Cortical Abnormalities in Schizophrenia Identified by Structural Magnetic Resonance Imaging

ORIGINAL ARTICLE Cortical Abnormalities in Schizophrenia Identified by Structural Magnetic Resonance Imaging

Jill M. Goldstein, PhD; Julie M. Goodman, PhD; Larry J. Seidman, PhD; David N. Kennedy, PhD; Nikos Makris, MD, PhD; Hang Lee, PhD; Jason Tourville; Verne S. Caviness, Jr, MD, DPhil; Stephen V. Faraone, PhD; Ming T. Tsuang, MD, PhD

Background: Relatively few magnetic resonance imag- umes of brain regions, adjusted for age- and sex-corrected ing studies of schizophrenia have investigated the en- head size, were used to compare patients and controls. tire cerebral cortex. Most focus on only a few areas within a lobe or an entire lobe. To assess expected regional al- Results: The greatest volumetric reductions and largest terations in cortical volumes, we used a new method to effect sizes were in the middle frontal gyrus and paralim- segment the entire neocortex into 48 topographically de- bic brain regions, such as the frontomedial and fronto- fined brain regions. We hypothesized, based on previ- orbital cortices, anterior cingulate and paracingulate gyri, ous empirical and theoretical work, that dorsolateral pre- and the insula. In addition, the supramarginal gyrus, which frontal and paralimbic cortices would be significantly is densely connected to prefrontal and cingulate cortices, volumetrically reduced in patients with schizophrenia was also significantly reduced in patients. Patients also had compared with normal controls. subtle volumetric increases in other cortical areas with strong reciprocal connections to the paralimbic areas that Methods: Twenty-nine patients with DSM-III-R schizo- were volumetrically reduced. phrenia were systematically sampled from 3 public outpatient service networks in the Boston, Mass, area. Healthy Conclusion: Findings using our methods have impli- subjects, recruited from catchment areas from which the cations for understanding brain abnormalities in schizo- patients were drawn, were screened for psychopathologic phrenia and suggest the importance of the paralimbic ar- disorders and proportionately matched to patients by age, eas and their connections with prefrontal brain regions. sex, ethnicity, parental socioeconomic status, reading ability, and handedness. Analyses of covariance of the vol- Arch Gen Psychiatry. 1999;56:537-547

EVERAL MODELS havebeenpro- Despite the current emphasis on the posed to explain the wide- importance of cortical abnormalities in spread brain abnormalities in schizophrenia, structural imaging stud- patients with schizophrenia. ies of the entire cortex are relatively few. Early anatomical models were In fact, of 67 studies recently reviewed,8 based largely on hypothesized focal abnor- only 16 examined more than one cortical S 1 malities in particular brain regions, derived brain region in more than one lobe. Stud- mainly from adult lesion models of neuro- ies that have examined the entire cortex psychiatric disorders. Schizophrenia has have sampled primarily men and ac- more recently been understood as, in part, quired images with relatively large slices— a neurodevelopmental disorder2,3 in which 5-mm slices with 2.5-mm gaps.17,20,21 The altered connectivity or multifocal abnor- relatively small number of cortical struc- malities are more likely than focal dis- tural imaging studies may be due, in part, orders.4-6 The most frequently replicated to the difficult and time-consuming na- findings have been in subcortical structures, ture of segmenting these relatively small suchasthehippocampalregion7-10 andthala- areas of the brain. Furthermore, until re- mus.10,11 An increasing number of studies, cently, methods to assess in vivo the subtle however, have demonstrated abnormalities volumetric reductions in small cortical re- in cortical brain regions,12-21 indicative of gions, which require fine distinctions be- developmental origins.12,13,20,22-24 Neuro- tween brain regions, were not available for pathologicandneuralnetworkfindingshave the analysis of brain images. Thus far, most The affiliations of the authors suggested that schizophrenia may involve of the subtle abnormalities in the cortex appear in the acknowledgement a defect in neuronal migration,22-24 myelina- have been identified at the cellular level section at the end of the article. tion,5 and/or corticocortical pruning.25-27 using postmortem techniques.

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 METHODS The healthy controls were a proportionately matched comparison group. There were no significant differences in sex distribution, age, ethnicity, parental socioeconomic SAMPLE status, education, Wide Range Achievement Reading54 score, Wechsler Adult Intelligence Scale–Revised55,56 vocabulary Patients were systematically sampled from the universe of score, and handedness. There was a significant (P = .01) dif- outpatients at 3 public psychiatric hospitals in the Boston, ference in IQ, which is typical for schizophrenia. Mass, area that serve primarily patients with psychotic disorders.45-47 Inclusion criteria consisted of ages between 25 DIAGNOSTIC PROCEDURES and 66 years, at least an eighth-grade education, English as the first language, and an estimated IQ of at least 70. Exclu- Research DSM-III-R diagnoses were based on the Schedule sion criteria for subjects were substance abuse within the past for Affective Disorders and Schizophrenia57 and a system- 6 months, history of a head injury with documented cogni- atic review of the medical record. Patients primarily had un- tive sequelae or loss of consciousness longer than 5 min- differentiated or paranoid subtypes (Table 1). Interviews were utes, neurologic disease or damage, mental retardation, medi- obtained by master’s level interviewers with extensive diag- cal illnesses that substantially impair neurocognitive function, nostic interviewing experience. Senior investigators (Drs and a history of electroconvulsive treatment. Written in- Goldstein and Seidman) reviewed the transcripts from the formed consent was obtained after a complete description interview and the medical records to determine the consen- of the study was given to the subjects. sus, best-estimate, lifetime diagnosis. Blindness of assess- Healthy control subjects were recruited through ad- ments among psychiatric and MRI data was maintained. vertisements in the catchment areas and notices posted on bulletin boards at the hospitals from which the patients were IMAGING PROCEDURES recruited. They were proportionately matched to patients by age, sex, ethnicity, parental socioeconomic status,49 read- Image Acquisition ing ability, and handedness. Control subjects were screened for current psychopathological disorders using a short form Magnetic resonance imaging scans were acquired at the of the Minnesota Multiphasic Personality Inventory50 and Nuclear Magnetic Resonance Center of the Massachusetts a family history of psychoses or psychiatric hospital ad- General Hospital, Boston, with a 1.5-T MRI scanner (Gen- missions. We excluded potential controls if they had a cur- eral Electric Signa scanner; General Electric Corporation, rent psychopathological disorder; a lifetime history of any Waukesha, Wis). Contiguous 3.1-mm coronal spoiled- psychosis; a family history of psychosis or psychiatric hos- gradient echo images of the entire brain were obtained us- pitalization; or a score on any clinical or validity scale on ing the following parameters: repetition time, 40 millisec- the Minnesota Multiphasic Personality Inventory, except onds; echo time, 8 milliseconds; flip angle, 50°; field of view, the Masculinity-Femininity scale, above 70. 30 cm; matrix, 256ϫ256; and averages, 1. The MRI scans Patients were included if they had a DSM-III-R51 clini- were processed and analyzed at the Massachusetts Gen- cal diagnosis of schizophrenia. (Patients were rediag- eral Hospital Center for Morphometric Analysis for fur- nosed by research criteria, as described in the subsection ther processing and analysis. “Diagnostic Procedures.”) The sample consisted of 29 pa- Data were analyzed using image analysis workstations tients, 17 (59%) of them male. Table 1 presents a sum- (Sun Microsystems Inc, Mountain View, Calif). Images were mary of the sociodemographic and clinical characteristics positionally normalized by imposing a standard 3-dimen- of the patients and controls. sional coordinate system on each 3-dimensional MRI scan, The patients were a middle-aged sample, primarily non- using the midpoints of the decussations of the anterior and Hispanic white (25 [86%]), with an average education of posterior commissures and the midsagittal plane at the level partial college, who came from a middle to lower-middle of the posterior commissure as points of reference for rota- socioeconomic status. Measures of premorbid and cur- tion and (nondeformation) transformation.38,58 Scans were rent IQ were in the average range. They had a mean ± SD then resliced into normalized 3.1-mm coronal, 1.0-mm axial, age at illness onset of 23.6 ± 5.8 years (range, 16-45 years), and 1.0-mm sagittal scans and were analyzed. Positional nor- with 4.2 ± 3.1 hospital admissions, reflecting 22.0 ± 9.9 malization overcomes potential problems caused by varia- months of hospitalization and 20.9 ± 10.2 years of illness. tion in head position of subjects during scanning. The daily chlorpromazine-equivalent dose was 689.9 ± 591.6 mg of typical neuroleptic medications. In general, the pa- Gray Matter–White Matter Image Segmentation tients were clinically stable, being treated long term as outpatients, although they were rated as having mild to mod- Each slice of the T1-weighted, positionally normalized, 3-di- erate negative and positive symptoms.52,53 mensional coronal scans was segmented into gray and white

Neuropathologic studies of schizophrenia have iden- poral gyrus,7,18,29-31 planum temporale,19,32 and related tified abnormalities of cell size, orientation, and receptor sylvian fissure region33). A few studies—eg, Schlaepfer et density in the anterior cingulate gyrus22 and prefrontal ar- al29—have implicated the parietal cortex and occipital lobe eas.12,13,28 Structural magnetic resonance imaging (MRI) (reviewed in Shenton et al8), but findings in these areas studies have shown volumetric abnormalities in schizo- have been equivocal. Cortical volume reductions have been phrenia in the frontal lobe and prefrontal subregions (eg, estimated34,35 to range from only 4% to 6%. In general, pre- orbital14 and dorsolateral15,29); the prefrontal areas in gen- vious cortical studies suggested that prefrontal, paralim- eral21; and the temporal lobe, including the parahippo- bic, and left frontotemporal lobe areas are subtly but sig- campal gyrus7,16 and auditory cortex (eg, the superior tem- nificantly reduced in patients with schizophrenia.

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 matter and ventricular structures using a semiautomated in- Forty percent of the PUs had excellent reliabilities tensity contour–mapping algorithm38 and signal-intensity his- (ICCՆ0.80), and about 69% were very good (ICCՆ0.70). togram distributions. This technique, described in detail else- There were several PUs with ICCs of 0.55 or less. The brains where38,58,59 and illustrated in Figure 1, yields separate of 10 additional subjects were analyzed, after a discussion compartments of neocortex, subcortical gray nuclei, white of areas in which raters disagreed, and ICCs of these areas matter, and ventricular system subdivisions that generally were presented in the third column of Table 2. The ICCs correspond to the natural tissue boundaries distinguished remained low for only 3 areas: frontal operculum, basal fore- by signal intensities in the T1-weighted images. brain, and occipital pole. Finally, intrarater reliability was The focus of the present study was the subdivision of conducted using images from 6 subjects (Table 2, last col- the neocortex into parcellation units (PUs). umn) and was generally excellent. Only the fusiform gyrus, lingual gyrus, and superior parietal lobule had fair re- Parcellation of the Neocortex liabilities (ICC = 0.50, ICC = 0.57, and ICC = 0.62, respectively). The neocortex, defined by the gray-white matter segmentation procedure, was subdivided or “parcellated” into 48 DATA ANALYSES bilateral PUs based on the system originally described by Rademacher,36 modified in Caviness et al,37 and shown in Three approaches were used to test for volumetric Figure 1. This is a comprehensive system of neocortical sub- differences between patients and controls, given dis- division designed to approximate architectonic and func- agreement among the investigators in the field as to the tional subdivisions and based on specific anatomical land- ideal statistical model. Adjusted PU volumes were marks present in all brains.37 expressed as a percentage of the total cerebral Two types of landmarks specify the boundaries of the volume—PU volume divided by total cerebral PUs: major fissures of the hemisphere (Figure 1) and ana- volume—to control for individual variations in brain tomically specified single nodal points along the longitu- size. The total cerebral volume was also used as a covar- dinal axis of the brain. The fissures and nodal points are iate in an analysis of covariance (ANCOVA). Finally, the easily identifiable and normally present in all brains. Nodal z-score method60 was used to adjust for a normal varia- points are specified by diverse anatomical structures, most tion in age- and sex-corrected head size, as measured by of which lie in the cortex itself (eg, the intersection of 2 the total cerebral volume. Thus, z scores reflected volu- sulci or a sulcus within the hemispheric margin). Four nodal metric estimates for the patients relative to volumes points are specified by subcortical landmarks—the sple- expected from normal subjects of a particular head size, nium and genu of the corpus callosum, the decussation of age, and sex.17,21,34,60 the anterior commissure, and the lateral geniculate bod- Adjusted brain volumes and the z scores of the PUs ies. The PUs are mainly bounded by the major fissures of were analyzed using ANCOVA to assess the effect of the the brain (Figure 1). Where the anterior or posterior bor- group (ie, subjects with schizophrenia vs controls), con- der of a PU is not completely specified by major fissures, trolled for age, sex, and sex-by-group interaction. An this boundary is closed by a coronal plane through a nodal ANCOVA was appropriate because tests of normality point. Following parcellation, volumes were calculated for showed that the PU volumes were, in general, normally each PU by multiplying the area measurement of the PU distributed. A multivariate ANCOVA using all PUs on each slice by the slice thickness and then summing all would not be statistically powerful with our sample size slices on which the PU appeared. and, thus, would not provide accurate covariance structure estimates. However, we had some specific hypoth- RELIABILITY eses about certain PUs. Thus, as suggested by Roth- man,61 a multivariate ANCOVA was used that included Our collaborators at the Massachusetts General Hospital PUs hypothesized to be different between groups (the Center for Morphometric Analysis (Drs Kennedy, Makris, middle frontal gyrus, frontomedial cortex, fronto-orbital and Caviness), who developed these procedures, trained cortex, divisions of the cingulate and parahippocampal and maintained quality control of the segmentation of the gyri, and insula), to control for a type I error. We were data. In previous studies37 using these procedures, reliabil- also interested in whether other areas, which were ity was good. For our study, the brains of 10 subjects were reflected in exploratory analyses, distinguished patients completely parcellated into 48 PUs in the right and left hemi- from healthy controls. In addition, relative volume dif- spheres by 2 well-trained image analysts who had a back- ferences and effect sizes62 between patients and controls ground in neuroanatomy. Table 2 presents the intraclass were estimated (Table 3). Effect sizes are unaffected correlation coefficients (ICCs) for the 48 PUs, which were by the sample size and, thus, can be compared across generally good. studies.

We introduce the application of a new brain seg- ume in specific areas of the entire cortex between pa- mentation technique to study patients with schizophre- tients with schizophrenia and normal controls. nia, with the goal of the better identification of subtly al- Neuropsychological studies,40-44 including our own, tered cortical tissue. The method, based on conceptual some45-47 using the same patients as in this study, have models of the cortex, was developed to divide the entire demonstrated impairments in working memory and other neocortex into 48 topographically defined brain ar- executive functions, verbal and visual short-term memory, eas36,37 and has been applied successfully to healthy sub- attention, olfaction, and motivation. These functions rely jects.37-39 The unique advantage of this technique is that heavily on circuitry that primarily includes the frontal it allows an estimation of the relative differences in vol- lobes (ie, working memory, executive functions, and ol-

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 cm3). The total neocortex was 591.4 ± 60.2 cm3 for pa- Table 1. Demographic, Cognitive, and Clinical Measures tients and 575.2 ± 65.8 cm3 for controls. Adjusted for the in Patients With Schizophrenia Compared total cerebral volume, the cortex was 51.9% ± 2.3% for With Normal Controls* patients and 53.4% ± 2.7% for controls (t53 = −2.2; P = .03). Table 3 presents the unadjusted mean volumes in Controls Patients Variable (n = 26) (n = 29) cubic centimeters for the PUs and total volumes by lobe. Tests of differences between the groups were based on Male sex, No. (%) 12 (46) 17 (59) Ethnicity white, No. (%) 24 (92) 25 (86) the adjusted values and z scores, and these did not dif- Right-handed, No. (%) 22 (85) 23 (79) fer across statistical methods, with significant differ- Age, y 39.8 ± 11.5 44.8 ± 10.5 ences illustrated in Figure 2. First, the overall F test Parental SES 2.8 ± 1.0 2.7 ± 1.4 (Wilks ␭) from the multivariate ANCOVA for our hy- Education, y 14.4 ± 2.3 13.5 ± 2.5 pothesized regions was significant (F9,45 = 3.17; PՅ.005), WAIS-R Vocabulary score 11.3 ± 2.7 10.1 ± 2.6 suggesting that patients and controls significantly dif- WAIS-R Block Design score 10.7 ± 2.5 9.1 ± 3.2† IQ estimate 106.9 ± 12.2 97.8 ± 14.0† fered in volumes of these areas. Table 3 shows that, within WRAT-R reading score 104.5 ± 10.6 106.1 ± 12.1 the frontal lobe, the middle frontal gyrus (F1,52 = 4.87; DSM-III-R schizophrenia, No. (%) P = .03) and the frontomedial cortex (F1,52 = 8.41; P = .005) Undifferentiated . . . 12 (41) were significantly reduced in patients with schizophre- Paranoid . . . 11 (38) nia. The relative volumetric reductions for patients com- Disorganized . . . 5 (17) pared with controls were 8.80% and 14.89%, respec- Schizoaffective, depressed . . . 1 (3) tively. When we examined the right and left hemispheres Age at onset, y . . . 23.6 ± 5.8 Duration, y . . . 22.0 ± 9.9 separately for hypothesized prefrontal areas, only the right No. of hospitalizations . . . 4.24 ± 3.10 fronto-orbital cortex was significantly reduced in pa- Global negative and positive tients and not the left (F1,52 = 3.94; P = .05) (relative volu- symptom rating‡ metric reduction of the right fronto-orbital cortex among Affective flattening . . . 1.9 ± 1.2 the patients was 8.5% compared with controls; effect Alogia . . . 1.4 ± 1.3 size, 0.56). The middle frontal gyrus and frontomedial Avolition . . . 1.7 ± 1.3 Anhedonia . . . 2.4 ± 1.4 cortex were bilaterally reduced, although the middle Attention . . . 1.1 ± 1.2 frontal gyrus showed greater reduction on the left. Hallucinations . . . 2.1 ± 1.8 Patients also exhibited significant volumetric re- Delusions . . . 1.9 ± 2.0 ductions in PUs approximating the medial paralimbic cor- Bizarre behavior . . . 0.5 ± 0.7 tex, in particular, the anterior cingulate gyrus (F1,52 = 3.79; Formal thought disorder . . . 1.3 ± 1.3 P = .05) and paracingulate gyrus (F1,52 = 9.46; P = .003), with reductions of 11.14% and 7.99%, respectively, com- *Data are given as mean ± SD unless otherwise indicated. SES indicates socioeconomic status; WAIS-R, Wechsler Adult Intelligence Scale–Revised; pared with controls. In addition, there was a large and WRAT-R, Wide Range Achievement Test–Revised; and ellipses, not significant volumetric reduction of the insula in pa- applicable. IQ estimate was derived from Vocabulary and Block Design tients (F1,52 = 11.90; P = .001) by almost 1 SD below that age-scaled scores (from Brooker and Cyr56). †PϽ.05. of controls (effect size, 0.88). Exploratory analyses of other ‡Negative symptoms rated using Scale for the Assessment of Negative cortical temporal areas showed no significant volumet- Symptoms (from Andreasen52), and positive symptoms rated using Scale for ric reductions in patients. 53 the Assessment of Positive Symptoms (from Andreasen ). The parietal and occipital cortices also showed few significant differences in individual PUs. The posterior faction) and frontolimbic (verbal and visual short-term supramarginal gyrus, however, was significantly and bi- memory) or paralimbic (attention and motivation) re- laterally reduced in patients compared with controls gions. Based on previous reports, we hypothesize that the (F1,52 = 3.95; P = .05). When combined to encompass the primary cortical abnormalities in schizophrenia will be inferior parietal cortex as a whole—ie, anterior and pos- in the prefrontal, especially dorsolateral prefrontal cor- terior supramarginal gyri, angular gyrus, and parietal oper- tex, and paralimbic48 regions (eg, cingulate and parahip- culum—the volume was not significantly reduced among pocampal gyri and the frontal orbital cortex)—ie, areas the patients. All analyses were rerun after omitting 8 sub- involved in communication between the prefrontal and jects aged 60 years or older, equally distributed across limbic brain regions. Although these hypothesized ar- the groups, and results were unchanged. In addition, in eas are not unique, this study is the first to examine all patients, cortical volumes of the significant PUs were un- cortical areas in one study in a substantial number of sub- correlated with the neuroleptic medication dose. jects with schizophrenia. COMMENT RESULTS This study provides new evidence that there are cortical The unadjusted (mean ± SD) total cerebral volume was abnormalities in schizophrenia, detectable using struc- significantly different between groups (patients, tural MRI. The brain areas that showed a significant re- 1140.9 ± 116.9 cm3; and controls, 1077.3 ± 97.4 cm3) duction in patients with schizophrenia compared with (t53 = 2.2, unpaired, 2-tailed test of significance; P = .03) well-matched healthy controls were primarily in PUs that but was not significant when adjusted for the total brain approximated regions of the prefrontal and medial volume (patients, 87.1 ± 0.9 cm3; and controls, 88.7 ± 0.9 paralimbic cortices. Significant frontal lobe reductions

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C D

SMC E F1 F1 F2

PRG

CGa CO F3o PRG

F3o

CO PP INS INS

T1a BFsbmp T1a

T2a PHa T2a PHa

T3a TFa TFa T3a

Figure 1. Cortical parcellation method. A, Normalized midbrain coronal slice at the level of the anterior commissure. B, Gray and white matter segmented; subcortical areas are shown. C, Cortical parcellation begins with the identification of cortical sulci using axial, sagittal, and coronal views. Shown here are several sulci (multicolored) that indicate where the final sulcal lines (shown in yellow) are drawn. These yellow lines delineate the cortical parcellation units. D, Nodal points based on anatomical criteria define anterior and posterior boundaries of the cortical parcellation units after sulci are identified (from Caviness et al 37 ). The resulting parcellation units are shown. E, Cortical brain regions are identified by parcellation units. The labels for the regions are as shown in the first 2 columns of Tables 2 and 3. BFsbmp indicates basal forebrain subcomponent.

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 were in the middle, medial, and right-sided fronto- Table 2. Intraclass Correlation Coefficients (ICCs) orbital cortices, the last 2 of which are considered part for the Cortical Parcellation Units* of the paralimbic cortices.48 The anterior cingulate and paracingulate gyri and insula were also significantly re- 2 Raters ICCs, duced in patients compared with controls, the last 2 by ICCs ICCs Intrarater almost 1 SD. The relative differences in volumes be- Parcellation Units Label (n = 10) (n = 10) (n=6) tween patients and controls were primarily in the range Frontal Lobe of 7% to 15%. The largest effect sizes were in the middle Superior frontal gyrus F1 0.89 . . . 0.99 frontal gyrus and right fronto-orbital cortex, the insula, Middle frontal gyrus F2 0.77 . . . 0.83 Frontal pole FP 0.86 . . . 0.97 and the anterior cingulate and paracingulate gyri. Inferior frontal gyrus F3o 0.85 . . . 0.83 In general, our findings are consistent with those of Inferior frontal gyrus F3t 0.60 . . . 0.94 several previous MRI and neuropathological studies. Pre- Frontomedial cortex FMC 0.11 0.64 0.94 vious MRI studies that segmented specific prefrontal ar- Frontoorbital cortex FOC 0.59 . . . 0.94 Precentral gyrus PRG 0.93 . . . 0.73 eas reported significant reductions in dorsolateral pre- Supplementary SMC 0.55 0.86 0.98 frontal (ie, middle frontal gyrus)15,29,63 and orbital14 motor cortex cortices. A recent study64 using sophisticated segmenta- Frontal operculum FO 0.25 0.34 0.92 Central operculum CO 0.73 . . . 0.90 tion procedures did not find significant prefrontal volu- Basal forebrain BF 0.41 0.03 0.88 metric reductions. The investigators’ sample size of 15, Parietal Lobe however, would have only 26% to 38% statistical power Postcentral gyrus POG 0.21 0.71 0.73 to detect a medium effect size of 0.50, and effect sizes of Superior parietal SPL 0.27 0.84 0.62 the frontal gyri in our study ranged from 0.10 to 0.62. lobule Supramarginal gyrus, SGa 0.41 0.84 0.94 Their findings also suggested that connectivity with pre- ant frontal areas was abnormal in schizophrenia, which may Supramarginal gyrus, SGp 0.35 0.87 0.89 be consistent with our findings. post The largest effect sizes in our study were demon- Angular gyrus AG 0.52 0.68 0.77 Precuneus PCN 0.75 . . . 0.77 strated in paralimbic cortices, eg, anterior cingulate and Parietal operculum PO 0.72 . . . 0.94 paracingulate gyri and the insula. This is consistent with Occipital Lobe previous postmortem studies that reported cytoarchi- Occipital lateral gyri, sup OLs 0.62 0.78 0.72 tectonic and structural abnormalities in the cingu- Occipital lateral gyri, inf OLi 0.007 0.71 0.74 late22,65 and imaging studies that showed anterior cingu- Occipital pole OP 0.11 0.31 0.91 66,67 68 Cuneus CN 0.77 . . . 0.76 late gyral volumetric reductions and hypofunction Lingual gyrus LG 0.55 0.74 0.57 in patients. Lesion and functional neuroimaging studies Fusiform gyrus OF 0.05 0.76 0.50 of the anterior cingulate gyrus have shown a variety of Calcarine sulcus calc 0.64 0.93 0.92 neurobehavioral deficits69,70 and associations with inter- Temporal Lobe nally initiated thought and behavior,71,72 attention to ac- Temporal pole TP 0.96 . . . 1.00 73 74,75 76 Superior temporal gyrus, T1a 0.60 0.85 0.99 tion, divided attention, and learning. Thus, it has ant been suggested that abnormalities of the cingulate gy- Superior temporal gyrus, T1p 0.92 . . . 0.88 rus may be central in understanding schizophrenia.22 post Middle temporal gyrus, T2a 0.59 . . . 0.99 We would argue that our findings are not due to ant sample bias because patients were representative of a large Middle temporal gyrus, T2p 0.76 . . . 0.91 outpatient network serving 3 major hospitals in the Bos- post ton area. Furthermore, the healthy controls were simi- Middle temporal gyrus TO2 0.86 . . . 0.84 Inferior temporal gyrus, T3a 0.78 . . . 0.93 lar in sociodemographic background, including educa- ant tion, a variable typically affected by the illness. Finally, Inferior temporal gyrus, T3p 0.46 0.62 0.85 as in Pearlson et al,16 we used 3 different statistically ana- post lytic approaches to test our hypotheses, and these dem- Inferior temporal gyrus TO3 0.35 0.79 0.75 Fusiform gyrus, ant TFa 0.68 . . . 0.93 onstrated consistent findings across methods, suggest- Fusiform gyrus, post TFp 0.77 . . . 0.87 ing their validity. Fusiform gyrus TOF 0.52 0.73 0.89 What is most striking about our results is that, al- Planum polare PP 0.81 . . . 0.95 Insula INS 0.80 . . . 0.98 though we included 48 cortical PUs, the significant re- Heschl gyrus H1 0.76 . . . 0.84 ductions were in paralimbic cortices (ie, cingulate gy- Planum temporal PT 0.12 0.81 0.78 rus, insula, and frontomedial and fronto-orbital cortices) Medial Paralimbic Cortices and the prefrontal area—the middle frontal gyrus— Subcallosal cortex SC 0.50 0.69 0.92 which has strong reciprocal connections to paralimbic Paracingulate cortex PAC 0.88 . . . 0.94 and limbic brain regions.48,77 Furthermore, in a previ- Cingulate gyrus, ant CGa 0.84 . . . 0.99 10 Cingulate gyrus, post CGp 0.83 . . . 0.75 ous presentation of these patients, it was shown that Parahippocampal gyrus, PHa 0.92 . . . 0.88 among 10 subcortical regions tested, the thalamus and ant amygdala-hippocampal complex were the only subcor- Parahippocampal gyrus, PHp 0.11 0.81 0.93 post tical areas significantly volumetrically reduced—areas with reciprocal connections48,77,78 to the cortical areas that we *ant indicates anterior; post, posterior; sup, superior; inf, inferior; and found reduced in patients. (The pallidum and ventricles ellipses, not applicable. were significantly increased.10)

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 Table 3. Mean ± SD Differences in Volumes (in Cubic Centimeters) of Cortical Areas for Schizophrenic Patients vs Normal Controls*

Schizophrenics Controls Effect Relative Region Label (n = 29) (n = 26) Size Difference, % Frontal Lobe Frontal pole FP 62.99 ± 9.64 56.65 ± 10.36 −0.41 −5.49 Superior frontal gyrus F1 29.50 ± 3.81 28.84 ± 4.13 0.26 3.07 Middle frontal gyrus F2 27.09 ± 5.25 27.98 ± 3.98 0.62 8.80† Inferior frontal gyrus F3o 9.67 ± 2.51 9.30 ± 3.26 0.10 2.98 Inferior frontal gyrus F3t 6.40 ± 1.82 6.83 ± 1.99 0.42 11.17 Precentral gyrus PRG 39.06 ± 6.64 39.07 ± 5.80 0.34 5.00 Supplementary motor cortex SMC 6.29 ± 2.11 6.10 ± 1.73 0.03 2.59 Frontomedial cortex FMC 4.04 ± 0.76 4.52 ± 1.13 0.16 14.89‡ Frontoorbital cortex FOC 15.17 ± 2.60 15.20 ± 2.11 0.56§ 8.45§ Frontal operculum FO 4.29 ± 1.37 3.94 ± 1.31 −0.05 −1.61 Central operculum CO 10.17 ± 2.22 9.37 ± 1.92 −0.16 −2.91 Basal forebrain BF 3.58 ± 1.69 3.66 ± 1.56 −0.17 −7.26 Total frontal lobe 218.26 ± 21.26 211.45 ± 23.00 0.02 2.32 Medial Paralimbic Cortex Cingulate gyrus, ant CGa 12.38 ± 3.74 13.06 ± 2.74 0.50 11.14࿣ Cingulate gyrus, post CGp 12.94 ± 2.69 12.09 ± 2.36 0.01 0.19 Paracingulate cortex PAC 14.11 ± 2.06 14.55 ± 2.41 0.78 7.99‡ Subcallosal cortex SC 5.43 ± 1.06 5.02 ± 0.98 −0.14 −2.22 Parahippocampal gyrus, ant PHa 6.00 ± 1.48 5.31 ± 0.93 −0.29 −5.92 Parahippocampal gyrus, post PHp 5.49 ± 1.32 5.42 ± 0.78 0.21 4.59 Total medial paralimbic cortex 56.35 ± 8.30 55.46 ± 5.73 0.03 4.43 Temporal Lobe Superior temporal gyrus T1 13.06 ± 2.14 11.81 ± 2.04 −0.32 −4.53 Heschl gyrus H1 2.90 ± 0.87 3.01 ± 0.76 0.37 8.81 Planum temporal PT 6.34 ± 1.49 5.99 ± 1.25 0.004 0.08 Temporal pole TP 21.68 ± 4.77 21.97 ± 3.82 0.41 6.79 Middle temporal gyrus, ant T2 16.35 ± 2.65 15.75 ± 2.27 0.15 1.91 Middle temporal gyrus, post TO2 8.77 ± 2.34 8.25 ± 2.13 −0.01 −0.32 Inferior temporal gyrus, ant T3 13.27 ± 2.23 12.35 ± 2.03 −0.11 −1.49 Inferior temporal gyrus, post TO3 7.47 ± 2.63 6.84 ± 1.98 −0.07 −2.03 Fusiform gyrus, ant TF 13.16 ± 2.50 12.53 ± 2.04 0.08 1.23 Fusiform gyrus, post TOF 6.06 ± 2.01 6.01 ± 1.69 0.18 4.74 Planum polare PP 3.64 ± 0.74 3.44 ± 0.84 −0.01 −0.33 Insula INS 15.88 ± 1.73 16.28 ± 1.89 0.88 7.62¶ Total temporal lobe 196.45 ± 24.15 186.88 ± 23.10 0.004 0.58 Parietal Lobe Precuneus PCN 25.76 ± 3.59 24.63 ± 4.67 0.06 0.67 Postcentral gyrus POG 32.09 ± 4.98 30.27 ± 4.79 −0.006 −0.07 Superior parietal lobule SPL 9.22 ± 3.31 10.10 ± 4.83 0.31 11.74 Supramarginal gyrus, ant SGa 8.57 ± 2.48 7.83 ± 3.25 −0.14 −4.50 Supramarginal gyrus, post SGp 10.36 ± 3.59 11.72 ± 4.85 0.44 15.13† Angular gyrus AG 12.50 ± 5.58 10.50 ± 2.95 −0.30 −11.60 Parietal operculum PO 5.41 ± 1.40 4.73 ± 1.01 −0.29 −6.74 Total parietal lobe 103.91 ± 13.32 99.79 ± 15.49 0.007 1.16 Occipital Lobe Occipital pole OP 15.09 ± 10.15 14.41 ± 7.66 0.009 0.57 Cuneus CN 5.22 ± 1.89 5.57 ± 2.23 0.34 11.60 Occipital lateral gyrus, sup OLs 42.12 ± 9.90 42.42 ± 6.97 0.40 6.66 Occipital lateral gyrus, inf OLi 23.41 ± 5.93 22.90 ± 4.21 0.22 3.82 Lingual gyrus LG 15.39 ± 2.90 14.66 ± 2.95 0.05 0.68 Fusiform gyrus OF 8.07 ± 1.94 8.02 ± 1.72 0.23 4.59 Total occipital lobe 117.39 ± 19.12 115.87 ± 14.36 0.03 4.46

*Unadjusted mean volumes are presented. Tests of differences, however, are based on analyses of brain volumes, adjusted for total cerebral volume and controlled for sex effects, using the z-score method (Mathalon et al 60) to adjust for normal variations in age- and sex-corrected head size. Effect size (ES) between 62 normal controls (nc) and schizophrenic patients (sz) is calculated as follows: ES = (meannc − meansz)/(pooled SD)—ie, the difference in SD units (Cohen for adjusted volumes. Relative difference (RD) is calculated as follows: RD = [(meannc − meansz)/meannc] ϫ 100%—ie, the percentage difference between adjusted volumes of controls and patients. ant indicates anterior; post, posterior; sup, superior; and inf, inferior. †Left side is significant ( PϽ.05). ‡PϽ.01. §Right side is significant ( PϽ.05). ࿣Total is significant ( PϽ.05). ¶PϽ.001.

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SPL P O PRG JPL PRG G F1 S F1 POG PCN G AG P CGa F2 CN CGp OLs SGa PAC SCLC TO2 T1p F3o OF FP OP FP OLi T2p T1a calc TO3 F3t SC T3p T2a FMC TP FOC T3a

C Supramarginal Gyrus, Posterior

Middle Frontal Gyrus FO I I FO Frontoorbital Cortex N N CO S S CO Paracingulate Cortex PO PO Cingulate Gyrus, Anterior

Frontomedial Cortex

Insula

Figure 2. Cortical brain regions significantly reduced in patients compared with normal controls. Topography is based on methods described by Caviness et al 37: A, lateral surface; B, medial surface; and C, inferior surface. Areas of significant cortical volume reduction in schizophrenic patients vs normal controls are in color. All reductions were bilateral, except in the fronto-orbital cortex, in which only the right side was significantly reduced (P = .05). The labels for the regions are as shown in the first 2 columns of Tables 2 and 3.

The functional consequences of the reduced size of nected to prefrontal and cingulate cortices. This is a po- the insula in patients is as yet unclear. The insular cor- tentially important finding, given the area’s role in at- tex, however, is highly interconnected with somatosen- tention and memory identified in lesion and functional sory and other cortical areas and limbic structures (peri- imaging studies.75,80,81 Although most studies8,82 have rhinal and entorhinal cortex and amygdala). It plays a shown that the parietal cortex as a whole is not signifi- role in sensory, motor, and language functions and has cantly reduced in patients with schizophrenia, previous been described79 as a limbic-integration area. In addi- work29 reported significant reductions in specific areas, tion, the insula has connections to several brain areas that such as the inferior parietal cortex—ie, the supramar- were found to be volumetrically reduced in this sample ginal and angular gyri. We have further suggested that of patients, including the orbital and medial frontal cor- volumetric reductions in this cortex may be in area 40, tices, the cingulate gyrus, and the amygdala. Insular ab- rather than the angular gyrus (area 39). Structural defi- normalities in schizophrenia may be related to an im- cits in area 40 are consistent with functional stud- pairment in integrating sensory stimuli with internal ies71,72,75,81 of attention in patients with schizophrenia and motivational states, a hypothesis that warrants further healthy subjects. These studies showed abnormalities in investigation in patients with schizophrenia. perfusion or activation in this area during sustained at- The importance of the paralimbic areas is also sug- tention tasks. gested by 2 of our previous analyses44,46 of neuropsycho- We also found that several cortical PUs—the basal logical deficits of patients, including those in the pres- forebrain, subcallosal cortex, operculum, and the fron- ent study. Olfactory and executive function deficits tal pole—were larger, although not significantly, in pa- appeared to separate patients into 2 groups with dis- tients than in controls. These subtle volumetric in- tinct cognitive profiles, suggesting some heterogeneity creases were in cortical areas that have strong reciprocal among patients with cognitive deficits that may be asso- connections to the areas we found significantly re- ciated with the fronto-orbital and hippocampal divi- duced. This may reflect an orchestrated developmental sions48,77 of the paralimbic cortices. Furthermore, these mechanism representing brain plasticity. There is some patients have exhibited other significant cognitive defi- precedent for posing this hypothesis because it is con- cits that are dependent on limbic and paralimbic corti- sistent with animal models and functional stud- ces, ie, executive function, attention, olfaction, and ies5,25,42,83 of schizophrenia that showed hypofunction in memory functions. 45,46 particular cortical areas (eg, dorsolateral prefrontal cor- We also found a significant volumetric reduction in tex) and hyperfunction in subcortical (eg, hippocam- the posterior supramarginal gyrus, which is densely con- pus) or other cortical areas. It is also consistent with a

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©1999 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/01/2021 recent study of schizophrenia84 that suggested disrup- Accepted for publication February 10, 1999. tions in the dopaminergic regulation of intracortical and From the Department of Psychiatry (Drs Goldstein, corticostriatal connectivity associated with the orbito- Goodman, Seidman, Lee, Faraone, and Tsuang) and the In- frontal cortex. Thus, there may not be a focally acting stitute of Psychiatric Epidemiology and Genetics (Drs Gold- pathological process producing volumetric reductions in stein, Seidman, Lee, Faraone, and Tsuang), Massachusetts specific brain regions in patients with schizophrenia. Mental Health Center; the Departments of Neurology and Rather, there may be cortical systems, ie, limbic- Radiology Services, Center for Morphometric Analysis, Mas- paralimbic, that exhibit subtle abnormalities in their con- sachusetts General Hospital (Drs Goodman, Kennedy, nections that result in reductions in some cortical areas Makris, and Caviness and Mr Tourville), Harvard Medical and increases in others. Although this study did not test School; and the Department of Epidemiology, Harvard School this hypothesis, it warrants further investigation. of Public Health (Dr Tsuang), Boston; and the Department There were no significant volumetric reductions in of Psychiatry, Harvard Medical School and Brockton– other cortical regions, and the effect sizes of volumetric West Roxbury Veterans Affairs Medical Center (Drs Gold- reductions in other cortical areas were negligible, ex- stein, Seidman, Faraone, and Tsuang), Brockton, Mass. Dr cept for visual primary and association cortices, ie, 0.34 Lee is now at the Center for Vaccine Research, University and 0.40, respectively, in the cuneus and superior lat- of California–Los Angeles Medical Center. eral occipital gyrus. This is consistent with a recent study13 This work was supported by grants K21 MH00976 that reported cytoarchitectonic abnormalities in neuro- (1992-1994) and RO1 MH56956 (1997-2000) (Dr Gold- nal density in patients with schizophrenia in the pri- stein) and Merit Award MH 43518 (Dr Tsuang) from the mary visual cortex, area 17. National Institute of Mental Health, Bethesda, Md; a grant Schizophrenia, however, is a heterogeneous disor- from the Fairway Trust (Dr Kennedy); and a Dissertation der. Other brain areas—in particular, the superior tem- Award from the Scottish Rite Foundation, Lexington, Mass poral, Heschl and parahippocampal gyri, and planum tem- (Dr Goodman). porale—have been found7,16,18,29,30-32,85,86 to be Reprints: Jill M. Goldstein, PhD, Harvard Institute of volumetrically reduced in patients. In all studies of the Psychiatric Epidemiology and Genetics, Massachusetts superior temporal gyrus, however, the samples were men Mental Health Center, 74 Fenwood Rd, Boston, MA 02115 only or a 2:1,16 3:1,31 or approximately 5:130 ratio of men (e-mail: [email protected]). to women. Furthermore, some of these samples were pa- 7 tients with primarily positive symptoms, and positive REFERENCES symptoms, such as hallucinations and thought disorder, have been associated with superior temporal gyral 7,18 1. Andreasen NC, ed. Can Schizophrenia Be Localized in the Brain? Washington, abnormalities. DC: American Psychiatric Press; 1986. Our sample was a mix of male and female patients 2. Murray RM. Neurodevelopmental schizophrenia: the rediscovery of dementia prae- with mixed symptomatology. In fact, DeLisi et al19 had cox. 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