Reorganized cerebral metabolic interactions in temporal lobe epilepsy

\ PERGAMON

Neuropsychologia 26 "0888# 514Ð525

Reorganized cerebral metabolic interactions in temporal lobe epilepsy N[P[ Azaria\ U[ Knorrb\ S[ Arnolda\c\ C[ Antkea\ A[ Ebnerc\ H[ Niemannc\ K[D[ Pettigrewd\ O[W[ Wittea\ R[J[ Seitza\ a

Department of Neurolo`y\ Heinrich!Heine!University\ Duesseldorf\ Germany b Department of Neurolo`y\ University of Frankfurt\ Frankfurt\ Germany c Bethel Epilepsy Center\ Bielefeld\ Germany d NIMH:NIH\ Bethesda\ MD\ U[S[A[ Received 0 April 0887^ accepted 7 October 0887

Abstract Patients with left temporal lobe epilepsy demonstrate language impairments that are not well understood[ To explore abnormal patterns of brain functional connections with respect to language processing\ we applied a principal component analysis to resting regional cerebral metabolic data obtained with positron emission tomography in patients with right! and left!sided temporal lobe epilepsy and controls[ Two principal components were expressed di}erentially among the groups[ One principal component comprised a pattern of metabolic interactions involving left inferior frontal and left superior temporal regions*corresponding to Broca|s and Wernicke|s areas\ respectively*and right mesial temporal cortex and right thalamus[ Functional couplings between these brain regions were abnormally enhanced in the left!sided epilepsy patients[ The right thalamicÐleft superior temporal coupling was also abnormally enhanced in the right!sided epilepsy patients\ but di}erentially from that in the left!sided patients[ The other principal component was characterized by a pattern of metabolic interactions involving right and left mid prefrontal and right superior temporal cortex[ Although both the right! and left!sided epilepsy patients showed decreased functional couplings between left mid prefrontal and the other brain regions\ a weaker rightÐleft mid prefrontal coupling in the left!sided epilepsy patients best distinguished them from the right!sided patients[ The two mutually independent\ abnormal metabolic patterns each predicted verbal intelligence de_cits in the patients[ The _ndings suggest a site!dependent reorganization of two independent\ language!subserving pathways in temporal lobe epilepsy[ Þ 0888 Elsevier Science Ltd[ All rights reserved[ Keywords] Brain^ Functional imaging\ Glucose metabolism^ Language^ Principal component analysis^ Epilepsy

0[ Introduction Functional imaging studies indicate that brain areas beyond two left!hemisphere language regions*left inferior frontal "Broca|s# and left superior temporal "Wer! nicke|s#*participate in language function ð00\ 05\ 12\ 29\ 25\ 30\ 34\ 37\ 38\ 61\ 62Ł[ However\ there is substantial individual variability regarding the localization and num! ber of normal language!subserving regions ð31\ 32Ł[ In contrast\ patient groups may demonstrate abnormal\ yet homogeneous cerebral metabolic patterns ð5\ 7Ł\ which can provide insight into normal brain functional organ! ization[ Imaging data from brain!injured patients provide useful information regarding relations between cognitive processes and brain function ð05\ 10Ł[  Corresponding author[ Tel[] 38!100!700!6778^ fax] 38!100!700! 7374^ e!mail] seitzÝneurologie[uni!duesseldorf[de

Patients with temporal lobe epilepsy "TLE# show lan! guage!related di.culties that are greater in left than in right TLE patients ð03\ 15\ 23\ 39\ 41Ł[ Although there is some evidence for hemispheric brain functional correlates of TLE cognitive impairments ð41\ 42\ 55Ł\ it is yet unclear which speci_c brain regions are most involved[ Studies using positron emission tomography "PET# and ð07FŁ!~uoro!1!deoxy!D!glucose "FDG# to measure regional cerebral metabolic rates "rCMRglc# in epilepsy patients demonstrate interictal hypometabolism at the site of the epileptic focus ð0\ 07\ 08\ 22\ 53\ 54Ł[ However\ TLE patients also show disturbances in areas remote from the medial temporal lobe*the site of the epileptic focus ð4\ 07\ 08\ 14\ 41Ł\ suggesting a disruption in func! tional pathways which mediate normal cognitive func! tions[ In a previous PET!rCMRglc study of TLE patients ð4Ł\ we reported that the greatest metabolic depressions in

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left TLE patients were in left!hemisphere inferior frontal and superior temporal regions "corresponding to left Bro! ca|s and Wernicke|s areas\ respectively#[ Further\ lan! guage impairments in the left TLE patients correlated with the metabolic de_cits in these two regions[ Recently\ we showed that a prefrontal metabolic asymmetry was also more frequently observed in left as compared to right TLE patients\ and this asymmetry correlated with TLE language performance ð21Ł[ We thus suggest that dis! turbances in two\ independent language!subserving net! works may underlie the di}erential language abilities in right and left TLE] one involving left!hemisphere inferior frontal and superior temporal cortex\ and a second involving prefrontal cortex[ To test this hypothesis\ we applied a multivariate stat! istical analysis to PET!rCMRglc data in controls\ right TLE\ and left TLE patients[ This analytic technique uses principal component analysis\ and can identify group! di}erentiating\ independent patterns of brain metabolic interactions ð44Ł[ The aim of the present study was to see if there are TLE!di}erentiating patterns of brain functional interactions re~ecting a disruption and:or reorganization of language!subserving pathways[ 1[ Methods 1[0[ Subjects 1[0[0[ Temporal lobe epilepsy patients Subjects were 19 adults "mean2SD  20202 years\ range  04Ð48 years# who had seizures of either right! hemisphere "5 women\ 3 men# or left!hemisphere "3 women\ 5 men# mesiotemporal origin[ Exclusion criteria for the study were] history of cerebral trauma or other cerebral systemic disease\ prior neurosurgical procedures\ and evidence of brain tumors\ hamartomas\ cortical dys! plasias\ or vascular malformations "as detected by mag! netic resonance imagesÐMRI#[ All subjects were right! handed[ Eighteen of the patients underwent intracarotid amytal testing ð46Ł\ which con_rmed left!hemisphere dominance for language processing[ Except for hip! pocampal sclerosis in 06 of the patients\ MRI scans were considered normal[ Further details on these subjects have been published previously ð4Ł[ 1[0[1[ Controls Subjects were 09 healthy adults who were age! and sex! matched to the epilepsy patients "mean2SD age  27201[6 years\ range  14Ð48 years#[ All were right!handed[ Further details on these subjects have been published ð69Ł[ In brief\ control subjects were free of neurological\ psychiatric\ or medical disorders[ All were informed of the purpose of the study[ Written informed consent was obtained in accordance with guidelines of the Declaration of Human Rights\ Helsinki\ 0864\ and

was approved by the Ethics Committee of the Heinrich! Heine!University of Duesseldorf[

1[0[2[ Positron emission tomography "PET# PET scanning was performed with the Scanditronix PC3985:6WB PET camera\ as described in detail pre! viously ð48Ł[ In short\ image reconstruction was per! formed with a Hanning 4 mm _lter leading to an e}ective image resolution ðfull!width at half!maximum "FWHM#Ł of 6[0 mm and axial resolution "FWHM# of 5[4 mm ð45Ł[ Subjects were placed comfortably on a padded table\ and the PET camera gantry was aligned with the orbital! meatal line[ There was no noise in the scanner room\ speech was prohibited\ and the lights were dimmed[ Sub! jects were asked not to move or speak\ but to keep their eyes open[ Before PET scanning\ the subjects| left hands were warmed up to 39>C for 34 min to ensure arterial! ization of venous blood samples with an oxygen satu! ration of ×89)[ Through a small canula in the right brachial vein\ a bolus of 199 mBq 1!ð07FŁ!~uoro!1!deoxy! D!glucose "FDG# was injected ðFDGŁ[ Calculating rCMRglc was performed according to Phelps et al[ ð35Ł[ The kinetic constants and lumped constant of 9[41 were taken from Reivich et al[ ð43Ł[ PET image evaluation was performed on a SPARC 19 SUN workstation[ For anatomical evaluation of the rCMRglc images\ the computerized brain atlas "CBA# program of Bohm and Greitz ð13Ł was used[ The atlas brain was _tted inter! actively by translations\ angulations\ and elastic linear and non!linear scaling to the individual brain of each subject\ as described in detail earlier ð13Ł[ In no case was distortion of brain anatomy from the lesion or secondary atrophy such that the ~exibility of the non!linear scaling parameters did not allow an accurate _t[ The anatomical database of the CBA allowed for drawing regions of interest "ROIs# on the rCMRglc images that followed anatomical borders[ A total of 15 ROIs were drawn in both cerebral and cerebellar hemispheres "Table 0#[ Data used for the principal component analysis "see below# were mean!corrected mean rCMRglc "mmol:099 g:min# values in the 15 identi_ed ROIs for each epilepsy patient and each control subject[ Mean!correction consisted of a double!normalization of the rCMRglca data ð3Ł] "a# the global mean across all ROIs for each subject was sub! tracted from each rCMRglc value for each subject\ and then "b# the mean rCMRglc value for each ROI computed across all subjects was subtracted from each rCMRglc value[ As shown in Table 0\ the 15 ROIs considered for this study included two language areas ð11\ 31Ł\ left inferior frontal cortex "tentatively identi_ed as Broca|s area\ and left superior temporal cortex "tentatively ident! i_ed as Wernicke|s area#[ For categorical comparisons\ the mean rCMRglc "mmol:099 g:min# values of each ROIs were also normalized in relation to the non!a}ected calcarine cortex in each patient[

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Table 0 Mean "SD# metabolic values "rCMRglc in mmol:099:min# in the 15 regions of interest "ROIs# for the right!sided "RIGHT# and left!sided "LEFT# temporal lobe epilepsy "TLE# patients and controls "NORMAL#[ TLE!data are given raw as well as corrected "LEFT and RIGHT scaled to match the mean metabolic values in right and left calcarine of NORMAL# ROI

NORMAL mean "SD#

RIGHT mean "SD#

RIGHT corr mean "SD#

LEFT mean "SD#

LEFT corr mean "SD#

R CEREB L CEREB R THAL L THAL R PUT L PUT

21[12 "4[69# 21[31 "5[39# 27[38 "4[62# 27[17 "5[13# 39[14 "4[23# 39[04 "4[16#

29[44 "7[06# 29[90 "6[76# 20[27 "6[69# 22[34 "6[92# 25[71 "7[99# 26[07 "8[83#

21[38 "7[58# 20[81 "7[26# 22[69 "7[08# 24[46 "6[37# 28[05 "7[40# 28[44 "8[40#

16[11 "3[97# 16[41 "3[48# 23[27 "4[93# 21[85 "4[77# 25[55 "5[73# 24[45 "5[13#

"18[51 "3[43# 18[83 "4[99# 26[30 "4[37# 24[76 "5[39# 28[78 "6[34# 27[58 "5[68#

R CING L CING R ORB FRON L ORB FRON

26[89 "6[08# 27[97 "6[43# 28[03 "5[11# 27[75 "5[32#

22[18 "8[26# 23[47 "8[18# 22[21 "8[27# 22[73 "8[02#

24[39 "7[80# 25[67 "8[78# 24[33 "8[87# 24[88 "8[60#

23[91 "5[39# 21[28 "5[76# 22[49 "6[58# 21[08 "6[75#

26[91 "5[85# 24[14 "6[36# 25[34 "7[26# 24[91 "7[45#

R INF FRON L INF FRON R MID PRE FRON L MID PRE FRON

39[28 "5[19# 28[43 "5[62# 27[63 "5[46# 28[10 "6[95#

23[65 "7[82# 25[16 "7[47# 21[17 "7[76# 24[56 "6[89#

25[86 "8[49# 27[46 "8[01# 26[41 "8[32# 26[83 "8[36#

24[07 "5[88# 20[87 "7[17# 24[25 "5[45# 23[56 "5[84#

27[17 "6[50# 23[68 "8[91# 27[37 "6[03# 26[62 "6[46#

R CENT L CENT R PAR L PAR

24[72 "5[63# 24[78 "6[09# 26[50 "5[07# 26[49 "5[16#

20[10 "6[58# 21[13 "6[35# 22[71 "6[84# 23[30 "7[35#

22[08 "7[07# 23[18 "6[82# 24[86 "7[35# 25[48 "8[99#

20[66 "4[33# 20[95 "4[76# 22[39 "4[83# 21[31 "5[14#

23[46 "4[80# 22[68 "5[28# 25[24 "5[36# 24[16 "5[70#

R INF TEMP L INF TEMP R MES TEMP L MES TEMP R SUP TEMP L SUP TEMP

23[24 "4[15# 23[04 "4[52# 15[79 "4[04# 15[83 "4[39# 28[12 "5[52# 28[77 "5[37#

15[09 "7[60# 18[92 "7[12# 07[53 "4[52# 12[90 "5[61# 21[22 "7[72# 25[91 "8[00#

16[65 "8[15# 29[77 "7[65# 08[72 "4[88# 13[36 "6[04# 23[28 "8[28# 27[20 "8[58#

29[99 "4[63# 13[46 "3[25# 10[64 "3[91# 07[10 "2[25# 22[95 "4[81# 20[40 "5[67#

21[53 "5[14# 15[62 "3[63# 12[56 "3[26# 08[71 "2[55# 24[86 "5[34# 23[18 "6[27#

R CALC L CALC

39[51 "6[04# 39[34 "5[88#

26[84 "8[39# 27[16 "7[83#

39[25 "09[99# 39[60 "09[46#

26[39 "5[19# 26[00 "4[35#

39[58 "5[64# 39[27 "4[83#

Mean:mean "SD# SEM:SD

26[93 "5[18# 9[64 "2[72#

21[45 "7[25# 9[77 "3[49#

23[65 "7[78# 9[84 "3[71#

20[65 "4[88# 9[89 "3[50#

23[45 "5[41# 9[87 "4[91#

 P ³ 9[94\ di}erent from NORMAL\ rCMRglc data "t!tests\ uncorrected#^ CEREB\ cerebellum^ THAL\ thalamus^ PUT\ putamen^ CING\ cingulate^ ORB FRON\ orbital frontal^ INF FRON\ inferior frontal^ MID PRE FRON\ mid prefrontal^ CENT\ central^ PAR\ parietal^ INF TEMP\ inferior temporal^ MES TEMP\ mesial temporal^ SUP TEMP\ superior temporal^ CAL\ calcarine[ R denotes right\ L denotes left[

1[0[3[ Statistical analysis A principal component analysis "PCA^ ð44Ł# was applied to the mean!corrected metabolic data of the TLE patients and controls to see if there was su.cient variability pre! sent in the combined metabolic data "across groups# such that independent patterns of rCMRglc interactions* principal components "PCs#*could be identi_ed[ The three groups were then compared on the resultant com! bined!data metabolic patterns "PCs# to determine which patterns were di}erentially expressed between groups[ To further examine the nature of the group!di}erentiating metabolic patterns\ functional couplings between pairs of mean!corrected metabolic values in ROIs charac! terizing the group!distinguishing PCs were explored[ Finally\ to see if the metabolic patterns were related to

language performance\ the relationships between indi! vidual subject PC!values and verbal:language per! formance measures in the right and left TLE patients were examined[ More speci_cally\ the analysis consisted of two parts[ First\ a PCA was applied to the combined mean!corrected rCMRglc data of controls\ right TLE and left TLE sub! jects "total N  29#[ Mean!corrected rCMRglc data were used for this analysis because intra!individual di}erences in rCMRglc are much smaller than inter!individual di}erences ð16\ 17Ł[ Only those PCs with a load of absol! ute value greater than 9[4 were considered reliable and considered for further analysis[ Between!group com! parisons on reliable PCs were conducted using inde! pendent t!tests "signi_cance taken as P ³ 9[94\

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uncorrected for multiple comparisons#[ Second\ to fur! ther explore the group!di}erentiating PC patterns\ regression lines were computed for pairs of metabolic values in important constituent ROIs for each group! di}erentiating PC\ and groups were compared on the slopes[ To examine predictive relations between the meta! bolic patterns and behavioral measures\ regression lines were computed between individual PC!values and ver! bal:language measures in the right and left TLE patients ð4Ł[ 2[ Results 2[0[ Group mean comparisons on metabolic values Consistent with our earlier report ð4Ł\ the left TLE patients showed more severe and widespread rCMRglc de_cits than did right TLE patients "Table 0#[ As shown in Table 0\ the greatest metabolic de_cit for each respective patient group was in the mesial temporal lobe area\ and each patient group demonstrated lower values relative to the other patient group in ROIs within the respective epileptic!site hemisphere[ Thus\ the right TLE patients showed greater de_cits in right!hemisphere regions\ and the left TLE patients had greater metabolic loss in left! hemisphere regions[ 2[1[ Principal component analysis "PCA#:between!group comparisons on PCs Seven principal components were identi_ed which accounted for 79) of the variability in the data[ Of these\ signi_cant group mean di}erences "P ³ 9[94\ t!tests\ uncorrected# were revealed in the second "PC1\ account! ing for 05) of the variability# and third "PC2\ accounting for 02) of the variability#[ As shown in Fig[ 0\ PC1 was expressed di}erentially among all three groups "mean¦SD] controls  −0[9721[31^ right TLE  4[6124[92^ left TLE  −3[53¦2[08\ P ³ 9[94\ right TLE and left TLE vs controls^ P ³ 9[94\ right TLE vs left TLE^ t!tests\ uncorrected#[ The right TLE patients di}ered from both the controls and the left TLE patients on PC2 "mean2SD] controls  −1[2825[31^ right TLE  1[4121[68^ left TLE  −9[0223[10^ P ³ 9[94\ right TLE vs controls and left TLE#[ In contrast\ no signi_cant di}erence on PC2 was revealed between the left TLE and control groups[ Thus\ the PC1 pattern di}erentiated all three groups\ and PC2 selectively dis! tinguished the right TLE patients from both the left TLE patients and the controls[ Note that\ because principal components are orthogonal "i[e[\ mutually independent^ ð02Ł#\ the metabolic patterns represented by PC1 and PC2 are likewise independent of one another[ Figure 0 high! lights the greater heterogeneity of PC1 for the control subjects as compared to either the right TLE or left TLE

groups\ and the relatively smaller individual variability on PC2 for the right TLE patients as compared to con! trols or the left TLE patients[ These observations are consistent with studies showing that patient groups may demonstrate greater homogeneity on patterns of brain functional interactions than do control groups\ even though the patterns are abnormal ð5\ 7Ł[ 2[2[ Important constituent ROIs The most important constituent brain regions "PC! load of absolute value ×9[4*at a rate of ×89)# in the PC1 pattern were the left inferior frontal\ left superior temporal\ and right mesial temporal cortical areas\ as well as the right thalamus "Table 1#[ The constituent PC2 regions were the left mid prefrontal\ right superior temporal\ and left central areas[ Because we reported recently that an asymmetry between right! and left!hemi! sphere prefrontal areas di}erentiated our right TLE and left TLE patients ð21Ł\ and because the right mid pre! frontal region in the present study approached the criteria of being an {important| constituent brain region for PC2\ we also included right mid prefrontal cortex as an impor! tant constituent region of PC2[ However\ in keeping within the limits of our hypothesis\ we considered the right mid prefrontal region only with respect to its func! tional coupling with the left mid prefrontal region[ Table 1 shows also the weights associated with the important constituent regions of PC1 and PC2[ Thus\ for PC1 the weights for left inferior frontal and left superior temporal regions were positive\ and those for right mesial temporal cortex and the right thalamus negative[ Note that the weights for the PC2 important constituent regions were positive with the exception of the right superior temporal cortex[ 2[3[ Metabolic coupling patterns Exploration of metabolic coupling patterns between pairs of metabolic values associated with the constituent regions of PC1 revealed that the left TLE patients had abnormally enhanced functional couplings between PC1 ROIs[ That is\ whereas control subjects demonstrated no signi_cant metabolic dependencies\ the left TLE patients showed enhanced negative left inferior frontalÐright thalamus "R1  9[29\ P ³ 9[94\ slope di}erent from zero# and left superior temporalÐright mesial temporal coup! lings "R1  9[27\ P ³ 9[94\ slope di}erent from zero#\ and an enhanced positive right mesial temporalÐright thalamus coupling "R1  9[32\ P ³ 9[94\ slope di}erent from zero#[ The right TLE and left TLE groups were best distinguished by an abnormal and di}erentially enhanced functional relationship between the right thalamus and left superior temporal cortex\ which was positive for the right TLE patients "R1  9[13\ P ³ 9[97# and negative for the left TLE patients "R1  9[18\ P ³ 9[95# "P ³ 9[94\

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Fig[ 0[ Individual and group mean principal component "PC# values on the second and third principal components "PC1 and PC2\ respectively# for NORMAL subjects\ RIGHT\ and LEFT TLE patients[ Note the relative greater individual variability on PC1 for the controls subjects as compared to RIGHT and LEFT TLE patients[ Note also the relatively small individual variability on PC2 for the RIGHT TLE patients as compared to either the LEFT TLE patients or the NORMAL subjects[ P ³ 9[94\ di}erent from NORMAL "t!tests\ uncorrected#^ ¦P ³ 9[94\ LEFT TLE vs RIGHT TLE "t!tests\ uncorrected#[ Other abbreviations the same as for Table 0[

Table 1 Principal component analysis "PCA# results for the most reliable\ and group!di}erentiating principal components "PCs# PC

VALUE

PERCENT

CONSTITUENT ROIs

PC1

20[80

05[97

¦"9[26# L INF FRON ¦"9[23#  L SUP TEMP −"9[49#  R MES TEMP −"9[29#  R THAL

PC2

13[74

01[41

−"9[29#  R SUP TEMP ¦"9[30#  L CENT ¦"9[21#  L MID PRE FRON ¦"9[29#  R MID PRE FRON

The PCs are listed left!most in the table\ and the respective most impor! tant constituent regions of interest "CONSTITUENT ROIs# are listed to the right of each PC "e[g[ the most important constituent ROIs for PC1 are L INF FRON\ L SUP TEMP\ R MES TEMP\ and R THAL#[ VALUE is the PC!value obtained from the combined data set "i[e[\ N  29#[ PERCENT denotes the amount of variance accounted for by the given PC[ Other abbreviations the same as for Table 0[

di}erent slopes for right TLE vs left TLE#[ Fig[ 1 illus! trates the abnormal coupling patterns in the TLE pati! ents\ and highlights the group!di}erentiating functional dependency involving the right thalamus and two lan! guage areas[ The metabolic coupling patterns observed for PC2 revealed that both the right TLE and left TLE patients showed abnormally decreased functional dependencies between the left mid prefrontal cortical area and other PC2 constituent regions[ That is\ the TLE patient groups showed a loss of couplings between the left mid prefrontal region and the right superior temporal region "control] R1  9[22\ P ³ 9[94\ slope di}erent from zero^ right TLE] R1  9[90^ left TLE] R1  9[90^ P ³ 9[90 di}erent from slope for controls#\ and between the left mid prefrontal region and the left central region "control] R1  9[63\ P ³ 9[990\ slope di}erent from zero^ right TLE] R1  9[96^ left TLE] R1  9[92^ P ³ 9[90\ slope di}erent from slope for controls#[ The coupling pattern that dis!

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Fig[ 1[ Group!di}erentiating coupling patterns between important constituent brain regions characterizing the second principal component "PC1#[ Plotted are mean!corrected metabolic values for right thalamus "R THAL# vs two language areas*left inferior frontal and left superior temporal cortex[ Note that the NORMAL subjects show no signi_cant coupling between R THAL and the language areas "i[e[\ the slopes of the regression lines are not di}erent from zero\ P × 9[94#[ Thus\ the enhanced negative functional dependency for the LEFT TLE patients between R THAL and L INF FRON is abnormal " P ³ 9[94\ slope di}erent from zero#\ as is the di}erentially enhanced coupling between R THAL and L SUP TEMP for the RIGHT and LEFT TLE patients "P ³ 9[94\ LEFT TLE vs RIGHT TLE\ di}erent slopes#[ Other abbreviations the same as for Table 0[

tinguished the right! from the left!TLE patients\ however\ was the right!left mid prefrontal interaction[ Thus\ although both the TLE patients and controls dem! onstrated a signi_cant right!left mid prefrontal depen! dency\ the left TLE patients showed a weaker right!left mid prefrontal relationship than did either the right TLE patients or the controls "control] R1  9[89\ P ³ 9[990^ right TLE] R1  9[67^ left TLE] R1  9[42^ P ³ 9[94\ slopes di}erent from zero^ P ³ 9[90\ left TLE vs controls^ P ³ 9[94 left TLE vs right TLE#[ Fig[ 2 illustrates the weaker coupling pattern between the right and left mid prefrontal areas for the left TLE patients[ The strong relationship between the right and left mid prefrontal mean!corrected metabolic values in the control group was not unexpected\ given the high degree of inter!regional interdependencies in PET metabolic normal control data ð16\ 17Ł\ especially between homologous right!left ROI pairs ð16Ł[

2[4[ Relation between individual PC!values and TLE lan! guage performance Table 2 summarizes the lower verbal:language per! formance for the TLE patients[ On all three measures the left TLE patients were signi_cantly impaired "P ³ 9[94# compared to control data and the right TLE patients[ The right TLE patients showed a clear impairment in verbal ~uency "VFL# and verbal recall "VREC# which was\ however\ not signi_cant due to the large individual variability[ The verbal intelligence "VIQ# was in the nor! mal range in the right TLE patients[ A predictive relation! ship was revealed between individual PC!values and verbal intelligence measures for the TLE patients[ Fig[ 3 shows that greater expression of the abnormal PC1 metabolic pattern in the right TLE patients predicted poorer verbal intelligence scores "R1  9[20\ P ³ 9[94\ slope di}erent from zero#\ and that a similar predictive

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520

Fig[ 2[ Group!di}erentiating coupling patterns between important constituent brain regions characterizing the third principal component "PC2#[ Plotted are mean!corrected metabolic values for the right vs left mid prefrontal cortical area "R MID PRE FRON and L MID PRE FRON\ respectively#[ Note that all three groups demonstrate a signi_cant coupling between R and L MID PRE FRON regions " P ³ 9[94\ slope di}erent from zero#[ However\ the dependency for the LEFT TLE patients was weaker than that for either the RIGHT TLE patients or the NORMAL subjects[ "P ³ 9[90\ LEFT TLE vs NORMAL\ di}erent slopes^ P ³ 9[94\ LEFT TLE vs RIGHT TLE\ di}erent slopes#[ Other abbreviations the same as for Table 0[

Table 2 Summary of verbal:language!related neuropsychological performance in LEFT and RIGHT TLE patients

VIQ VFL VREC

LEFT

RIGHT

78[9928[49 10[0925[39 62[19213[39

092[69207[87 18[4925[69 68[99229[89

Signi_cant "P ³ 9[94# impairments were observed for the LEFT as compared to RIGHT TLE patients on all measures shown in the table[ Depicted are Mean2SD for] VIQ  verbal intelligence ð51Ł\ VFL  verbal ~uency ð7Ł\ VREC  verbal recall ð04Ł[ Other abbrevi! ations the same as for Table 0[

relationship was suggested in the left TLE data "R1  9[05\ P ³ 9[01# "Fig[ 3#[ Note that because the mean PC1!value for the right TLE group was greater than zero\ and the mean PC1!value for the left TLE

group was less than zero "see also Fig[ 0#\ the predictive relationships between PC1!values and verbal intelligence "although similar for the two TLE patients groups# are expressed as slopes in opposite directions[ That is\ a PC1! value which approaches zero in a right TLE patient re~ects weaker expression of the PC1 metabolic pattern\ but greater expression thereof in a left TLE patient[ Thus\ greater expression of an abnormal PC1 pattern in the TLE patients was related to poorer language perform! ance[ Also illustrated in Fig[ 3 is the predictive relation! ship between the PC2 metabolic pattern and verbal intelligence scores[ However\ a statistically signi_cant relationship was revealed only in the left TLE patients "R1  9[27\ P ³ 9[94\ slope di}erent from zero^ R1  9[90\ right TLE patients#[ Note that the direction of the predictive relationship in the left TLE patients suggested that the more negative a PC2!value for a left TLE patient "i[e[\ in the same direction as that of the mean PC2!value in the controls#\ the better the verbal

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Fig[ 3[ Relationship between individual principal component "PC#!values and verbal intelligence scores "VIQ# for the RIGHT and LEFT TLE patients[ Note that because the mean PC1!value for the RIGHT TLE group was greater than zero\ and that for the LEFT TLE group less than zero "Fig[ 0#\ the predictive relationships involving PC1\ although similar\ are expressed as slopes in opposite directions for the two TLE patient groups[ Thus\ a PC1!value which approaches zero re~ects weaker expression of the PC1 metabolic pattern in a RIGHT TLE patient\ but greater expression thereof in a LEFT TLE patient[ Thus\ greater expression of PC1 was related to poorer VIQ performance in both TLE patient groups[ Note also that the direction of the relationship between PC2 and VIQ in the left!hemisphere TLE patients suggests that the more negative an individual LEFT TLE PC2!value ði[e[\ the more the PC2!value is in the same direction as that of the control PC2 mean value "Fig[ 0#Ł\ the better the VIQ performance[  P! values refer to testing if the slope is di}erent from zero[ Other abbreviations the same as for Table 0[

intelligence performance in that left TLE patient[ In sum\ the abnormal metabolic patterns re~ected by both PC1 and PC2 were related to verbal intelligence performance in the TLE patients[ None of the other TLE language measures were signi_cantly related to the PC!values[

3[ Discussion In the present study we report evidence for a site! dependent reorganization of two independent\ language! subserving pathways in temporal lobe epilepsy "TLE#[ The _ndings\ which are summarized in Fig[ 4\ are con! sistent with multi!level disturbances in language pro! cessing networks ð24\ 26Ł\ and may provide further insight into the di}erential language impairments observed

between right and left TLE patients ð03\ 15\ 21\ 23\ 39\ 41Ł[ The brain functional pattern best able to distinguish the left TLE patients from both the right TLE patients and controls "i[e[\ PC1# was characterized by brain regional functional dependencies involving two language areasÐleft inferior frontal "tentatively identi_ed as Bro! ca|s area# and left superior temporal "tentatively ident! i_ed as Wernicke|s area# cortex\ as well as the right! hemisphere thalamus and mesial temporal cortex "Fig[ 4#[ Both Wernicke|s and Broca|s areas\ as well as the left thalamus participate in language functions\ as evident from intrasurgical mapping and functional activation studies in normals ð31\ 32Ł\ and there is evidence for anatomical projections from both Broca|s area and the mesial temporal lobe to the left thalamus ð2\ 27\ 53\ 57Ł[

N[P[ Azari et al[ : Neuropsycholo`ia 26 "0888# 514Ð525

Fig[ 4[ Summary illustration of two independent language!subserving networks\ which are disrupted and reorganized in RIGHT and LEFT TLE[ Shown is an axial slice of the brain on which is depicted the group! discriminating functional metabolic coupling patterns in NORMAL subjects\ RIGHT\ and LEFT TLE patients[ The right hemisphere is shown on the left side of the _gure\ and the left hemisphere is shown on the right[ The dashed line separates the coupling patterns expressed by the two independent metabolic patterns "i[e[\ the second and third principal components*PC1 and PC2\ respectively#[ Coupling patterns below the dashed line correspond to those expressed in PC1[ Note that only the TLE patients show any functional interactions involving the right thalamus and the left inferior frontal and left superior temporal cortical areas[ The stipple!_lled arrow denotes a strong positive coup! ling\ and the un_lled arrow denotes a strong negative coupling between pairs of brain regions[ Coupling patterns above the dashed line cor! respond to those expressed in PC2[ The solid black arrows denote a signi_cant "P ³ 9[94# right!left mid prefrontal functional dependency for all three groups[ However\ the thickness of the arrow re~ects the relative strength of the coupling\ which was di}erent between groups[ Thus\ the signi_cantly weaker right!left mid prefrontal coupling in the LEFT TLE patients as compared to both the RIGHT TLE patients and the NORMAL subjects is indicated by the thinnest arrow[ Other abbreviations the same as for Table 0[

Interestingly\ our _ndings suggest that functional inter! actions involving the right thalamus and cortical lan! guage areas participate in reorganized language functions[ Animal studies provide evidence for inter!thal! amic ð49Ł as well as crossed thalamo!cortical projections ð09\ 36Ł[ Although cortical regions corresponding to Bro! ca|s and Wernicke|s areas are unique to humans\ the present results may be re~ective of crossed thalamo!cort! ical as well as inter!hemispheric thalamic functional con! nections in humans which was recently demonstrated anatomically ð06Ł[ It is of interest to note that the left mesial temporal cortex "site of the epileptic focus in the left TLE patients# was not among the most important constituent regions characterizing PC1\ despite the fact that this area is clearly associated with left TLE both pathophysiologically ð4\ 08\ 41Ł and pathoanatomically ð1\ 01\ 14\ 47\ 59\ 52Ł[ Therefore\ the PC1 pattern re~ected

522

more than the most severe regional metabolic de_cits in the left TLE patients[ Rather\ given the di}erential language abilities between the right and left TLE patients\ the PC1 pattern as evident in the left TLE patients may re~ect a TLE site!dependent disruption in a language! subserving pathway[ The fact that the right TLE patients also could be distinguished from controls on the PC1 pattern\ despite their relative preservation of language! related abilities\ may indicate that the PC1 pattern as expressed in the right TLE patients re~ected an abnormal compensatory reorganization of functional interactions involving language!related regions[ The individual PC1!values for both TLE patient groups were related to the TLE verbal intelligence scores\ which further suggests that the PC1 metabolic pattern was related to language processes[ The relatively weaker predictive relationship between PC!values and verbal intelligence scores in the left TLE group may be due to the smaller variability for these patients "as compared to the right TLE patients# in both their metabolic measures and PC1!values\ as well as on their verbal intelligence scores[ The fact that individual PC1!values in the right TLE patients were related to their verbal intelligence scores supports the suggestion that abnormal PC1 pat! tern in the right TLE patients may serve as a com! pensatory mechanism resulting in relative preservation of language abilities ð03\ 15\ 23\ 39\ 41\ 42\ 55Ł[ It is not immediately clear\ however\ why greater expression of the PC1 pattern in the right TLE patients predicted poorer verbal intelligence[ Rausch et al[ ð41Ł reported that in their sample of both right TLE and left TLE patients\ relatively reduced metabolism in the left thalamus cor! related with poorer recall of logical prose\ a measure of verbal memory[ The right thalamus\ which may have connections to the left thalamus ð49Ł\ was one of the important PC1 constituent regions[ Although specu! lative\ a right TLE compensatory reorganization may be operative only within a limited range\ such that an excess plasticity involving the thalamus and other language! subserving cortical areas may lead to subtle language de_cits in right TLE patients[ It is also curious that\ of the three language!related measures\ only verbal intelligence was predicted by the PC1 pattern in the TLE patients[ It may be that the PC1 pattern of functional interactions was able to identify a relatively speci_c TLE!related lan! guage de_cit[ Clearly\ further imaging studies in TLE with special attention to external cognitive measures are needed to more carefully examine these issues[ The coupling patterns between pairs of metabolic values corresponding to constituent PC1 regions pro! vided additional insight into the speci_c site!dependent TLE abnormalities\ suggesting that both TLE patient groups showed functional reorganization[ That is\ both of the TLE patient groups demonstrated abnormally enhanced functional couplings between PC1 constituent regions[ These abnormal enhancements were most evi!

523

N[P[ Azari et al[ : Neuropsycholo`ia 26 "0888# 514Ð525

dent in the left TLE patients\ who demonstrated increased negative functional couplings between the right thalamus and two language areasÐleft inferior frontal and left superior temporal cortex "tentatively identi_ed as Broca|s and Wernicke|s areas\ respectively#[ However\ most revealing with respect to TLE group!distinguishing patterns was a di}erentially enhanced functional inter! action for the right and left TLE patients between the right thalamus and the left superior temporal cortex[ Whereas this coupling was abnormally positive in the right TLE patients\ it was abnormally negative in the left TLE patients[ Furthermore\ the left TLE patients also showed an increased negative coupling between the right thalamus and the left inferior frontal cortex[ Given the di}erential language abilities between the right and left TLE patients\ the abnormal PC1 coupling patterns in the TLE patients may re~ect a di}erential cortical*sub! cortical reorganization of a language!subserving func! tional network\ which for the right TLE patients was compensatory and for the left TLE patients disruptive[ It is of interest to note the control subjects showed no signi_cant functional couplings between pairs of PC1 constituent regional metabolic values[ This observation is consistent with other PET!rCMRglc resting studies\ wherein normal controls demonstrated few signi_cant functional interactions between normalized metabolic values in subcortical regions and frontal or temporal regions ð6\ 17Ł[ Also\ the controls demonstrated more heterogenous PC1!values "Fig[ 0# as compared to either of TLE patient groups[ In this regard\ our data may re~ect the large degree of individual variability\ both structurally and functionally\ observed in language! related areas in normals ð28\ 31\ 32Ł[ Despite the fact that group mean values on PC2 did not di}er signi_cantly between the left TLE patients and controls\ the PC2 functional coupling patterns suggested meaningful ð58Ł brain functional abnormalities in the left TLE patients[ A weaker right!left mid prefrontal PC2 coupling pattern in the left TLE patients di}erentiated them from the right TLE patients and from the controls "Fig[ 4#[ Furthermore\ lesser expression of the PC2 pat! tern in our left TLE patients predicted poorer verbal intelligence "Fig[ 3#\ suggesting that the PC2 pattern was part of a second di}erentiating\ independent language subserving pathway\ which was most sensitive to changes in the metabolic dependency between homologous mid prefrontal areas[ These results provide additional support for our hypothesis that the language de_cits in left TLE may also be related to disruptions in a second language! subserving brain functional network involving the pre! frontal cortex ð21Ł[ The fact that the right TLE patients who fared better on language scores showed an abnormal greater expression of the PC2 pattern may be re~ective of explicit memory or learning de_cits observed in right TLE ð03\ 15\ 23\ 39\ 41\ 55Ł[ Because the left prefrontal cortex has been shown by imaging studies to mediate

verbal!related memory functions ð19\ 56\ 60Ł\ the di}er! ential expression of the PC2 pattern in the right TLE patients may have highlighted changes corresponding to a memory!related component of the PC2 pattern\ and the subtle PC2 coupling abnormalities observed in the left TLE patients\ a verbal component[ Site!dependent\ yet subtle\ functional changes in such a hypothesized multi!component pathway may provide insight as to why non!verbal cognitive de_cits in right as compared to left TLE are not as robust as are the verbal:language de_cits in left as compared to right TLE ð41\ 42\ 55Ł[ Given the exploratory nature of covariance analyses as applied to PET data ð17\ 18Ł\ our conclusions as regards a speci_city for language are necessarily guarded[ Thus\ the signi_cant regressions observed here between lan! guage scores and PC!values admittedly may be mediated by some non!speci_c variable\ such as severity of the seizure disorder[ Although a retrospective history revealed comparable type and mean frequency of the seizures\ as well as mean onset and duration of the seizure disorder\ it cannot be ruled out that the severity of the disorder was identical for the right and left TLE patients[ Clearly the present _ndings will be strengthened by additional anatomical and physiological data ð40Ł[ In sum\ our data show functional dependencies among sites known to be involved in language processing as evident from activation studies in normals ð05\ 10Ł[ The results encourage our inference that the pathophysiology of epilepsy may be distributed over many brain regions\ and that this distribution may be mediated by group: behavior!speci_c patterns of connectivity[ These _ndings provide evidence for a di}erentially a}ection of two inde! pendent\ language!subserving pathways in right and left TLE[ Acknowledgements We would like to thank Dr Barry Horwitz for o}ering helpful comments and suggestions[ This work was sup! ported in part by an Alexander von Humboldt Research Fellowship awarded to N[ P[ Azari and by a grant from the Deutsche Forschungsgemeinschaft Wi 729:6!0[

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