Decreased left amygdala and hippocampal volumes in young offspring at risk for schizophrenia

Schizophrenia Research 58 (2002) 173 – 183 www.elsevier.com/locate/schres

Decreased left amygdala and hippocampal volumes in young offspring at risk for schizophrenia Matcheri S. Keshavan a,*, Elizabeth Dick b, Ilona Mankowski a, Keith Harenski a, Debra M. Montrose a, Vaibhav Diwadkar a, Michael DeBellis a a

Department of Psychiatry, UPMC Health System-Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, 3811 O’Hara Street, Room 984, Pittsburgh, PA, 15213, USA b Department of Experimental Psychology, Cambridge University, Cambridge, UK Received 21 September 2001; received in revised form 15 November 2001; accepted 19 November 2001

Abstract Abnormalities in the structural integrity and connectivity of the medial temporal and the prefrontal cortex are well documented in schizophrenia, but it is unclear if they represent premorbid indicators of neuropathology. Studies of young relatives at high-risk for schizophrenia (HR) provide an opportunity to clarify this question. We herein provide data from a magnetic resonance imaging (MRI) study of these structures in young offspring of schizophrenia patients. A series of 17 young HR offspring of schizophrenic patients were compared with 22 healthy comparison subjects (HC). Morphometric comparisons of the right and left dorsolateral prefrontal cortex (DLPFC), and the anterior and posterior amygdala – hippocampal (A – H) complex were conducted using high-resolution whole brain T1 weighted brain images. Compared with the HC group, HR subjects had significant decreases in intracranial volume. The volumes of the left anterior and posterior A – H complex were reduced in the HR subjects after adjusting for intracranial volume. HR subjects also showed a significant leftward (Right > Left) asymmetry of the anterior A – H complex compared to the HC subjects. No significant changes were seen in the DLPFC. Thus, lateralized alterations in the volume of the left A – H complex are evident in unaffected young offspring of schizophrenia patients and may be of neurodevelopmental origin. Follow-up studies are needed to examine the predictive value of these measures for future emergence of schizophrenia in at-risk individuals. D 2002 Elsevier Science B.V. All rights reserved. Keywords: Amygdala; Hippocampus; Prefrontal cortex; Magnetic resonance imaging; Schizophrenia; High-risk

1. Introduction Ever since the early descriptions of schizophrenia, researchers have been interested in the role of brain structural alterations in this illness, notably the frontal *

Corresponding author. Tel.: +1-412-624-2794; fax: +1-412624-1459. E-mail address: [email protected] (M.S. Keshavan).

and the medial temporal lobes (Kraepelin, 1919 –1971; Southard, 1910). Cognitive functions such as working memory and executive functions are mediated by the prefrontal cortex (Fuster, 1989); the temporal –limbic regions, hippocampus and the amygdala, respectively, are critical for memory functions (Squire and Zola, 1996), and affect perception (Morris et al., 1996). These functions are impaired in schizophrenia (for a review see Elvevag and Goldberg, 2000), underlining

0920-9964/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved. PII: S 0 9 2 0 - 9 9 6 4 ( 0 1 ) 0 0 4 0 4 - 2

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the importance of examining the structural integrity of frontal and medial temporal lobes. Several neuropathological and neuroimaging studies have consistently documented volume reductions in medial temporal lobe regions (for reviews see McCarley et al., 1999; Pruessner et al., 2000; Schultz and Andreasen, 1999; Shenton et al., 2001). Volume reductions in the amygdala – hippocampal (A – H) complex are observed in both chronic and first episode schizophrenia patients and appear to be more prominent on the left side, especially in male patients (Shenton et al., 2001); the Right>Left asymmetry of the hippocampus and amygdala, usually seen in healthy persons (Pruessner et al., 2000; Szabo et al., 2001), may be exaggerated in schizophrenia (Galderisi et al., 1999; Hirayasu et al., 1998; Wang et al., 2001), though not all studies support this (Kulynych et al., 1995; Luchins et al., 1979). Functional neuroimaging studies (Andreasen et al., 1992; Perlstein et al., 2001; Weinberger et al., 1986) provide converging support for the decreased function of the dorsolateral prefrontal cortex (DLPFC) in schizophrenia (‘‘hypofrontality’’); post-mortem studies also support the presence of prefrontal structural alterations in schizophrenia (Glantz and Lewis, 2000; Selemon et al., 1998). However, MRI studies in schizophrenia have been equivocal, though subtle differences in prefrontal cortical volume are seen, and appear to be correlated with functional measures of prefrontal cortical dysfunction (Shenton et al., 2001; Wible et al., 1995). At least in part, negative findings in this brain region may be related to the fact that most studies have examined the prefrontal cortex as a whole, and have not separately examined functionally important components such as the DLPFC (Shenton et al., 2001). Some studies also suggest that the integrity of the frontolimbic networks might be impaired; decreased medial temporal volumes have been found to correlate with abnormal prefrontal structure (Breier et al., 1992) as well as function (Weinberger et al., 1992). What remains unclear is whether prefrontal and limbic abnormalities in schizophrenia occur prior to disease onset, or are a consequence of the disease process (Copolov et al., 2000). This issue is timely in the context of the clinical, epidemiological, and neuropathological evidence suggesting that schizophrenia is a neurodevelopmental disorder (Schultz and Andreasen, 1999; Weinberger, 1995). Neurodevelopmental models posit either a dysfunctional neural network as

a result of early (pre- or perinatal) developmental deviations (Murray and Lewis, 1987; Weinberger, 1987) or an emergent disorder of brain maturational processes such as synaptic pruning in late childhood and adolescence (Keshavan et al., 1994). These models propose that brain abnormalities predate overt clinical manifestations prompting investigation of potential premorbid precursors in persons at risk for schizophrenia. Since genetic factors are among the best-established risk factors for schizophrenia (Erlenmeyer-Kimling et al., 1995; Parnas et al., 1993), relatives of schizophrenic parents represent a valuable population to conduct such investigations. Indeed, computed tomography (CT) (Cannon et al., 1994) and magnetic resonance imaging (MRI) studies of adult relatives of schizophrenic patients have observed significant brain structural abnormalities including volumetric reductions in the medial temporal lobes and the thalamus (Lawrie et al., 1999; Seidman et al., 1999; Staal et al., 1998). Studies of adult relatives are limited by the fact that many of these individuals may have crossed the typical age of risk for onset of schizophrenia, i.e. adolescence. Thus, individuals who have crossed the age of risk may have a smaller load of genetic risk, since they in effect have ‘‘escaped’’ the illness. Only a few studies (Keshavan et al., 1997; Lawrie et al., 1999; Schreiber et al., 1999) have addressed the question whether brain alterations are present in predisposed individuals before the typical period of age of risk. Lawrie et al. (1999) and Schreiber et al. (1999) observed no changes in prefrontal volumes, but significant reductions in the A – H complex, in young relatives at risk for schizophrenia. These studies did not separately examine the functionally important regions of DLPFC, amygdala, and hippocampi. The Pittsburgh study of high-risk (HR) offspring of schizophrenic probands has attempted to address this issue by examining MRI abnormalities in the prefrontal and limbic brain regions and their inter-relationships in a group of young non-psychotic offspring of schizophrenic parents.

2. Methods 2.1. Subjects Subjects included consecutively recruited offspring of a parent with schizophrenia (HR: n = 17; age 13– 22)

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and age and sex matched healthy comparison subjects (HC: n = 22; age 9 – 22) without psychiatric history in self or first-degree relatives. The study was approved by the Institutional Review Board of the University of Pittsburgh Medical Center. After complete description of the study to the subjects, written informed consent was obtained. For subjects aged less than 18, the parent/guardian provided the informed consent with the assent of the subject. HR subjects were recruited by approaching patients in our Schizophrenia Service as well as children and adolescents from the Child Psychiatry Service at the Western Psychiatric Institute and Clinic. HC subjects were recruited from the same communities from which the HR subjects were recruited; we chose not to match HC and HR subjects pairwise because of the logistical difficulties caused by multiple potentially confounding variables (age, sex, socioeconomic status, IQ and handedness). Eleven HR and 12 HC subjects had been included in a previous preliminary MRI report (Keshavan et al., 1997). HR subjects and healthy comparison subjects did not significantly differ in gender (eight males and nine females in HR group; 11 males and 11 females in the HC group; Chi2 = 0.03; df = 1; p = 0.85), IQ (HR subjects): 102.9 F 18.84 and HC subjects 112.95 F 16.60; F = 3.10; df = 1, 37; p = 0.08), age (15.57 F 3.0 and 14.60 F 4.62 years, respectively, in the HR and HC groups; F = 0.56; df = 1, 37; p = 0.46), or handedness (HR: 15 right handed and HC: 21 right handed subjects; Chi2 = 0.70; df = 1; p = 0.40). HR subjects had lower parental socioeconomic status (SES) as measured by the Hollingshead Scale (Hollingshead, 1975) (30.67 F 15.32) than HC subjects (46.45 F 10.92) ( F = 14.11; df = 1,37; p < 0.001). 2.2. Clinical assessments All subjects were clinically evaluated using the Schedule for Affective Disorders and Schizophrenia— Child Version (K-SADS) (Ambrosini et al., 1989) or Structured Clinical Interview for DSM-IV Schizophrenia (SCID) (First et al., 1995); subjects with neurologic or medical illness or IQ < 75 were excluded. We also excluded HR subjects who had any lifetime evidence of psychotic disorders, in view of our goal of identifying prepsychotic neurobiological precursors. Ten of the HR subjects had one or other life time diagnosis of psychiatric disorders: attention deficit hyperactivity

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disorder, n = 4; depressive disorder, n = 4; bipolar disorder, n = 1; separation anxiety disorder, n = 1. None of the HC subjects had any lifetime Axis I disorder as determined by SCID or K-SADS interviews, history of neurological disorders, chronic medical illnesses, substance abuse or dependence, treatment with psychotropic drugs, or any contraindication to MRI. None had a history of Axis I psychiatric disorder in any firstdegree family member as determined by Family History Research Diagnostic Criteria interviews (Andreasen et al., 1977). The diagnoses in the parents of the HR group, based on SCID interviews, were schizophrenia (n = 12) and schizoaffective disorder (n = 5). To obtain a measure of psychosis-related psychopathology the HR and HC subjects were assessed using two of the Chapman psychosis-proneness scales. The Perceptual Aberration and Magical Ideation Scales (Chapman et al., 1978; Eckblad and Chapman, 1983), in particular, were chosen because they have been shown to have some predictive power for future psychosis (Chapman et al., 1994), and were combined to yield a composite schizotypy score. 2.3. MRI Studies All volumetric MRI scans were conducted at the University of Pittsburgh Medical Center (1.5-T Signa Whole Body Scanner, General Electric Medical Systems, Milwaukee, WI). Image quality and clarity as well as patient head position were determined with a sagittal scout series. Total brain volume was measured with a three-dimensional spoiled gradient recalled acquisition in the steady state (SPGR) pulse sequence that obtained 124 1.5-mm-thick contiguous coronal images (echo time = 5 ms, repetition time = 25 ms, acquisition matrix = 256  192, field of view = 24 cm, flip angle = 10j). In order to facilitate image orientation, coronal slices were obtained perpendicular to the anterior – commissure – posterior – commissure line. Axial proton density and T2-weighted images were obtained for thalamic measurement and to exclude structural abnormalities on MRI scans. NIH image software (version 1.56) was used to measure brain anatomy (Rasband, 1993). This technique, developed by the National Institutes of Health, yields valid and reliable neuroanatomic measurements of the regions of interest with a semiautomated segmentation approach (Keshavan et al., 1995). None of the MRI

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scans in this data set showed motion and magnetic field inhomogeneity artifacts. Anatomical measurements were conducted by a trained and reliable rater (ED) and were supervised by one of the authors (MSK). All measurements were performed by individuals who were blind to subject identity and clinical data. Inter-rater (KH, ED) reliabilities (intraclass correlations; n = 10), computed on 10 scans not used in this study were as follows (intracranial volume: 0.98; brain volume: 0.96; anterior A – H complex: right: 0.95; left: 0.94; posterior A – H complex; right: 0.99; left: 0.99; dorsolateral prefrontal cortex, right: 0.99; left: 0.98); intra-rater reliabilities for measurements by the same rater (ED), conducted approximately 1 month apart on 10 independent scans, were as follows: intracranial volume: 0.99; brain volume: 0.99; anterior A –H complex: right: 0.99; left: 0.97; posterior A –H complex; right: 0.99; left: 0.97; dorsolateral prefrontal cortex right: 0.99; left: 0.93. Neuroanatomic boundaries were determined by reference to standard neuroanatomical atlases (Daniels et al., 1987; Talairach and Tournoux, 1988). The intracranial volume was used as a covariate in comparison to volumetric measures of the structures listed above, across diagnostic groups. Intracranial volume included the total brain, dura, ventricular and extraventricular CSF, brain stem and cerebellum; this was measured by manually outlining the outer limit of the tracing along the inner border of the inner table of skull. Total brain volume included the combined volume of the cerebral hemispheres, cerebellum and the brainstem. Since it is generally difficult to distinguish the amygdala and the hippocampus in brain imaging studies, most investigators combine these two structures (the amygdala –hippocampal complex); an attempt is usually made, however, to delineate an anterior portion, comprising mainly the amygdala, and a posterior portion which is mainly the hippocampus (for a review see Shenton et al., 2001). We used the most anterior slice in which the temporal stem was visible as the anterior limit of the A – H complex. This landmark approach is commonly used in psychiatric studies of children and adolescents using MRI by our group (DeBellis et al., 1999) and others (Castellanos et al., 1996; DeBellis et al., 1999; Giedd et al., 1996). The amygdala has the alveus as the inferior boundary; the lateral and superior boundaries were defined by the

temporal lobe white matter. The last slice on which the anterior amygdala –hippocampal complex was measured was the one just anterior to the anterior-most slice in which the mamillary body is seen. The posterior part of A – H complex was measured beginning with the anterior-most slice showing the mamillary bodies, and posteriorly up to the image where right and left inferior and superior colliculi were jointly visualized (the point of separation of the crus of the fornix from the fimbria of the hippocampus). Our measurement of the A –H complex included the cornu ammonis, hippocampus proper, dentate gyrus, alveus, and subiculum; but excluded the crus of the fornix, the isthmus of the cingulate gyrus, and the parahippocampal gyrus. The number of slices for the amygdala and hippocampal measurements did not differ between HR and HC subjects. Asymmetry indices were calculated for the anterior and posterior A –H complex using the formula: (Right Left)/(Right + Left)  100. Positive values on this index reflect leftward (Right>Left) asymmetry (Oldfield, 1971). The dorsolateral prefrontal cortex was manually outlined and measured in the coronal plane by a previously published method (Gilbert et al., 2000; Seidman et al., 1994). The most posterior part of the genu was located and used as the anterior limit of the DLPFC. The superior boundary was the superior frontal sulcus, and the inferior boundary was the posterior lateral fissure and the horizontal ramus of the anterior lateral fissure. The lateral border was the edge of the cerebral cortex and the medial border was created by connecting the deepest points on the superior frontal sulcus and the lateral fissure. Ten successive anterior slices were measured. The DLPFC was segmented and the volumes were measured (Fig. 1). 2.4. Statistical analysis First, data were checked for normality (Shapiro and Wilks W statistic) before conducting parametric comparisons. Where the distributions were non-normal, appropriate transformations were carried out (square root transformations for the schizotypy scores). Categorical measures (e.g. gender, handedness) were compared using Chi-square tests. The A – H complex volumes were compared between subjects using analysis of covariance (ANCOVA) with the intracranial volume and parental SES as covariates. The relations

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Fig. 1. This figure illustrates the manual tracing technique used in quantifying the right and left amygdala – hippocampal complex. Panel A illustrates the anterior portion of this structure, which mainly comprises of the amygdala. Panel B illustrates the posterior part of the structure mainly comprising the hippocampi.

between brain structural alterations and subject characteristics (age, IQ) were examined using Pearson Correlation Coefficients. Significance testing was done with two-tailed tests and alpha was set at p < 0.05.

3. Results HR subjects had non-significantly smaller intracranial volume (ANCOVA with parental SES as a covariate; HR: 1400.53 F 165.51 cm3, HC: 1511.39 F 145.9 cm3; df = 1,36; F = 2.05; p < 0.16) and brain

volume (ANCOVA with parental SES as a covariate; HR: 1116.95 F 137.39 cm3, HC: 1237.55 F 129.02 cm3; df = 1,36; F = 3.84; p = 0.058). ICV was used as a covariate (in addition to parental SES) in comparing the A – H complex volumes between HR and HC groups. As seen in Table 1 and Fig. 2, HR subjects had significant reductions in the left anterior and posterior A – H complex than the HC subjects, after covarying out ICV and parental SES. No significant differences were seen in DLPFC. The A –H complex reductions continued to be significant when only the right handed subjects were compared (left anterior:

Table 1 Morphometric measures in high-risk offspring and healthy comparison subjects HR

HC

F (df )

Amygdala – hippocampal complex Left anterior 1.29 (0.41) Right anterior 1.84 (0.53) Left posterior 3.22 (0.63) Right posterior 3.15 (0.52)

1.72 2.08 3.67 3.50

Dorsolateral prefrontal cortexa Left 11.43 (1.85) Right 11.02 (1.46)

12.27 (2.08) 11.51 (2.35)

(0.46) (0.41) (0.68) (0.62)

Effect size (Cohen’s d )

p

9.45 (1,35) 4.59 4.23 (1,35) 3.31 (1,35)

0.99 0.51 0.68 0.61

0.004 0.045 0.047 0.08

0.20 (1,34) 0.51 (1,34)

0.42 0.27

0.65 0.48

Amygdala – hippocampal complex and dorsolateral prefrontal cortex volumes in high-risk (HR; n = 17) and healthy comparison subjects (HC: n = 22). Analyses of covariance (ANCOVA) were conducted with intracranial volume and socioeconomic status as covariates. Standard deviations are shown in parentheses. a Missing data in one subject.

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Fig. 2. The right and left amygdala – hippocampal (A – H) complex volumes (anterior and posterior) in high-risk (HR) and healthy control (HC) subjects. Bars denote mean values for the groups.

df = 32; F = 10.06; p < 0.003; left posterior: df = 1,32; F = 3.15; p = 0.08). In view of the trend-worthy IQ differences between HR and HC subjects ( p = 0.08;

effect size, Cohen’s d = 0.56) we used IQ and ICV as covariates and the findings with the left A –H complex remained (left anterior: df = 1,35; F = 8.16; p = 0.007;

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left posterior: df = 1,35; F = 2.09; p = 0.16). HR subjects with (n = 10) and without (n = 7) psychopathology did not differ in regard to left anterior (df = 1,13; F = 0.42; p = 0.53) or left posterior A – H complex (df = 1,13; F = 0.12; p = 0.73). HR subjects with parents having a schizophrenic diagnoses (n = 12) and those with parents having schizoaffective disorder (n = 5) did not differ in regard to left anterior (df = 1,13; F = 0.07; p = 0.80) or left posterior A – H complex (df = 1,13; F = 0.22; p = 0.65). We also examined the A – H complex asymmetry between the groups. The HR subjects had a highly significant increase in leftward (Left < Right) anterior A – H complex asymmetry compared to HC subjects (ANCOVA with parental SES as a covariate; F = 8.11; df = 1,36; p < 0.007). Again, this difference persisted when only right handed subjects were analyzed (df = 1,33; F = 8.48; p < 0.006). HR subjects with and without psychopathology did not differ in regard to the anterior A – H complex asymmetry (df = 1,14; F = 1.89; p = 0.19). Posterior A – H complex asymmetry ratios did not differ between HR and HC groups (ANCOVA with parental SES as a covariate; F = 0.80; df = 1,36; p = 0.38). Age and IQ did not correlate significantly with any of the MRI measures. There were no significant gender effects or gender by diagnosis interactions for any of the MRI measures (all p values >0.05). We also examined the relations between Chapman’s schizotypy scores (square root transformed) and the A – H and DLPFC measures, since the HR subjects had nearly significant elevations in the combined magical ideation –perceptual aberration scale scores (HR subjects: 2.21 F 1.26; HC subjects: 1.44 F 1.09; F = 3.96; df = 1,36, p = 0.054). None of the correlations were significant (Pearson r < 0.3; p>0.2).

4. Discussion The main findings of this study were brain volume reductions in the left A – H complex volumes and increased leftward asymmetry of the anterior A – H complex among HR subjects. The brain volume reductions ( f 10%) were more prominent than previously described ( f 5%, Lawrie et al., 1999). The A –H complex volume reductions are consistent with previous neuroimaging observations of medial temporal lobe abnor-

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malities in chronic schizophrenia (Breier et al., 1992; Rossi et al., 1994; Gur et al., 2000) and first episode schizophrenia (Hirayasu et al., 1998); the findings confirm our own preliminary observations in HR offspring (Keshavan et al., 1997) and findings from other groups (Lawrie et al., 1999; Schreiber et al., 1999; Seidman et al., 1999; Staal et al., 1998) of decreased amygdala and hippocampal volumes in HR relatives. Volume reductions were more prominent (about 25%) in the left anterior A – H complex, which largely comprises the amygdala. Abnormalities in the amygdala have been described by several authors using neuropathological studies (Bogerts et al., 1985; Reynolds, 1983). Magnetic resonance imaging studies in schizophrenia suggest that amygdala volume reductions may be more prominent on the left side (Rossi et al., 1994). The observations are of considerable interest in the context of the current pathophysiological models of schizophrenia. Amygdala and striatal structures and their interactions have been involved in the mediation of affect perception (Louilot and Besson, 2000). Poor perception of nonverbal social and emotional cues has also been described in patients with first episode schizophrenia (Edwards et al., 2001) and among relatives of schizophrenic patients (Toomey et al., 1999). Our observation of increased leftward (Left < Right) asymmetry of the anterior A –H complex is of interest in light of data suggesting lateralization of neurochemical systems implicated in schizophrenia, such as dopamine. A specific increase in dopamine in the left amygdala has been implicated in the pathophysiology of schizophrenia (Reynolds, 1983). A proton magnetic resonance spectroscopy (MRS) of the A – H complex suggested predominantly left sided reduction in Nacetyl aspartate in schizophrenia (Maier et al., 2000), again supportive of the view that there might be lateralized neurochemical dysfunction in temporolimbic regions in schizophrenia. However, the first MRS study of the medial temporal lobe in schizophrenia showed more prominent NAA reductions on the right side (Nasrallah et al., 1994). Future studies need to examine the relation between neurochemical asymmetry and anatomical asymmetry in schizophrenia and in those at risk for the disorder. Left posterior A – H complex volume reductions, mainly reflecting the hippocampal changes, were also seen, but were less prominent (about 9.5% volume

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decrement). Hippocampal volume reductions have been consistently observed in schizophrenia (Nelson et al., 1998) and in relatives at risk for this disorder (Lawrie et al., 1999). Relatives of schizophrenia patients also have reductions in N-acetyl aspartate, a marker of neuronal viability in the hippocampus (Callicott et al., 1998). The hippocampal formation plays an important role in cognitive functions such as memory consolidation, and sensory gating, both of which are affected in schizophrenia. Recent postmortem studies of schizophrenia brains suggest the potential role of amygdala in the induction of the hippocampal abnormality in this disorder. It has been suggested that amygdala might contribute to the induction of abnormalities in the CA3 and CA2 sections of the hippocampus (Benes and Berretta, 2000). We did not observe any changes in DLPFC volumes in HR subjects. MRI studies in schizophrenia have generally yielded equivocal findings, the few studies that have evaluated functionally important sub-regions within the frontal lobe such as DLPFC have also led to conflicting findings (Baare et al., 1999; Gur et al., 2000). By contrast, evidence for functional deficits in DLPFC in schizophrenia is fairly impressive (Andreasen et al., 1992; Wible et al., 1995). Our inability to find structural alterations in DLPFC in HR subjects contrasts with cognitive impairments indicative of prefrontal dysfunction among offspring at risk for schizophrenia observed by our group (Diwadkar et al., in press) and by others (Deakin et al., 1997). We also did not observe any correlations between volume deficits in the A – H complex and DLPFC volumes. First, it may be that the DLPFC abnormalities are subtle and are below the limit of detection. It is also possible that A – H abnormalities might appear early on in individuals at risk for schizophrenia; abnormalities might manifest later in the prefrontal cortex in view of the fact that this is the last part of the brain to mature (Huttenlocher and Dabholkar, 1997). Our findings of altered amygdala and hippocampal structure in young HR subjects are compatible with the neurodevelopmental models of schizophrenia (Murray and Lewis, 1987; Weinberger, 1987). Early lesions of the hippocampus have been proposed as a neurodevelopmental model for schizophrenia; this model is based on observations that rats with neonatally induced excitotoxic hippocampal lesions show behavioral indices consistent with increased mesolimbic dopaminer-

gic responsivity to stressful and to pharmacologic stimuli emerging in early adulthood (Lipska et al., 1993). Early amygdala damage has also been proposed as a model for neurodevelopmental psychopathological disorders (Wolterink et al., 2001). Observations of decreased amygdala and hippocampi in the HR offspring suggest that these abnormalities might indicate risk for the disorder, but do not clarify how these are mediated (genetic or shared environmental factors) or how they might relate to the clinical manifestations of the disorder. Hippocampal volume reductions have been noted to be greater in the affected twins in discordant monozygotic twin pairs (Suddath et al., 1990) and in schizophrenic patients with a history of perinatal complications (McNeil et al., 2000) suggesting an environmental contribution to these structural alterations. Within the HR group, we did not see any significant relationships between the amygdala –hippocampal volumes or asymmetry and the Chapman indices of schizotypic psychopathology, considered to reflect indices of familial vulnerability to schizophrenia (Kendler et al., 1996). In another study involving high-risk subjects, amygdala – hippocampal alterations have been found to be unrelated to the presence of psychotic symptoms among high-risk relatives of schizophrenics (Lawrie et al., 2001). Thus, structural alterations in the amygdala and hippocampi may serve as nonspecific predisposing factors among individuals predisposed to the disorder. By themselves, they may not explain the emergence of psychopathology in such individuals; other contributory factors such as perinatal brain damage, psychosocial stress, drugs and hormonal changes may serve to interact with genetic factors to mediate the genesis of psychopathology, and should be studied in the HR subjects in future investigations. The strengths of our study include the investigation of a young pre-psychotic population of offspring of schizophrenia patients, and the examination of the functionally distinct components of the A – H complex. However, our study was limited by the relatively small sample size, especially when the HR group is subdivided into those with and without psychopathology. The only other studies that have examined brain structure using MRI in this population were those of Schreiber et al. (1999) and Lawrie et al. (1999); both examined the amygdala – hippocampal structures as a whole. Nevertheless, these studies have led to remark-

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