Anterior hippocampal volume reduction in male patients with schizophrenia

Quantitative high resolution magnetic resonance imaging (MRI) was utilized to measure anterior, posterior, and total hippocampal volumes in 27 male patients with chronic schizophrenia and 24 male controls. To optimize measurement techniques, hippocampal volumes were: (1) acquired with 1.4-mm slices; (2) excluded with the amygdala; (3) normalized for position; and (4) corrected for total intracranial volume (ICV). The results of a linear mixed effects regression analysis, which made it possible to analyze total anterior and total posterior hippocampal volumes separately, indicated that the anterior hippocampus was significantly smaller in the schizophrenic group relative to the control group. There were no significant group differences with respect to posterior hippocampal volumes, and no significant correlations between hippocampal volumes and illness duration. A significant lateralized asymmetry was also noted in both groups with the right hippocampal volume being larger than the left. These preliminary findings support a significant anterior hippocampal volume reduction in men with schizophrenia as well as a similar hippocampal volume asymmetry in both male controls and schizophrenics.     

Volumetric magnetic resonance imaging study of the anterior cingulate gyrus in schizotypal disorder

Lack of normal structural asymmetry of the anterior cingulate gyrus (ACG) in patients with schizophrenia has been reported in our previous study. However, to our knowledge, no morphological studies of the brain have examined changes in ACG volume in patients with schizotypal features. We investigated the volume of the gray matter and the white matter of the ACG by three-dimensional magnetic resonance imaging (MRI) in 24 patients who met the ICD-10 criteria for schizotypal disorder (12 males, 12 females) in comparison with 48 age- and gender-matched healthy control subjects (24 males, 24 females) and 40 patients with schizophrenia (20 males, 20 females). As we reported previously, right ACG gray matter volume was significantly reduced in the female patients with schizophrenia compared with the female controls. On the other hand, the gray and white matter volume of the ACG in the patients with schizotypal disorder did not differ significantly from the values in the healthy controls or the patients with schizophrenia. However, the female patients with schizotypal disorder showed a lack of right-greater-than-left asymmetry of the ACG gray and white matter found in the female controls. These results suggest that both schizotypal and schizophrenic subjects share, at least in part, the same cerebral asymmetry abnormalities. Received: 28 May 2002 / Accepted: 30 October 2002 Correspondence to T. Takahashi     

Shortening of the hippocampal formation in first-episode schizophrenic patients

Abstract Shortening of hippocampal formation (HF) in chronic schizophrenic patients have been demonstrated in our previous study. The purpose of the present study is to test if shortening of the HF occurs in schizophrenic patients suffering their initial psychotic episode. We performed contiguous, 1 mm thick, magnetic resonance imaging scans in 20 first-episode schizophrenic patients, 21 chronic schizophrenic patients, and 25 healthy subjects. Both groups of schizophrenic patients demonstrated significant shortening of the HF compared with normal controls (first-episode schizophrenia, 5.3%; chronic schizophrenia, 8.0%). However, the HF length was not significantly different between the first-episode and chronic schizophrenic patients. No significant correlation was seen between the HF length and the duration of illness in chronic schizophrenic patients. These results suggest that the HF shortening observed in schizophrenic patients may be genetic and/or developmental in origin.     

Increased <Emphasis Type="SmallCaps">d</Emphasis>-amino acid oxidase expression in the bilateral hippocampal CA4 of schizophrenic patients: a post-mortem study

An important risk gene in schizophrenia is d-amino acid oxidase (DAAO). To establish if expression of DAAO is altered in cortical, hippocampal or thalamic regions of schizophrenia patients, we measured gene expression of DAAO in a post-mortem study of elderly patients with schizophrenia and non-affected controls in both hemispheres differentiating between gray and white matter. We compared cerebral post-mortem samples (granular frontal cortex BA9, middle frontal cortex BA46, superior temporal cortex BA22, entorhinal cortex BA28, sensoric cortex BA1–3, hippocampus (CA4), mediodorsal nucleus of the thalamus) from 10 schizophrenia patients to 13 normal subjects investigating gene expression of DAAO in the gray and white matter of both hemispheres of the above-mentioned brain regions by in situ-hybridization. We found increased expression of DAAO-mRNA in the hippocampal CA4 of schizophrenic patients. Compared to the control group, both hemispheres of the hippocampus of schizophrenic patients showed an increased expression of 46% (right, P = 0.013) and 54% (left, P = 0.019), respectively. None of the other regions examined showed statistically significant differences in DAAO expression. This post-mortem study demonstrated increased gene expression of DAAO in the left and right hippocampus of schizophrenia patients. This increased expression could be responsible for a decrease in local d-serine levels leading to a NMDA-receptor hypofunction that is hypothesized to play a major role in the pathophysiology of schizophrenia. However, our study group was small and results should be verified using larger samples.     

Association studies of the adenosine A2a receptor (1976T > C) genetic polymorphism in Parkinson’s disease and schizophrenia

Summary. Given the implications with respect to the pathogenesis of dopaminergic dysfunction in schizophrenia and Parkinson’s disease (PD), as well as the reciprocal antagonistic interactions between adenosine A2a receptor (A2aAR) and the dopamine D2 receptors, A2aAR may be a candidate gene conferring susceptibility to PD or schizophrenia. In this study, we tested the hypothesis that the A2aAR 1976T > C genetic variant confers susceptibility to or is related to the onset age of schizophrenia or PD using a sample population consisting of 94 PD and 227 schizophrenic patients. We also tested whether the A2aAR 1976T > C relates to antipsychotic-induced tardive dyskinesia in the schizophrenic population. The results demonstrated that in comparing PD patients and controls the distribution of the A2aAR 1976T > C genotypes (P = 0.788) and alleles (P = 0.702) did not vary significantly. Furthermore, the PD onset age was not significantly different amongst the three A2aAR 1976T > C genotypic groups. In comparing schizophrenic patients and controls, the distribution of the A2aAR genotypes (P = 0.330) and alleles (P = 0.632) also did not differ significantly. The onset age of schizophrenia and tardive dyskinesia (evaluated with Abnormal Involuntary Movements Scale) were similar within the three A2aAR genotypic groups. Our findings suggest that it is unlikely that the A2aAR 1976T > C polymorphism plays a major role in the pathogenesis of PD, schizophrenia, or antipsychotic-induced tardive dyskinesia in the Chinese population.     

Onset-age dependent MRI based hippocampal volume asymmetries in intractable partial complex temporal lobe epilepsy

The purpose of this study was to determine whether the age at onset of temporal lobe epilepsy influences hippocampal volume. Fifteen right-handed patients with medically intractable partial complex epilepsy of temporal origin were studied in quantified magnetic resonance imaging (MRI) and neuropsychological tests. In seven patients (mean age: 24 years) epilepsy began before the age of three (? YOUNG), in eight patients (mean age: 29 y) after the age of three (= OLDER). Education, social integration, duration of epilepsy and seizure frequency were equal in YOUNG and OLDER. The mean hippocampal volume, after normalization to total intracranial volume was for the right and for the left side smaller in YOUNG than in OLDER (p ≤ 0.02). The side-to-side asymmetry of absolute hippocampal volume was in patients with left-side focus more pronounced in YOUNG than in OLDER (p < 0.03). The number of patients with right-side focus was too small for statistical analysis. Results of neuropsychological testing showed no significant differences between YOUNG and OLDER. Onset-age of epilepsy before three years is associated with a higher risk of bilateral hippocampal hypotrophy and unilateral hippocampal asymmetry. Performance in neuropsychological testing seems not to be significantly influenced by hippocampal volume or age at onset.     

Asymmetry analysis of deformable hippocampal model using the principal component in schizophrenia

The hippocampus is thought to play an important role in learning and memory processing, and impairments in memory, attention, and decision making are found commonly in schizophrenia. Although many studies have reported decreases in hippocampal volume in the left hemisphere in schizophrenia, regionally specific hippocampal volume loss has not been revealed consistently using volume analysis. Recently, many studies have analyzed shape asymmetry using 3-D models; however, inconsistent results have been reported, mainly due to methodologic differences. We therefore used an active, flexible, deformable shape model for surface parameterization, and compared shape asymmetry based on principal component analysis (PCA) in the hippocampi of schizophrenic patients with those of the normal controls. Although the overall pattern of the statistical results did not change according to the number of principal components, the reconstructed results based on six major components were much more distinguishable. Although the left hemispheric hippocampal volume was larger than the right hemispheric was in this study, the difference was not significant. In shape asymmetry analysis, the right hemisphere hippocampus was bilaterally larger than the left hemisphere hippocampus was in the head of the superior CA1 and smaller in the tail and head of the inferior CA1. The asymmetry in the schizophrenia group was statistically smaller than that in the control group through reduction of the left hemisphere hippocampus volume.     

Identification of the N-acylsphingosine amidohydrolase 1 gene (ASAH1) for susceptibility to schizophrenia in a Han Chinese population

Abstract

Objectives. To study the involvement of the N-acylsphingosine amidohydrolase 1 gene (ASAH1) in the susceptibility to schizophrenia in the Han Chinese population. Methods. We performed cDNA microarray analysis to exam the gene expression profile in six schizophrenic patients and six healthy controls. We evaluated the ASAH1 expression levels in 30 subjects with chronic schizophrenia and 30 healthy controls by using real-time polymerase chain reaction (PCR). A total of 254 unrelated probands with schizophrenia and their biological parents were also genotyped at three single nucleotide polymorphisms (SNPs: rs3753118, rs3753116, and rs7830490) of the ASAH1 gene for association analysis. Results. In the microarray analysis, the ASAH1 gene was down-regulated in all schizophrenic patients compared with healthy controls. In real-time PCR, the ASAH1 expression levels for schizophrenic patients with positive family history were significantly decreased (P = 0.020). In the association analyses, two SNPs (rs7830490 and rs3753118) and one haplotype (rs7830490 (A)-rs3753116 (G)) of ASAH1 showed significant evidence of nominal associations with schizophrenia (P = 0.026; P = 0.046; P = 0.007, respectively). The haplotype remained statistically significant (empirical P = 0.045) after correction for multiple testing. Conclusions. This study supports that the ASAH1 gene may be a potential candidate gene for schizophrenia in Han Chinese subjects.     

Left posterior hippocampal density reduction using VBM and stereological MRI procedures in schizophrenia

Structural deficits in the hippocampus have been implicated in the pathophysiology of schizophrenia. However the role played by structural impairments in the hippocampus in the memory deficits of schizophrenic patients remains unclear. Magnetic resonance imaging was used in this study to investigate left, right, anterior and posterior hippocampal volume and density in 28 schizophrenic patients and 33 normal controls. Voxel-based morphometry analysis showed that schizophrenics had significantly lower density in the right and posterior hippocampus than controls. MRI stereological analysis revealed significant differences in left posterior hippocampus than controls. MRI stereological analysis revealed significant differences in anterior and posterior on both sides, with the left posterior region predominating. Schizophrenics showed significant impairments in verbal learning and long term retention (P<0.001). The correlation analyses between hippocampal density and memory variables yielded a significant correlation between forgetting and density of the anterior hippocampus. These findings support the hypothesis of a regional atrophy within the hippocampus in schizophrenic patients.     

P50 sensory gating deficit is a common marker of vulnerability to bipolar disorder and schizophrenia

Objective: P50 gating in schizophrenia has contributed much to our understanding of the pathophysiology of the illness. We examined euthymic bipolar patients to determine if they also have a P50 gating deficit. Method: P50 gating was measured in 81 euthymic bipolar patients (50 with a lifetime history of psychotic symptoms), 92 stable schizophrenic patients, and 67 control subjects. Results: P50 gating was significantly lower in control subjects than in bipolar patients with a lifetime history of psychosis (P = 0.001) and schizophrenic patients (P = 0.0001). In all patient groups, the percentage of patients with P50 gating was higher than in the control group (χ² = 30.596; P < 0.0001). There was no statistically significant correlation between P50 gating and other clinical variables. Conclusion: Our data suggest that P50 gating deficit is a neurobiological marker that is present in stable schizophrenic patients and euthymic bipolar patients.     

Hippocampal volume reduction in schizophrenia: effects of genetic risk and pregnancy and birth complications.

BACKGROUND: Hippocampal volume reduction has been repeatedly demonstrated in schizophrenia. The relative contribution of genetic and environmental factors to this is unclear. METHODS: To address this question, we compared volumetric measurements of the left and right hippocampus, obtained using stereological methods from brain MRI scans, from two groups of patients with schizophrenia as well as healthy controls (n = 26). Patients (n = 27) in the first group, had no family history of schizophrenia and had experienced severe pregnancy and birth complications (PBCs). The second group comprised of patients (n = 21) without a history of severe PBCs from families multiply affected with schizophrenia. RESULTS: Reduction of the left hippocampal volume was associated with the diagnosis of schizophrenia but was present only in patients with a history of severe PBCs; in this group the smaller hippocampal volume, the earlier the onset of psychosis. CONCLUSIONS: Our findings suggest that environmental factors, in this case severe PBCs, make a significant contribution to hippocampal abnormalities in schizophrenia.     

Frontotemporoparietal asymmetry and lack of illness awareness in schizophrenia

Introduction: Lack of illness awareness or anosognosia occurs in both schizophrenia and right hemisphere lesions due to stroke, dementia, and traumatic brain injury. In the latter conditions, anosognosia is thought to arise from unilateral hemispheric dysfunction or interhemispheric disequilibrium, which provides an anatomical model for exploring illness unawareness in other neuropsychiatric disorders, such as schizophrenia. Methods: Both voxel‐based morphometry using Diffeomorphic Anatomical Registration through Exponentiated Lie Algebra (DARTEL) and a deformation‐based morphology analysis of hemispheric asymmetry were performed on 52 treated schizophrenia subjects, exploring the relationship between illness awareness and gray matter volume. Analyses included age, gender, and total intracranial volume as covariates. Results: Hemispheric asymmetry analyses revealed illness unawareness was significantly associated with right < left hemisphere volumes in the anteroinferior temporal lobe (t = 4.83, P = 0.051) using DARTEL, and the dorsolateral prefrontal cortex (t = 5.80, P = 0.003) and parietal lobe (t = 4.3, P = 0.050) using the deformation‐based approach. Trend level associations were identified in the right medial prefrontal cortex (t = 4.49, P = 0.127) using DARTEL. Lack of illness awareness was also strongly associated with reduced total white matter volume (r = 0.401, P < 0.01) and illness severity (r = 0.559, P < 0.01). Conclusion: These results suggest a relationship between anosognosia and hemispheric asymmetry in schizophrenia, supporting previous volume‐based MRI studies in schizophrenia that found a relationship between illness unawareness and reduced right hemisphere gray matter volume. Functional imaging studies are required to examine the neural mechanisms contributing to these structural observations. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.     

Hippocampal volume in schizophrenia and its relationship with risperidone treatment: a stereological study

The purpose of this study was to assess the significance of the hippocampal volume differences and its relation with risperidone treatment in schizophrenia. In schizophrenic patients who were on risperidone treatment (n = 11) and in healthy volunteers (n = 11), volumes of the hippocampi were estimated using magnetic resonance images (MRIs). A detailed systematic series of coronal MRIs of the entire brain (3 mm thickness, T(1)-weighted, TR/TE 400/10 ms) was obtained for each subject. All estimations were done according to Cavalieri's method by a modified point-counting grid placed on surface areas of hippocampal slices. The mean right and left hippocampal volumes in schizophrenics and control subjects were 1059.4 and 1003.2 mm(3), and 1780.1 and 1589.1 mm(3), respectively. The corresponding coefficients of errors were 0.05 and 0.068, and 0.059 and 0.081, respectively. The volumes of left and right hemispheres were not significantly different in both schizophrenic patients and controls (p > 0.05). However, a statistically significant difference (p < 0.05) was found between hippocampal volumes of the schizophrenic patients and controls. In conclusion, the hippocampal volume of the schizophrenic patients is significantly smaller than of the healthy controls. The patients who responded well to risperidone treatment had significantly greater hippocampal volumes than the patients who did not respond properly. Thus, hippocampal volume may be a predictor of the treatment response of schizophrenics to risperidone.     

Interleukin-1 beta gene polymorphism and its interactions with neuregulin-1 gene polymorphism are associated with schizophrenia

Interleukin-1β (IL-1β) and neuregulin-1 (NRG-1) have an important role in development of the central nervous system. Several recent studies suggest that their genetic polymorphisms are associated with schizophrenia. We studied the effects of the IL-1β gene (IL-1B) -511 and NRG-1 SNP8NRG221533 polymorphisms and their interactions on the risk and age of onset of schizophrenia in 113 Finnish schizophrenic patients and 393 healthy controls. The allele and genotype frequencies of IL-1B and NRG-1 did not differ between schizophrenic patients and healthy controls, but the risk of schizophrenia was more than 10 times higher (odds ratio 10.20, 95% CI 2.53–41.09, p = 0.001) among subjects with the IL-1B 2.2, NRG-1 CC genotypes compared to subjects with the IL-1B 2.2, NRG-1 T-allele carriage. There was also a trend for an association between the interaction between IL-1B and NRG-1 polymorphisms and the age at onset of schizophrenia (χ² = 2.80; df = 1; p = 0.09, log rank test). IL-1B-511 allele 1 homozygotes had a significantly higher age of onset than allele 2 carriers (mean age of onset 25.9 ± 7.7 and 22.7 ± 5.4 years, t-test: t = 2.46; p = 0.032). Our results suggest that there is an interaction between the IL-1B and NRG-1 genes in schizophrenia. In addition, the IL-1B-511 polymorphism seems to be associated with the age at onset of schizophrenia.     

Cross‐education after high‐frequency versus low‐frequency volume‐matched handgrip training

Introduction: Cross‐education training programs cause interlimb asymmetry of strength and hypertrophy. We examined the cross‐education effects from a high‐frequency (HF) versus a low‐frequency (LF) volume‐matched handgrip training program on interlimb asymmetry. Methods: Right‐handed participants completed either HF (n = 10; 2 × 6 repetitions 10 times per week) or LF (n = 9; 5 × 8 repetitions 3 times per week) training. Testing occurred twice before and once after 4 weeks of right‐handed isometric handgrip training totaling 120 weekly repetitions. Measures were maximal isometric handgrip and wrist flexion torque, muscle thickness, and muscle activation (electromyography; EMG). Results: Grip strength was greater in both limbs posttraining, pooled across groups (P < 0.001). Trained limb muscle thickness increased in both groups (P < 0.05; untrained, P = 0.897). EMG and wrist flexion torque did not change (all P > 0.103). Discussion: Both LF and HF induced cross‐education of grip strength to the untrained limb, but HF did not reduce asymmetry. These findings have implications for injury rehabilitation. Muscle Nerve 56 : 689–695, 2017     

The hippocampus in families with schizophrenia in relation to obstetric complications

BACKGROUND: Hippocampal volume reduction is a well replicated finding in schizophrenia. Evidence indicates a contribution of genetic and environmental factors, especially the influence of obstetric complications to this volume reduction. The aim of this study was to compare hippocampal volume of schizophrenic patients as well as and their relatives with control subjects and to quantify the additional contribution of obstetric complications. METHODS: T1 weighted MRI brain scans of 50 schizophrenic patients, 88 first-degree relatives and 53 healthy control subjects were used to perform volumetric measurements on the left and right hippocampus. A set of clinical measures including obstetric complications were recorded for all family members. RESULTS: Numerically our measurements revealed a hippocampal volume reduction in schizophrenic patients (left: - 14%, right: - 15%) and, although less pronounced, in their unaffected relatives (left: - 6%, right: - 10%). Noted differences in hippocampal volume between schizophrenic patients and controls were only significant for the left side. Hippocampal volumes of patients and their relatives with obstetric complications were reduced bilaterally. CONCLUSIONS: Hippocampal volume reduction is present in schizophrenic patients and their first-degree relatives, suggesting an influence of genetic factors.. In addition, however, obstetric complications have also been shown to play a major role.     

Volumetric MRI, pathological, and neuropsychological progression in hippocampal sclerosis

OBJECTIVE: To examine the relationships between age at onset and duration of seizure disorder with severity of hippocampal sclerosis (HS) and cognitive functioning in patients with HS and unilateral temporal lobe epilepsy. METHODS: Twenty-six subjects had left temporal lobe seizure onset; 20 had right temporal onset. Measures were age at seizure onset, duration of seizure disorder divided by age (seizure duration), history of febrile convulsion (FC), ratio of the smaller hippocampal volume to the larger (HF) as determined by volumetric MRI, and pathologic HS grade. RESULTS: Results showed that pathologic HS grade and HF were positively related to seizure duration, and negatively related to seizure onset. When subjects were divided into onset prior to age 10 versus later, subjects with earlier onset had higher mean pathologic HS grade and smaller (more asymmetric) mean HF. When subjects were divided into seizure duration <0.5 (i.e., less than half current lifetime) vs greater, subjects with seizure duration > or =0.5 had higher mean pathologic HS grade and lower mean HF. There was also evidence for earlier age at seizure onset and longer seizure duration being associated with worse performance on neuropsychological measures. FC was not related to either seizure duration or age at seizure onset, but patients with a history of FC showed higher pathologic HS grade and lower HF. A history of FC was not related to cognitive functioning. CONCLUSIONS: Unilateral HS patients with earlier seizure onset and longer duration of epilepsy have more severe HS and greater hippocampal volume asymmetry. This suggests that HS may be a progressive disorder with risk for cognitive dysfunction.     

Ultrastructural abnormalities of astrocytes in the hippocampus in schizophrenia and duration of illness: A postortem morphometric study

There is a lot of evidence of astrocytic dysfunction in schizophrenia. We performed an electron microscopic morphometric study of astrocytes in the CA3 hippocampal region in 19 cases of schizophrenia and 16 normal controls. No significant group differences were found in cell size, volume fraction (Vv) and area density (Na) of mitochondria and lipofuscin granules. Young control subjects (<50 years old) had significantly lower area of cell, nucleus and cytoplasm and higher Vv and Na of mitochondria than old controls (>50 years old), and young and old schizophrenic cases. No significant differences between young and old schizophrenic subgroups were found. Vv and Na of mitochondria correlated negatively (r=?0.66, r=?0.72, P<0.01) and Vv of lipofuscin granules correlated positively (r=0.72, P=0.001) with duration of illness. These parameters did not correlate with age in controls and in schizophrenic subjects. Both Vv and Na of mitochondria were significantly lower in the subgroup of cases with duration of disease of>21 years. than in the control group and in the subgroup of cases with duration of illness of<21 years (P<0.01). The data suggest progressive disturbances of astrocyte function due to the deficit of mitochondria in schizophrenia.     

Effects of common <Emphasis Type="Italic">GRM5</Emphasis> genetic variants on cognition,hippocampal volume and mGluR5 protein levels in schizophrenia

GRM5 (coding for metabotropic glutamate receptor 5, mGluR5) is a promising target for the treatment of cognitive deficits in schizophrenia, but there has been little investigation of its association with cognitive and brain phenotypes within this disorder. We examined the effects of common genetic variation in GRM5 with cognitive function, hippocampal volume, and hippocampal mGluR5 protein levels in schizophrenia patients relative to healthy controls. Two independent GRM5 variants rs60954128 [C>T] and rs3824927 [G>T] were genotyped in a schizophrenia case/control cohort (n=249/261). High-resolution anatomical brain scans were available for a subset of the cohort (n=103 schizophrenia /78 control). All participants completed a standard set of neuropsychological tests. In a separate postmortem cohort (n=19 schizophrenia/20 controls), hippocampal mGluR5 protein levels were examined among individuals of different GRM5 genotypes. Schizophrenia minor allele carriers of rs60954128 had reduced right hippocampal volume relative to healthy controls of the same genotype (?12.3%); this effect was exaggerated in males with schizophrenia (?15.6%). For rs3824927, compared to major allele homozygotes, minor allele carriers with schizophrenia had lower Intelligence Quotients (IQ). Examination in hippocampal postmortem tissue showed no difference in mGluR5 protein expression according to genotype for either rs60954128 or rs3824927. While these genetic variants in GRM5 were associated with cognitive impairments and right hippocampal volume reduction in schizophrenia, they did not affect protein expression. Further study of these mechanisms may help to delineate new targets for the treatment of cognitive deficits in schizophrenia, and may be relevant to other disorders.     

Hippocampal volume in familial and nonfamilial schizophrenic probands and their unaffected relatives.

BACKGROUND: There is evidence for hippocampal volume loss in schizophrenia, but the etiology of this remains unclear. The aim of our study was to assess the contribution of familial liability and obstetric complications to hippocampal volume reduction in schizophrenia. METHODS: Hippocampal volumes were obtained using stereological methods from magnetic resonance scans performed on 35 schizophrenic probands from multiply affected families and 63 of their unaffected relatives, as well as 31 schizophrenic probands from families with no other affected members, 33 of their unaffected relatives, and 68 control subjects. RESULTS: Probands with schizophrenia, regardless of family history, had significant volume reduction of the left hippocampus. Hippocampal volume was not significantly reduced in either group of relatives. Obstetric complications were associated with left hippocampal volume reduction. CONCLUSIONS: We failed to find evidence that hippocampal volume loss is associated with familial liability to schizophrenia but have confirmed the association between hippocampal volume reduction and exposure to obstetric complications.