Original ArticlesThalamic and amygdala–hippocampal volume reductions in first-degree relatives of patients with schizophrenia: an MRI-based morphometric analysis
Introduction
Schizophrenia is a complex, often catastrophic, illness characterized by dysfunctions in thought, affect, social behavior, and neurocognition. In an effort to characterize brain alterations in schizophrenia, more than 200 neuroimaging and postmortem studies have investigated structural brain abnormalities in patients Bogerts 1993, Shenton et al 1997. Although no discrete brain area is abnormal consistently, and clinical–pathologic correlations have yet to be documented with certainty (Heckers 1997), the data tend to indicate a distributed abnormal circuitry involving (at least) prefrontal and temporal lobes, limbic and paralimbic structures, the thalamus, and basal ganglia Andreasen et al 1998, Buchsbaum 1990, Seidman 1983, Weinberger et al 1992.
Despite heterogeneity of patient samples and methodologies, structural neuroimaging studies consistently implicate subtle abnormalities in the limbic system and enlargement of the third and lateral ventricles. The enlargement of the lateral ventricles is probably one of the most consistently replicated biological findings in patients with schizophrenia. Abnormalities found in the thalamus, frontal lobe, corpus callosum, superior temporal gyrus, basal ganglia, cerebellum, and septum pellucidum have been less consistently reported using magnetic resonance imaging (MRI) (Shenton et al 1997) or postmortem tissue (Heckers 1997). Postmortem studies have also demonstrated subtle anomalies in limbic and paralimbic structures, including hippocampus, parahippocampal gyrus, entorhinal cortex, amygdala, cingulate, and septum (Heckers 1997). Thus, there is some convergence between morphometric and neurohistologic studies, most consistently implicating dysfunction in limbic and temporal lobe sites (Shenton et al 1997).
Genetic factors play a substantial role in the etiology of schizophrenic disorders, and these factors may contribute to the predisposition to schizophrenia through brain abnormalities Gottesman 1991, Tsuang 1993. However, despite substantial evidence of genetic involvement and brain abnormalities in schizophrenia, few data indicate which specific brain regions and processing deficits are genetically linked (Seidman 1997). Because studies of the pathophysiology of genetically at risk subjects can further refine the search for useful phenotypes for genetic studies, many investigators have studied nonpsychotic relatives of schizophrenic persons to search for measures that would reflect their unexpressed vulnerability to the disorder (Faraone et al 1995a). Moreover, studies of nonpsychotic relatives are not confounded by antipsychotic drug treatment, chronic hospitalization, and the potential neurotoxic effects of psychosis (Wyatt 1995). Thus, the study of relatives of schizophrenic patients provides potential evidence of vulnerability to the illness, identification of phenotypic markers, and a window into the core pathophysiology of the disorder less burdened by confounds than studies of patients.
Studies of biological relatives of schizophrenic patients have identified a wide range of abnormalities typically found in persons with schizophrenia, although the deficits in relatives are generally milder than in patients (Seidman 1997). Substantial data indicate that both child and adult relatives of patients with schizophrenia are at risk for a variety of biobehavioral abnormalities, even when they do not manifest “schizophrenia-like” or “spectrum” diagnoses such as schizotypal personality (SPD) or psychotic disorders (Olin and Mednick 1996). Studies of adult relatives, who are assessed after the peak ages of risk (which is typically from 20 to 35 years of age) for schizophrenia, are unlikely to contain subjects who will develop schizophrenia, and thus offer a sample of genetically at risk but “unaffected” relatives. These data are useful for distinguishing the latent abnormalities that are presumably part of the genetic vulnerability to schizophrenia apart from the illness itself (endophenotypes). Adult relatives of schizophrenic patients have, for example, increased prevalences of: schizotypal and paranoid personality traits (Lenzenweger 1994), eye-tracking dysfunctions (Levy et al 1994), attentional impairment (Cornblatt and Keilp 1994), flat affect (Tsuang et al 1991), thought disorder (Shenton et al 1989), neurologic signs (Erlenmeyer-Kimling et al 1982), cognitive impairments in executive functions and memory (Kremen et al 1994), backward masking deficits (Green et al 1997), and abnormal auditory evoked potentials (Friedman and Squires-Wheeler 1994). Neuropsychological deficits in attention and memory were shown to be relatively stable over a 4-year period (Faraone et al 1999).
These findings suggest that components of the neurobiological predisposition to schizophrenia could be expressed in the relatives of schizophrenic patients as structural brain abnormalities that occur independent of psychosis. Although there are relatively few brain imaging studies of nonpsychotic adult relatives of schizophrenic patients, some studies have tended to demonstrate structural abnormalities (Cannon and Marco 1994). Not surprisingly, most studies using computed tomography (CT) demonstrated more abnormalities (typically ventricular enlargement) in patients with schizophrenia than in unaffected relatives Cannon and Marco 1994, Delisi et al 1986, Reveley et al 1982, Silverman et al 1998, Weinberger et al 1981, Zorilla et al 1997. However, some studies showed that cortical anomalies and ventricular enlargement increased with genetic risk in nonpsychotic offspring of schizophrenic subjects (Cannon et al 1993), and that adult nonpsychotic siblings also had enlarged ventricles (Weinberger et al 1981).
Compared with CT studies, MRI studies have the advantage of greater spatial resolution, particularly for identification and measurement of subcortical gray structures thought to be important in schizophrenia (e.g., amygdala–hippocampus, thalamus). The relatively recent application of MRI to the investigation of brain structure in relatives of schizophrenic patients has yielded findings similar to those obtained by CT. That is, the general tendency is to find greater volume loss in the brains of schizophrenic patients than the biological relatives of patients Sharma et al 1998, Suddath et al 1990, although the unaffected relatives may also have abnormalities (such as enlarged lateral ventricles), particularly those with SPD or with an especially strong genetic loading for schizophrenia (Sharma et al 1998). In our pilot MRI study, we found that a group of six nonpsychotic, adult female siblings of schizophrenic patients had significant volume reductions in the amygdala–hippocampal region, putamen, thalamus, and brainstem compared to female control subjects (Seidman et al 1997). A subsequent MRI report demonstrated reduced cortical gray matter in unaffected siblings of schizophrenic patients (Cannon et al 1998). Staal and co-workers (1998) identified thalamic abnormalities in adult siblings of patients with schizophrenia. Adolescent offspring of persons with schizophrenia were found to have reduced left amygdala volume, enlarged third ventricle volume, and smaller overall brain volume than children of normal parents (Keshevan et al 1997). Thus, there is support for the hypothesis that structural brain abnormalities may be found in nonpsychotic relatives of schizophrenic patients, particularly in the subcortical regions commonly found to be abnormal in schizophrenic patients.
These data led us to carry out a more systematic study of a larger sample of adult relatives of patients with schizophrenia. Based on previous work, including our pilot study, we hypothesized that subcortical regions thought to be crucial in the pathology of schizophrenia and showing reasonably consistent abnormalities in patients with schizophrenia (i.e., amygdala–hippocampal region and thalamus) would be significantly different in first-degree relatives of schizophrenic patients compared to control subjects without the predisposition to the illness. In a more exploratory vein, we also assessed whether other subcortical gray regions (e.g., basal ganglia structures) or ventricular structures would differ in first-degree relatives compared to control subjects.
Section snippets
Subjects and diagnostic procedures
All subjects were 20 to 65 years of age when scanned, had at least an eighth-grade education, English as their first language, and an estimated IQ of at least 70. The study criteria for all subjects required absence of: 1) substance abuse within the past 6 months; 2) history of head injury with documented cognitive sequelae or loss of consciousness greater than five minutes; 3) neurologic disease or damage; and 4) medical illnesses that significantly impair neurocognitive function. After
Demographic, clinical, and cognitive measures
The groups did not differ significantly on age, gender, parental social-economic status (SES), ethnicity, handedness, years of education, IQ estimate (and on its component subtests, Vocabulary and Block Design), or on global assessment of social functioning (GAS) (see Table 1). Relatives performed significantly worse than control subjects on the WRAT-R reading test (t[53] = 2.5, p < .05), a measure of expected intellectual ability (Kremen et al 1995). While there was no significant difference
Discussion
We found substantial support for the hypothesis that nonpsychotic, adult relatives of schizophrenic patients have structural brain abnormalities in some subcortical regions found to be abnormal in schizophrenia. Using a comprehensive segmentation of MR-derived brain images, and two different statistical methods, we found that compared to control subjects, relatives had significant, bilateral volume reductions in the amygdala–hippocampal region and in thalamus. There was weaker and inconsistent
Acknowledgements
Preparation of this article was supported in part by the National Institute of Mental Health Grants MH 43518 and MH 46318 to Dr. Ming T. Tsuang, Stanley Foundation Awards to Dr. Larry J. Seidman, National Institute of Mental Health Grants SDA K21 MH 00976 and MH 56956 to Dr. Jill M. Goldstein, a Scottish Rite Dissertation Fellowship Award to Dr. Julie M. Goodman, and a grant from the Fairway Trust to Dr. David Kennedy.
This work was presented, in part, as a poster at the Sixth International
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