Superior temporal gyrus and the course of early schizophrenia: Progressive, static, or reversible?

\ PERGAMON

Journal of Psychiatric Research 21 "0887# 050Ð056

Superior temporal gyrus and the course of early schizophrenia] progressive\ static\ or reversible< Matcheri S[ Keshavan\ Gretchen L[ Haas\ Charles E[ Kahn\ Eduardo Aguilar\ Elizabeth L[ Dick\ Nina R[ Schooler\ John A[ Sweeney\ Jay W[ Pettegrew Western Psychiatric Institute and Clinic\ 2700 O|Hara Street\ Pittsbur`h\ PA 04102!1482\ U[S[A[ Received 5 May 0886^ received in revised form 00 July 0886^ accepted 11 July 0886

Abstract Accumulating evidence suggests alterations in brain structure\ especially in the prefrontal and temporal cortex\ in schizophrenia[ Previous studies examining the progression of brain structural alterations in schizophrenia have led to con~icting results[ Mor! phometric studies of the superior temporal gyrus "STG# volumes were conducted in a series of neuroleptic!naive _rst!episode schizophrenic patients\ non!schizophrenic _rst!episode psychotic patients\ and matched healthy controls[ Three!dimensional MRI scans were carried out in these subjects before and after one year of treatment[ Volume reductions were seen at baseline in the left superior temporal gyrus "adjusted for intracranial volume# in both of the patient groups[ Pretreatment illness duration was inversely related to the volume of the left superior temporal gyrus^ this relation was con_ned to males[ One!year follow!up MRI investigations in a smaller subset of patients suggested that the STG volume reductions may be reversible[ No signi_cant changes were noted in the STG volumes in matched healthy controls who were also scanned at baseline as well as at one!year follow!up[ These _ndings have implications for understanding the nature of the neuropathological processes in early schizophrenia\ as well as the potential impact of early treatment[ Þ 0887 Elsevier Science Ltd[ All rights reserved[

0[ Introduction Compelling evidence for brain structural abnormalities in schizophrenia has accumulated over the last decade[ Among the brain structures\ the temporal cortex has attracted considerable attention\ especially in view of the prominent involvement of the language functions in this disorder[ The temporal lobe contains limbic and par! alimbic "hippocampus\ entorhinal cortex# as well as neo! cortical "i[e[ superior temporal cortex# regions[ Schizo! phrenia has been reported to be associated with volume reductions in the medial temporal lobe in the hippo! campus and amygdala "Bogerts et al[\ 0889\ 0882^ Suddath et al[\ 0889^ Shenton et al[\ 0881# as well as reductions in the superior temporal gyrus "STG# "Barta et al[\ 0889^ Shenton et al[\ 0881#[ STG is a critically important brain region with important connections to other heteromodal association cortex regions as well as to temporal limbic brain regions^ it plays a major role in the production\ interpretation and self!monitoring of language "Ross and Pearlson\ 0885#[ It has been hypo! thesized that pathology of this structure\ by disrupting

Corresponding author[ Tel] 301 513!9703^ fax] 301 513!0348[ 9911Ð2845:87:,08[99 Þ 0887 Elsevier Science Ltd[ All rights reserved[ PII] S 9 9 1 1 Ð 2 8 4 5 " 8 6 # 9 9 9 2 7 Ð 0

key cortical networks\ leads to the cardinal positive symp! toms of schizophrenia[ Indeed\ reductions in STG volume have been observed to correlate with hallucinations "Barta et al[\ 0889#\ thought disorder "Shenton et al[\ 0881#\ delusions "O|Donnell et al[\ 0882#\ and reduction in amplitude of the P299 Evoked Response Potentials "ERP# "McCarley et al[\ 0882#[ Impairments in verbal memory\ abstraction\ and categorization have also been correlated with reduced STG volume "Nestor et al[\ 0882#[ The questions of whether STG abnormalities are present at illness onset\ and the impact of illness course and:or treatment on these alterations\ remain unclear[ Since the evolution of the concept of schizophrenic illness\ it has been argued that for at least some patients with this illness\ a progressive disease process may under! lie the functional decline over the course of illness[ This view dates back to Kraepelin who suggested that a full recovery might bring the original diagnosis into question[ Bleuler\ who acknowledged that some patients recover\ noted that the patient may never achieve a full restitutio ad inte`rum[ On the contrary\ the current neu! rodevelopmental model"s# of schizophrenia "reviewed by Weinberger\ 0884# predict that cerebral structural alter! ations may occur at "or before# illness onset\ and may not progress over time[ Cross!sectional comparison of

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M[S[ Keshavan et al[ : Journal of Psychiatric Research 21 "0887# 050Ð056

chronic and _rst!episode patients reveals more prominent abnormalities in smooth pursuit eye movements and neu! ropsychological test performance as compared to _rst! episode patients "Haas et al[\ 0880^ Bilder et al[\ 0881^ Sweeney et al[\ 0881#[ Ventricular enlargement and tem! poral lobe volume reductions have been observed cross! sectionally to be more prominent in chronic schizo! phrenic patients than in _rst!episode cases "Bogerts et al[\ 0889\ 0882^ DeLisi et al[\ 0880^ Lieberman et al[\ 0881#[ It is\ therefore\ possible that temporal lobe structures show progressive abnormalities during the early active phase of the schizophrenic illness[ Only a few studies have examined these brain structures in a prospective longitudinal design[ Con~icting reports have appeared in the literature pertaining to the course of brain structural alterations in schizophrenia\ with reports of both pro! gressive atrophy "DeLisi et al[\ 0884# and no change "Jaskiw et al[\ 0883#[ This paper presents preliminary data on the following questions from our ongoing investigations of neuroleptic naive psychotic patients[ First\ are there alterations in the volume of the superior temporal gyrus in previously untreated schizophrenic patients< Second\ do these alter! ations progress during the untreated\ early phase of the schizophrenic illness< This question is best addressed by examining the relation between untreated illness duration and the observed structural changes prior to treatment initiation[ Finally\ do the morphological abnormalities change during the early phase of the illness after treat! ment is begun< Data from our preliminary prospective follow!up studies of schizophrenic patients from early in treatment are provided to examine questions relating to the impact of illness course and:or treatment on the neu! robiological and clinical characteristics of this disorder[

1[ Methods 1[0[ Subjects A series of seventeen _rst!episode\ treatment!naive pat! ients with schizophrenia and related psychotic disorders ðschizophrenia "n02#\ schizoa}ective "n1#\ and schizophreniform "n1#Ł\ eight patients with non!schizo! phrenic psychotic disorders ðbipolar disorder with psy! chotic features "n2#\ major depression with psychotic features "n1# psychosis\ not otherwise speci_ed "n2#Ł\ and seventeen normal controls were studied[ All subjects provided informed\ written consent after complete description of the study[ Approximately one month after entry into the study\ a consensus conference was held by the senior diagnostician:clinical researchers "MSK\ GLH\ NRS#[ During this meeting\ patients were given a DSM!III!R "American Psychiatric Association\ 0876# diagnosis based upon available clinical information and data gathered using the Structured Clinical Interview for

DSM!III!R diagnosis "SCID# "Spitzer et al[\ 0889#[ Exclusion criteria included age greater than 49 or less than 03\ medical illness a}ecting the central nervous sys! tem function\ prior neuroleptic treatment\ and IQ lower than 69[ None of the patients had a current or lifetime history of substance dependence and one had a history of alcohol abuse[ These patients continue to participate in a longitudinal\ prospective study which includes a careful diagnostic re!review to evaluate diagnostic stability "Keshavan and Schooler\ 0881#[ Illness durations were computed from the date of onset of prodromal symptoms to the date of entry into the study[ Clinical ratings were carried out using the Brief Psychiatric Rating Scale "BPRS# "Overall and Gorham\ 0851#[ Handedness was determined by the 01 items of the Annett Handedness Scale "Annett and Manning\ 0889#\ and right!handedness was de_ned using a criterion of eight or more items des! ignated as right!handed[ Determination of date of onset of the schizophrenic illness is often frought with problems of reliability "Beiser et al[\ 0882#[ In order to obtain the onset dating as accurately as possible\ we timed the dates of onset of the _rst identi_able psychotic and prodromal symptoms on the basis of a best!estimate approach using data gathered from multiple sources\ including the medi! cal record\ direct patient interview\ and when possible\ family interview[ Dating of the onset of the _rst prod! romal or psychotic symptom was estimated to the closest month "estimated range of error 20 month#\ when poss! ible[ Two patients\ in whom it was not possible to estab! lish the durations of the prodrome and psychosis\ were excluded from analysis[ Healthy\ non!psychiatric control subjects were recruited by advertisement in local neighborhoods and communities in which the patient subjects resided[ Exclusion criteria included any lifetime history of psy! chiatric disorder\ prior exposure to psychotropic drugs\ history of neurologic disorders or any other chronic medi! cal problems with potential to in~uence CNS function\ or IQ less than 69[ None had any lifetime history of substance abuse or dependence[ Healthy\ non!psychiatric controls were matched\ as a group\ with the schizophrenic patients for age\ gender\ race and parental socioeconomic status using the Hollingshead Four!Factor Index "Hol! lingshead\ 0864#[ After an initial telephone screening\ these subjects were interviewed by a senior clinician "MSK or GLH# using the SCID "NP version#[ 1[1[ MRI studies MRI scans were conducted using a 0[4 Tesla G[E[ Signa system "G[E[ Medical Systems\ Milwaukee# at the University of Pittsburgh Medical Center\ Pittsburgh\ PA[ A series of sagittal scout scans were _rst obtained "nine to eleven 4!mm!thick sagittal slices with a 0 mm interslice gap using a spin echo pulse sequence^ TR399 msec\ TE19 msec^ 145×145 acquisition matrix\ NEX0\

M[S[ Keshavan et al[ : Journal of Psychiatric Research 21 "0887# 050Ð056

FOV19 cm^ ~ip angle09>#[ Axial scans\ parallel to the Anterior!Commmissure!Posterior Commissure line as determined by the sagittal scans\ were obtained "MRI parameters] slice thickness1[5 mm^ no interslice gap^ 2! dimensional spoiled gradient recalled acquisition "SPGR# pulse sequence^ TR39 msec^ TE19 msec^ FOV19 cm#[ These axial scans were resliced to a coronal plane "perpendicular to axial scans# and the resultant 1[5 mm thick slices were used for measurement of regional cerebral volumes[ The image data were transferred onto optical disks from the Signa unit to a Macintosh 739 AV work station\ identi_ed by scan number alone to retain blindness\ and analyzed using NIH IMAGE software "Version 0[44# "Rasband\ 0882#[ Trained raters "ELD\ CK#\ blind to the study hypotheses\ subject identi_cation and clinical data\ measured all scans[ Regional cerebral volumes were measured using a semi!automated seg! mentation algorithm "Keshavan et al[\ 0883a\ b#[ Details of the image analysis methodology are described else! where "Rosenberg et al[\ 0886#[ The inter!rater reliabilities measured on a set of 09 scans "intraclass correlation\ ICC# were high for all of the measures "ICC9[86Ð9[88#[ TestÐretest reliability was also high "9[83Ð9[86#[ 1[1[0[ Neuroanatomical de_nitions 1[1[0[0[ Intracranial volume[ The intracranial volume was used as a covariate in the comparison of STG volumetric measures\ across diagnostic groups[ This was calculated by summing up areas of successive coronal slices includ! ing gray\ white and cerebrospinal ~uid "CSF# and mul! tiplying by slice thickness[ All of the frontal\ parietal\ temporal and occipital cortex\ cerebellum\ and the brain! stem were included[ 1[1[1[ Superior temporal `yrus The superior temporal gyrus was de_ned as the area between the sylvian _ssure and the superior temporal sulcus[ The anterior boundary of the STG was de_ned as the most anterior slice in which the temporal stem was visible[ The appearance of the superior colliculi served as the posterior boundary[ Every slice that included STG was manually traced along these boundaries by a rater blind to subject identity[ Grey matter was then selected and the area of each appropriate slice was calculated[ STG volume was computed by summing up successive areas and multiplying by slice thickness[ 1[1[2[ Cerebellar volume We chose to examine the cerebellar volume in order to examine the regional speci_city of any _ndings predicted for STG[ Cerebellar area was measured in axial SPGR slices\ summed\ and multiplied by slice thickness to com! pute volume[ The cerebellar vermes were included and the CSF in the fourth ventricle was excluded from the measurements[ In view of the possible impact of di}er!

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ences in fourth ventricle volume on cerebellar measure! ments\ we measured this structure as well[ 1[2[ Statistical analysis An analysis of covariance was performed for the patient and control groups on the MRI morphometric measures using intracranial volume as a covariate[ Criteria for analysis of covariance were met "i[e[ homogeneity of covariance\ and correlation between covariate and depen! dent variables#[ Partial correlations were computed to examine the relation between illness duration and STG volumetric measures partialling out the e}ect"s# of intra! cranial volume[ Two!tailed p values were computed in all analyses[

2[ Results 2[0[ Study 0] relation between pre!treatment illness dur! ation and STG volume in schizophrenia The clinical and demographic characteristics of our study sample are provided in Table 0[ Group com! parisons "ANOVA with intracranial volume as a covari! ate# revealed a signi_cant diagnosis e}ect\ with schizo! phrenia and other psychotic patients having lower volume of left STG compared to the non!schizophrenia psychotic and healthy control groups "F4[2^ p9[998#[ No signi_cant di}erences were seen in right STG or cer! ebellar volume not including CSF in the fourth ventricle "Table 1#[ A signi_cant group di}erence was seen with the fourth ventricle being larger in the schizophrenic "1[0829[72 cc# and the control subjects "0[7229[57 cc# compared to the non!schizophrenic psychotic subjects "0[5329[11 cc# "F3[08^ p9[91#[ The cerebellar volume\ de_ned by including the fourth ventricular CSF had a trend to be smaller in the schizophrenic patients\ but this was not signi_cant "F1[61^ p9[96#[ We next examined the relation between illness duration and the regional brain volume measures[ The volume of the left STG was signi_cantly inversely related to both duration of prodrome "partial r−9[45^ p9[916# and the duration of psychosis "partial r−9[41^ p9[935# after partialling out the e}ects of intracranial volume[ When analyzed separately\ this relation was seen stronger in the male patients for both the prodromal duration "partial r−9[62^ p9[998^ n01# and psychosis dur! ation "p−9[61^ p9[90^ n01#[ The correlations were non!signi_cant in the female schizophrenic patients for the prodromal duration "n4^ partial r−9[78^ p9[00#\ and for the psychosis duration "n4^ partial r9[76^ p9[01#[ Age of psychosis onset was unrelated to left STG volume "partial r9[03\ p9[51#[ The prod! rome duration was not signi_cantly related to right STG "partial r−9[26^ p9[20# or cerebellar volume "partial

053

M[S[ Keshavan et al[ : Journal of Psychiatric Research 21 "0887# 050Ð056 Table 0 Clinical and demographic characteristics

Age Sex "M:F# Parental socioeconomic status Education Handedness "R:L# Prodrome duration "weeks# Psychosis duration "weeks# Age of onset "years#

Schizophrenia "n06#

Non!schizophrenia psychoses "n7#

Controls "n06#

14[30 "7[14# 01:4 2[65 "0[24# 02[42 "2[19# 01:4 161[45 "154[13# 051[41 "190[8# 11[36 "6[72#

10[64 "4[25# 3:3 2[26 "0[49# 02[99 "1[28# 5:1 057[60 "053[29# 091[21 "007[23# 19[01 "5[18#

12[69 "4[33# 01:4 2[54 "0[95# 03[94 "1[25# 05:0 Ð Ð

Table 1 Superior temporal gyrus "STG# volume in _rst!episode schizophrenia Schizophrenia "n06# Volume "cc# Left STG Right STG Cerebellum Intracranial volumeb a b

Non!schizophrenia psychoses "n7#

Controls "n06#

Diagnosis F

5[54 "0[16# 6[72 "0[37# 045[02 "12[43#

7[49 "0[96# 8[35 "0[21# 043[99 "04[85#

6[17 "0[07# 7[54 "0[74# 056[17 "07[30#

4[2a 0[66 1[26

0369[91 "071[85#

0458[35 "044[12#

0467[74 "059[22#

0[88

p³9[90[ p³9[94[

r9[92^ p9[76#[ The psychosis duration was also unre! lated to right STG "partial r−9[21^ p9[14# and cer! ebellar volume "partial r9[992^ p9[88#[ 2[1[ Study 1] follow!up MRI studies of STG in _rst episode schizophrenia We conducted repeat MRI studies in a series of patients with schizophrenia "n00^ 5 males and 4 females^ age 13[9827[38#\ patients with non!schizophrenic psychotic disorders "n3^ 2 males and 0 female^ age 13[4924[58#\ and healthy controls "n01^ 6 males and 4 females^ age 13[924[48#[ All patients "with the exception of one pati! ent who refused medication# had been treated with neu! roleptics during this period of follow!up of about one year[ Diagnostic re!reviews in all of the patients indicated stability of their diagnoses[ Follow!up scans were con! ducted at about one year following the baseline assess! ment using the same protocol^ the same image analysis method was used in measuring both baseline and follow! up scans[ STG and intracranial volumes were measured\ blind to diagnosis and time "baseline vs year# of scan\ by trained raters "CK and ED#[ On longitudinal analyses\ care was taken to ensure that both baseline and follow! up scans were measured by the same rater for any given subject in order to minimize the e}ects of systematic inter!rater variation[

Table 2 summarizes the results[ Total as well as right and left STG volumes increased at the one!year follow! up in the schizophrenic patients[ No signi_cant change was seen in total intracranial volume[ We also repeated the analyses comparing the STG:intracranial volume ratios[ The STG volume increase continued to be sig! ni_cant on the right side "p³9[94#\ but was trend! worthy "p9[97# for the left STG[ No signi_cant di}er! ences were seen in STG volumes between baseline and one year scans in healthy control subjects "Table 2#[ The STG volumes did not di}er between baseline and one year scans in the four non!schizophrenia psychotic sub! jects "right STG] t0[5^ p9[08^ left STG] t−1[0^ p9[02#[

3[ Discussion Consistent with previous studies "Barta et al[\ 0889^ Shenton et al[\ 0881#\ we observed a signi_cant reduction in left STG volume at baseline[ An inverse relation was seen between illness duration "as determined from the time of onset of prodromal as well as psychotic symp! toms# and the volume of the left STG[ These correlations were con_ned to male schizophrenic patients[ Previous studies examining the relation between brain structure and illness duration have led to inconsistent results[ Tur!

054

M[S[ Keshavan et al[ : Journal of Psychiatric Research 21 "0887# 050Ð056 Table 2 Superior temporal gyrus "STG# volume at baseline and follow!up in _rst!episode schizophrenic patients and healthy controls "paired t!tests# Volume "CC#

Baseline

0 year

t

p

Schizophrenic patients "n00# Right STG Left STG Intracranial volume

7[56 "1[05# 6[11 "0[22# 0366[17 "064[26#

8[56 "0[75# 6[76 "0[13# 0335[51 "051[66#

−1[28 −1[06 0[70

9[93 9[94 9[09

Controls "n01# Right STG Left STG Intracranial volume

09[40 "0[84# 7[47 "0[79# 0371[15 "073[06#

09[88 "1[08# 8[06 "0[21# 0420[99 "197[92#

−9[83 −0[09 −0[52

9[26 9[18 9[02

etsky et al[ "0884# observed a similar inverse relation between frontal lobe volume and illness duration[ How! ever "Marsh et al[\ 0883# failed to observe a relation between illness duration and medial temporal lobe or ventricular volume[ These disparities in the literature may result from the variable regions of interest as well as varying de_nition in illness duration across studies[ Thus\ further studies are needed to clarify this issue[ Age of onset was unrelated to STG volume\ suggesting that the observed relation between illness duration with the latter is unlikely to have resulted from an early age of onset[ Recent studies have failed to observe a relation between age of onset and gray matter volume de_cits in schizo! phrenia "Lim et al[\ 0885#[ Our observation is consistent with evidence that delay from onset of illness to _rst treatment is associated with more severe psychotic symp! toms\ poorer functioning\ and less adequate therapeutic response to anti!psychotic treatment "Wyatt\ 0880^ Haas et al[\ 0883^ Szymanski et al[\ 0885a\ b#[ It is therefore possible that the untreated\ early course of schizophrenia may be associated with progressive neurobiological de_! cits "Knoll et al[\ in press#[ Only a few longitudinal studies have been conducted to examine the impact of illness course and treatment on neurobiological de_cits associated with schizophrenic illness[ A preliminary prospective investigation of neu! robehavioral function in schizophrenic patients ascer! tained during treatment showed no evidence for any pro! gressive deterioration during the early course of schizophrenia "Haas et al[\ 0886#[ Indeed\ evidence of recovery in some cognitive functions in some patients was found in this sample*a _nding consistent with two other longitudinal studies of _rst episode patients "Nopoulos et al[\ 0883^ Ho} et al[\ 0886#[ Further\ nega! tive symptoms\ considered to represent the relatively per! sistent {{trait|| aspects of the disease\ may also recover somewhat\ albeit\ slowly "Szymanski et al[\ 0885a\ b#[ In this context\ our observation of a modest\ but signi_cant\ bilateral increase in STG volume at follow!up is of inter! est[ This observation is unlikely to be due to scanner

related variations\ since no signi_cant change was seen in brain volume\ and the control scans did not change signi_cantly during follow!up[ One possibility is that this volume increase is caused by antipsychotic treatment[ There is evidence for increased volume of the basal gan! glia following antipsychotic treatment "Chakos et al[\ 0883^ Keshavan et al[\ 0883a\ b^ Meshul et al[\ 0885#^ such volume increases have been attributed to compensatory increases in corticostriatal glutamate release "Chakos et al[\ 0883^ Keshavan et al[\ 0883a\ b#[ Similar changes may occur in neocortical regions as well\ following anti! psychotic treatment[ There is recent evidence for increased glial density following chronic neuroleptic treatment in monkeys "Selemon et al[\ 0886#[ Alternatively\ it may be that the STG volume reduction seen at pre!treatment evaluation is at least\ in part\ state! related\ and improves with stabilization of the illness[ Several mechanisms could underlie structural alterations occurring during the early course of schizophrenia[ These structural alterations may re~ect neuronal injury rather than neuronal death\ and thus could be potentially revers! ible[ First\ it has been suggested that brain structural abnormalities\ with consequent cognitive impairment\ may result from prolonged activation of the hypo! thalamicÐpituitary adrenal "HPA# axis "O|Brien\ 0886^ McEwen\ 0886#[ Such HPA axis activation has been pro! posed to underlie cortical atrophy in depression and dementia "O|Brien\ 0886#\ and may occur in schizo! phrenia as well "Lammers et al[\ 0884#[ Antipsychotic drugs may reduce HPA activation "Wik\ 0884#[ Second\ dopaminergic agents induce neuronal apoptosis in ani! mals "Simantov et al[\ 0885# and may cause cortical atro! phy in humans "Langendorf et al[\ 0885#[ Thus\ dopa! minergic hyperfunction\ presumed to underlie schizophrenia could potentially lead to cortical volume reductions[ Finally\ the deteriorative process in schizo! phrenia may be related to oxidative injury caused by persistent catecholaminergic over!activity coupled with an impaired antioxidant defense system early in the illness "Mukherjee and Mahadik\ 0883#[ Conceivably\ anti!

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M[S[ Keshavan et al[ : Journal of Psychiatric Research 21 "0887# 050Ð056

psychotic drugs may reduce the catecholaminergic activity\ and thereby reduce oxidative injury[ To our knowledge\ the possibility of reversible struc! tural alterations has not been previously addressed in schizophrenia research[ We provide provocative but very preliminary data suggesting that cortical volume de_cits in schizophrenia may be progressive in the untreated illness^ on the contrary\ they may be non!progressive or static\ or even in part\ reversible\ following treatment[ The strengths of our study include the use of previously untreated psychotic patients\ and the longitudinal pro! spective design[ However\ because of the small sample size\ our _ndings must be considered with caution\ and type I errors cannot be excluded[ If these observations are con_rmed in larger studies\ they point to the import! ance of early institution of treatment in averting the poss! ible deleterious e}ect of prolonged\ untreated psychotic illness on brain structure and function in schizophrenia "McGlashan and Johannessen\ 0885#[

Acknowledgements This work was supported in part by NIMH grants MH34045!90A0 "JWP#\ MH90261 "DRR#\ MH35503!90 "JWP#\ MH31858 "JAS#\ MH34045 "NRS#\ MH37381 "GLH# and a Scottish Rite Schizophrenia Foundation Grant "MSK and the Center for Neurosciences in Mental Disorders#[ Werner W[ Bagwell provided valuable sup! port for the morphometric aspects of the study[

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