesion as com! pared to those with lesion occurring later in childhood ð05\ 092Ð094Ł[ However\ these latter _ndings are not uncontentious[ The studies by Bates and colleagues ð73Ł on children with unilateral lesion occurring before age six months do not suggest any dramatic long!term language de_cits after damage to either hemisphere[ Data from F[ Vargha!Khadem and coworkers "pers[ comm[^ data presented in Ref[ ð74Ł# from a sample of 050 patients with lesion onset in the _rst decade of life seem to indicate a period of reduced compensatory plasticity for lesions occurring between six months and four years of age\ with better average outcome for congenital lesions and for

443

R[!A[ Muller et al[ : Neuropsycholo`ia 26 "0888# 434Ð446

those occurring between four and ten years of age[ About half of the patients in our early lesion group had a _rst risk between six months and four years of age[ Therefore\ it remains possible that the {subtractive| e}ects identi_ed in our activation studies are related to a period of vul! nerability suggested by neuropsychological studies[ How! ever\ since our study did not incorporate data on language and neuropsychological outcome\ no de_nitive link can be established[ Our _nding of rather limited enhancement of right perisylvian activations in left!lesion patients may be additionally related to sample heterogeneity[ For ethical reasons\ patients could not be actively recruited for opti! mal matching on clinical\ neuropsychological\ and demo! graphic variables\ but were studied for clinical purposes in the context of presurgical planning[ Thus we could only approximately match groups for handedness ratios by including one left!handed normal adult[ Occurrence of left handedness in the EL patients was probably mostly lesion!induced[ However\ when left!hemisphere injury occurs before establishment of consistent hand preference "typically around age three years#\ it is hardly possible to determine whether or not sinistrality is a consequence of brain damage[ Patient groups were also not precisely gender!matched\ and the male:female ratio was higher in the late lesion group as compared to the early lesion and normal adult groups[ It is an unsettled question whether language is ð095Ł or is not ð096Ð098Ł more strongly left! dominant in men than in women[ Assuming greater left dominance in male subjects\ it cannot be completely ruled out that gender di}erences between groups may have contributed to our _ndings[ However\ this does not seem likely\ since all signi_cant group di}erences showed a pattern of NA × LL × EL[ Thus\ of the two groups with slightly higher percentage of female subjects\ one "the normal adults# showed strongest left dominance while the other "the early lesion group# showed the strongest reduction or reversal of left dominance on regional com! parisons[ Additional cautions concern possible clinical confounds[ While all patients had functional impairment "as seen on glucose PET#\ not all had massive structural lesions in the left perisylvian cortex[ Theoretically\ the observed group di}erences could be due to more exten! sive damage in the early lesion patients "resulting in more severe {subtractive| e}ects in the lesional hemisphere#[ Quantitative volumetric data on lesion size were not available in the present study[ However\ when lesion size was grossly estimated in terms of the number of forebrain lobes with _ndings on MRI and FDG PET\ there were no signi_cant di}erences between patient groups[ On the other hand\ it cannot be ruled out that group di}erences in lesion site may have contributed to the _ndings\ since temporal involvement occurred more often in the early lesion group\ whereas frontal involvement was found more often in the late lesion group[ The patient groups

also di}ered signi_cantly in terms of time since lesion onset "_rst risk^ see Table 0#[ However\ at the time of study at least one year had elapsed since lesion onset in every patient[ In addition\ there were no signi_cant correlations between rCBF measures and time since lesion onset in any of the ROIs analyzed in our study[ Seizure disorder in all but three\ and the use of anti! epileptic medication in all but one of our patients may have had e}ects on brain regions away from the under! lying lesion ð009Ł and possibly in the contralesional right hemisphere\ reducing the potential for interhemispheric reorganization as compared to stroke patients examined in previous studies with adults ð31\ 32Ł[ E}ects of anti! epileptic medication\ however\ are mostly global ð000\ 001Ł and it is unlikely that they apply to activation studies comparing normalized "i[e[\ not absolute# values of regional blood ~ow for di}erent experimental conditions[ The caveats listed above re~ect the exploratory nature of our study and the clinical "rather than experimental# setting of data acquisition[ Further studies using func! tional MRI in more extensive and more tightly controlled patient samples and in age!matched healthy children will be necessary before any de_nitive conclusions can be drawn[ The preliminary conclusions from our present study are\ nonetheless\ well compatible with previous neuropsychological lesion studies and overall suggest more pronounced interhemispheric reorganization for language following early left lesion when compared to lesion acquired in adulthood[ Acknowledgements This research was in part supported by grants from the Deutsche Forschungsgemeinschaft to the _rst author and from the Children|s Hospital of Michigan Research Endowment Fund to authors RAM and RDR[ Special thanks to Satoshi Minoshima for support with regard to statistical image analysis[

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