0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Article |

Left Hippocampal Volume as a Vulnerability Indicator for Schizophrenia:  A Magnetic Resonance Imaging Morphometric Study of Nonpsychotic First-Degree Relatives FREE

Larry J. Seidman, PhD; Stephen V. Faraone, PhD; Jill M. Goldstein, PhD; William S. Kremen, PhD; Nicholas J. Horton, ScD; Nikos Makris, MD, PhD; Rosemary Toomey, PhD; David Kennedy, PhD; Verne S. Caviness, MD, DPhil; Ming T. Tsuang, MD, PhD
[+] Author Affiliations

From the Department of Psychiatry, Massachusetts Mental Health Center, Boston (Drs Seidman, Faraone, Goldstein, Toomey, and Tsuang), the Department of Psychiatry, Brockton/West Roxbury Veterans Affairs Medical Center, Brockton, Mass (Drs Seidman, Faraone, Goldstein, Toomey, and Tsuang), the Department of Psychiatry at Massachusetts General Hospital, Boston (Drs Seidman, Faraone, Goldstein, and Tsuang), Harvard Institute of Psychiatric Epidemiology and Genetics, Cambridge, Mass (Drs Seidman, Faraone, Goldstein, Toomey, and Tsuang); Department of Psychiatry, Davis School of Medicine, University of California– Davis Napa Psychiatric Research Center, Sacramento, Calif (Dr Kremen); Department of Epidemiology and Biostatistics, Boston University School of Public Health, Boston (Dr Horton), Department of Medicine, Boston University School of Medicine, Boston (Dr Horton), the Departments of Neurology and Radiology Services, Harvard Medical School, and the Center for Morphometric Analysis, Massachusetts General Hospital, Boston (Drs Makris, Kennedy and Caviness), and the Department of Epidemiology, Harvard School of Public Health, Boston (Dr Tsuang).


Arch Gen Psychiatry. 2002;59(9):839-849. doi:10.1001/archpsyc.59.9.839.
Text Size: A A A
Published online

Background  Clues to the causes of schizophrenia can be derived from studying first-degree relatives because they are genetically related to an ill family member. Abnormalities observed in nonpsychotic relatives are indicators of possible genetic vulnerability to illness, independent of psychosis. We tested 4 hypotheses: (1) that hippocampal volume is smaller in nonpsychotic relatives than in controls, particularly in the left hemisphere; (2) that hippocampi will be smaller in multiplex relatives as compared with simplex relatives, and both will be smaller than in controls;(3) that hippocampal volumes and verbal declarative memory function will be positively correlated; and (4) that hippocampi will be smaller in patients with schizophrenia than in their nonpsychotic relatives or in controls.

Methods  Subjects were 45 nonpsychotic adult first-degree relatives from families with either 2 people ("multiplex," n = 17) or 1 person ("simplex," n = 28) diagnosed with schizophrenia, 18 schizophrenic relatives, and 48 normal controls. Sixty contiguous 3-mm coronal, T1-weighted 3-dimensional magnetic resonance images of the brain were acquired on a 1.5-T magnet. Volumes of the total cerebrum and the hippocampus were measured.

Results  Compared with controls, relatives, particularly from multiplex families, had significantly smaller left hippocampi. Verbal memory and left hippocampal volumes were significantly and positively correlated. Within families, hippocampal volumes did not differ between schizophrenic patients and their nonpsychotic relatives.

Conclusions  Results support the hypothesis that the vulnerability to schizophrenia includes smaller left hippocampi and verbal memory deficits. Findings suggest that smaller left hippocampi and verbal memory deficits are an expression of early neurodevelopmental compromise, reflecting the degree of genetic liability to schizophrenia.

Figures in this Article

CURRENT perspectives on the cause of schizophrenia have focused attention on neurobiological vulnerability to the illness.13 Children at risk for schizophrenia, and nonpsychotic adult relatives manifest electrophysiological, neurocognitive, symptomatic, and behavioral abnormalities, usually to a milder degree than patients with frank psychosis.4,5 A few magnetic resonance imaging (MRI) studies of the brain in relatives have demonstrated abnormalities in structures relevant to schizophrenia.68 Both younger911 and older1216 nonpsychotic relatives manifest volumetric abnormalities, especially in the hippocampus-amygdala region and in the thalamus, suggesting that these abnormalities, at least in part, reflect vulnerability to the illness. Advances in understanding the biological vulnerability to schizophrenia will be facilitated by increasing the precision of measurement of the abnormalities, by evaluating whether putatively linked risk factors are related to each other (ie, left hippocampus and verbal declarative memory), and by determining whether these deficits are associated with genetic factors.

Of the myriad manifestations of schizophrenia, structural brain abnormalities and neurocognitive deficits are among the most replicated findings. The most consistent MRI abnormalities are enlarged ventricles and smaller temporal lobe and limbic system volumes, particularly in the hippocampus.1719 Postmortem studies have also demonstrated subtle anomalies in limbic structures, most consistently in the hippocampus,20 including reduced neuronal size and reduced levels of synaptic proteins.21,22 The hippocampus is considered to be important,2022 especially because of its role in learning and memory.2325 Some lateralized temporal lobe abnormalities have been observed in schizophrenia(more often left-sided),26 and some have proposed that this pattern reflects a genetic, neurodevelopmental vulnerability.27

Verbal declarative or "explicit" memory (the conscious recollection of words, stories, or events) is one of the most robustly impaired neurocognitive functions in schizophrenia.28,29 It is commonly impaired in diseases affecting the "medial temporal lobe memory system," particularly the left hippocampus.23,30 These findings suggest that hippocampal abnormalities, especially left-sided ones, and verbal memory deficits are associated candidates for vulnerability indicators.

The study of biological relatives is a valuable strategy used to investigate vulnerabilities to schizophrenia.57 Abnormalities in relatives may provide clues to the cause of the illness, suggesting potential genetic effects.31,32 Unlike patients, nonpsychotic relatives are not affected by antipsychotic medications, hospitalization, and putative neurotoxic effects of psychosis. Adult relatives, who have passed through the peak age of risk for psychosis(20-35 years) are unlikely to develop schizophrenia, and thus may manifest abnormal traits associated with vulnerability and not with psychosis.33

Our prior work suggests that verbal declarative memory34,35 and hippocampal volume13 might represent genetic markers of vulnerability to schizophrenia. Most researchers agree that a single gene theory is untenable, even if that theory allows for many different single gene variants.33,3639 The multifactorial model of schizophrenia has found some, although not complete, support.33,3639 In accordance with the multifactorial model, the amount of impairment in relatives should increase with their genetic loading for schizophrenia. Supporting this hypothesis, verbal memory was significantly worse in nonpsychotic persons from "multiplex" families (containing 2 first-degree relatives with schizophrenia) compared with persons from "simplex" families (containing 1 first-degree relative with schizophrenia).40 Other investigators have found similar results assessing "integrative" neurological signs.41

Based on this model, we tested 4 hypotheses. First, hippocampal volume will be smaller in relatives than in normal controls, and the abnormalities will be primarily left-sided. Second, hippocampal volume will be smaller in multiplex, as compared with simplex relatives, and both will be smaller than in controls. Third, hippocampal volume and verbal memory will be significantly and positively correlated. Fourth, hippocampal volumes will be smaller in patients with schizophrenia than in their nonpsychotic relatives or in controls.

SUBJECTS

Subjects comprised an extended sample from a previous study.13,34 Subjects (45 nonpsychotic, first-degree relatives of schizophrenic patients, 48 controls, and 18 patients with schizophrenia) were 20 to 68 years of age, had at least an eighth-grade education, with English as their first language, and an estimated IQ of at least 70. Exclusion criteria were (1) substance abuse within the past 6 months; (2) head injury with documented cognitive sequelae or loss of consciousness greater than 5 minutes; (3) neurologic disease; and (4) medical illnesses that impair neurocognitive function.

After describing the study, written informed consent was obtained, including permission by the schizophrenic patients ("probands") for us to contact their relatives. DSM-III-R42 diagnoses in patients were established using the Schedule for Affective Disorders and Schizophrenia43 or Diagnostic Interview for Genetic Studies,44 and a systematic review of the medical record. Substance use was assessed by a semi-structured interview to determine quantity, frequency, and duration of use.34 Blindness of assessments was maintained among psychiatric, neuropsychological, and MRI data.

Relatives

Relatives were free of psychosis during their lifetime. There were 28 simplex (16 siblings, 7 offspring, 5 parents) and 17 multiplex (16 siblings, 1 offspring) relatives from 34 unique families. Twenty-six families provided a single relative, 3 families had 3 relatives, and 5 families had 2 relatives. All available relatives were interviewed to determine if the family was simplex or multiplex. Relatives were interviewed with the Structured Clinical Interview for DSM-III-R45 or Diagnostic Interview for Genetic Studies for Axis I disorders, and the Structured Interview for DSM-III Personality Disorders.46 Fifty-six percent had nonpsychotic diagnoses—mainly Axis I disorders such as past major depressive disorder or substance abuse. One relative had schizotypal personality disorder. Three relatives had received a psychotropic medication (1 antianxiety and 2 antidepressant medications).

We also analyzed a subset of 18 (of 45) relatives (8 males, 10 females) from the 13 families who had a proband with schizophrenia who had an MRI scan. This sample included 1 father, 2 mothers, 13 siblings (6 sisters, 7 brothers), and 2 daughters of patients. Nine families had 1, three families had 2, and 1 family had 3 nonpsychotic relatives. Thirteen were from multiplex families, and 5 were from simplex families.

Patients With Schizophrenia

Eighteen patients participated. They are a subset of 90 patients (40 simplex and 50 multiplex) with schizophrenia who had received an MRI scan, and have been described elsewhere.47,48 There were 10 males and 8 females from 13 families (4 simplex, 9 multiplex). Of the 9 multiplex families, 5 had 2 ill members, and 4 had 1 member.

Healthy Controls

Forty-eight controls came from unrelated families acquired through advertisements in the catchment areas of the hospitals, from which the patients had been ascertained. Our goal was to acquire demographically similar controls as patients and relatives. Controls underwent a similar screening process, as did other subjects, except, as in our previously published studies with this control sample,12,13,34,35,40 they were screened for current psychopathological disorders using a short form of the Minnesota Multiphasic Personality Inventory (MMPI-168)49 rather than interviewed. We excluded potential controls if they had a personal or family history of psychosis or psychiatric hospitalization, or had MMPI elevations above 70 on the clinical scales. Controls were also administered the substance use section of the Schedule for Affective Disorders and Schizophrenia. We did not screen for a lifetime history of psychopathological or neuropsychological dysfunction. In choosing a control group, we attempted to balance 2 competing sources of bias. Unscreened controls frequently have rates of psychopathology and neuropsychological dysfunction above the population expectation.5052 Thus, unscreened controls can obscure the effects of interest. However, excessive screening of controls can exaggerate the effects of interest.53,54 The data we collected from tests having extensive normative data provide some indication of the "normalcy" of our controls. The mean (SD) score for controls on the Wide Range Achievement Test—Revised (WRAT-R)55 reading subtest was 105.6 (11.1), well within the normal range. Two controls received antianxiety medications.

NEUROPSYCHOLOGICAL MEASURES

The vocabulary and block design tests of the Wechsler Adult Intelligence Scale—Revised56 estimated current intelligence,57 and the reading test of the WRAT-R estimated intellectual potential.58 Handedness was determined by questionnaire.59 Verbal declarative memory was assessed with the Logical Memory Stories test of the Wechsler Memory Scale—Revised.60 Data consisted of raw scores at immediate and 30-minute delayed recall and the percentage retained61 (delayed recall/immediate recall × 100).

MRI PROCEDURES
MRI Image Acquisition and Morphometric Analysis

Subjects received a brain MRI scan usually after neuropsychological testing (median, 36 days). The MRI scans were obtained at the Massachusetts General Hospital (MGH) on a General Electric 1.5-T Signa Scanner (Milwaukee, Wis). Image acquisitions included conventional sagittal scout, a coronal T2-weighted sequence to rule out gross pathology and a coronal volumetric T1-weighted spoiled gradient echo imaging sequence for morphometric analysis, using the following parameters: pulse sequence, 3D-SPGR (spoiled GRASS-gradient refocused acquisition in the steady-state); TR (time to repeat), 40 ms; TE (echo time), 8 ms; flip angle, 50°; field of view, 30 cm; slice thickness, 3.0 mm; number of slices, 60 contiguous coronal images of the entire brain; matrix, 256 × 256; number of excitations, 1.

Images were positionally normalized to overcome variations in head position by imposing a standard 3-dimensional brain coordinate system on each scan using the midpoints of the decussations of the anterior and posterior commissures and the midsagittal plane at the level of posterior commissure as points of reference for rotation and translation.62,63

Gray matter–white matter segmentation was performed on each T1-weighted, normalized, 3-dimensional coronal scan using a semiautomated intensity contour algorithm for external border definition, and signal intensity histogram distributions for demarcation of gray-white borders.64 Regions of interest for this study included total cerebrum and the hippocampus. Prior to measurement of the hippocampus, volumetric morphometry was undertaken by methods employed previously for a series of adult controls,62,63 and in our previous study, which included 54 of the 111 subjects whose cases are reported here.13 To measure the hippocampus, we applied a new, entirely manual, anatomically guided, segmentation boundary that was adapted from a procedure described previously65(Figure 1).

Place holder to copy figure label and caption
Figure 1.

Method of segmentation of the hippocampus (observed in radiological convention) as performed in our study(under the supervision of Nikos Makris, MD, PhD). Identification of the hippocampus is achieved using a cross-referencing tool,66 which allows visualization of the structure in 3 coregistered cardinal views(coronal, axial, and sagittal). A-F, Dotted lines (b, c, e, f) on sagittal slices (A) and (D) indicate where coronal slices (B and E) and axial slices(C and F) lie. D presents a more medial view compared with A, while the image in F is more superior to that in C, and the image in E is more posterior than that of B. Colored outlines separating the hippocampus from its neighboring structures are shown. Colored lines distinguish the structures. Specifically, 2 lines were drawn to demarcate the boundary between the anterior hippocampus and amygdala (A, B, and C) and the boundary between the hippocampus and posterior thalamus (D, E, and F). G-J, Segmentation of the hippocampus is shown in 4 representative coronal sections, which is determined by outlines previously drawn in sagittal (A and D) and axial (C and F) planes. G, Coronal slice in the anterior tip of the hippocampus (where it borders amygdala). H, Coronal slice is in the middle of the hippocampus. I, Coronal slice is in the posterior hippocampus (where it borders posterior thalamus). J, Coronal slice in the tail of the hippocampus. K, Dotted vertical lines g, h, i, and j indicate the corresponding coronal planes.

Graphic Jump Location
Anatomical Definition

In our MRI system, the hippocampus is based on an anatomical definition of hippocampal formation65(p40),66 that excludes the parahippocampal gyrus.

Segmentation Procedure

The amygdala and hippocampus are first defined as a continuous gray matter mass in the primary segmentation.63 They are then manually partitioned from each other at the rostral coronal plane where the hippocampus appears (Figure 1). This includes clearly defined segments of hippocampus in ventromedial relation to the anterior tip of the ventral horn of the lateral ventricle. The caudal pole of the amygdala is present in medial and superior relation to the hippocampus in the coronal plane.67 The anterior tip of the hippocampus is separated from the ventral and posterior border of the amygdala. Using lateral and sagittal views, one can distinguish and trace this border of the amygdala, which is usually enhanced by the anterior end of the temporal horn of the inferior lateral ventricle. In cross-reference, corresponding axial views help identify this border. In the coronal view, the saw-tooth pattern of the hippocampus is identified and traced.

INTERRATER RELIABILITY

In 16 blindly segmented brains, intraclass correlation coefficients(r) were 0.93 for total cerebral volume, 0.91 for the left hippocampus, and 0.92 for the right hippocampus.

VOLUMETRIC ANALYSIS

The volume of each structure was calculated by multiplying the number of voxels assigned to that structure on each slice by the slice thickness, and summing across all slices in which the structure appeared.

DATA ANALYSIS

Primary comparisons were made between controls, relatives from simplex families, and relatives from multiplex families. Analyses included tests of overall group effects, linear trends (control-simplex-multiplex), and pairwise comparisons between each group of relatives with each other and with controls. Additional analyses compared schizophrenia probands with a subgroup of their relatives, and with normal controls. In testing for hippocampal differences, total cerebral volume and potential confounds (age, sex, handedness, ethnicity, and parental education) were used as covariates in all analyses. Some analyses also included psychiatric diagnosis and IQ as covariates, or were based on subsets of these subject groups (eg, subjects 36 years and older were studied to evaluate effects in relatives who are very unlikely to experience the onset of schizophrenia). Statistical significance was P<.05(2-tailed).

Some families yielded more than 1 subject. Generalized estimating equations regression models account for the potential error in the estimation of standard errors of parameter estimates resulting from correlations between family members.68,69 The generalized estimating equations approach provides consistent estimates of means and SEs under weak assumptions about the population distribution of the data. We used a working independence correlation structure implemented in SAS PROC GENMOD (SAS Institute Inc, Cary, NC; Version 6.12). Heuristically, the observations are assumed to be independent, and an empirical variance estimator is used to account for clustering within families. Previous research has shown this to be a good choice for small sample sizes.70,71

DEMOGRAPHIC AND CLINICAL CHARACTERISTICS IN RELATIVES AND CONTROLS

Groups did not differ significantly on age, parental socioeconomic status,72 parental education, ethnicity, handedness, or use of alcohol and other drugs (Table 1). There were significant differences by sex, education, and estimated IQ, and a nonsignificant trend in reading (P<.10).

Table Graphic Jump LocationTable 1. Demographic Variables for Controls and Relatives of Patients With Schizophrenia*72,56,55,57

Our primary regression models included main effects for group, sex, age, handedness, ethnicity, parental education, and total cerebral volume. We found no significant evidence for pairwise interactions between sex, age, or total cerebral volume.

EFFECTS OF RELATIVE AND CONTROL STATUS ON HIPPOCAMPAL VOLUMES

There were no significant differences for total cerebral volume, but group differences were significant for left hippocampal volume (Table 2). A test of the linear trend of hippocampal volumes (control>simplex>multiplex) was significant (Table 3). Multiplex relatives had significantly smaller left hippocampi than simplex relatives(Table 3). Multiplex subjects had significantly smaller left hippocampi compared with controls (Table 3 and Figure 2A). As a percentage of the control volume, the left multiplex hippocampus was 9.3% smaller. The effect size, taking into account the confounders, was 1.0. Simplex relatives showed a trend (P<.10) toward significantly smaller volumes as compared with controls. The left simplex hippocampus was 4.8% smaller than the control volume. The effect size was 0.44. Results were similar when controlling for IQ. There were no significant differences or nonsignificant trends for any comparison of the right hippocampus; thus, in Table 3, we report only the statistical comparison of left hippocampi.

Table Graphic Jump LocationTable 2. Brain Volumes and Verbal Memory Performance in Controls and Relatives of Patients With Shizophrenia*40
Table Graphic Jump LocationTable 3. Regression Models for Left Hippocampus Analyzing Different Subsets of Relatives vs Controls*
Place holder to copy figure label and caption
Figure 2.

Left and right hippocampal volumes proportionally adjusted for total cerebral volume in control subjects, relatives of schizophrenics, and patients with schizophrenia. A, Comparison of controls and nonpsychotic relatives. B, Comparison of controls, nonpsychotic relatives, and patients with schizophrenia. Percent of total cerebral volume indicates hippocampal volume/total cerebral volume × 100; SEs are corrected for intrafamilial correlation.

Graphic Jump Location
EFFECTS OF RELATIVE AND CONTROL STATUS ON HIPPOCAMPAL VOLUMES IN SUBGROUPS OF RELATIVES

Although sample sizes were smaller, results for relatives who would be highly unlikely to develop schizophrenia (those 36 years or older, beyond the peak age of risk) were comparable to the overall sample (Table 3 presents the size of effects as measured by β weights). Analyses for siblings only (multiplex, n = 16; simplex, n = 16) and males and females produced similar results to the overall sample and were comparable on most analyses. Eliminating 2 subjects with mild hypertension did not change the results (Table 2 and Table 3; Figure 2).

EFFECTS OF PSYCHIATRIC DIAGNOSIS ON HIPPOCAMPAL VOLUMES IN RELATIVES AND CONTROLS

To assess the potential confound of psychopathology, we examined the effect of the presence vs the absence of any psychiatric diagnosis and the number of psychiatric diagnoses per individual on hippocampal volumes. After correcting for the sum of diagnoses, group differences remained significant for the left hippocampus (χ22 = 7.7, P<.02). A test of linear trend was also significant (χ21 = 7.7, P<.006). Multiplex relatives (z = −3.86, P<.001) and simplex relatives (z = −2.10, P<.04) had significantly smaller volumes than controls. Multiplex relatives had significantly smaller left hippocampal volumes than simplex relatives (χ21 = 5.03, P<.03). For the right hippocampus, the results remained nonsignificant.

When we tested whether the presence (vs absence) of any psychiatric diagnosis would attenuate the results, the results did not change. The results did not change when excluding subjects who had other disorders that could affect hippocampal volume (past alcohol dependence [n = 5], schizotypal personality disorder [n = 1], major depressive disorder [n = 11]), nor while controlling for IQ in addition to the other confounders (Table 3).

RELATIONSHIP OF VERBAL DECLARATIVE MEMORY AND HIPPOCAMPAL VOLUMES

We used regression models for verbal memory variables with and without left and right hippocampal volumes included as predictors. Other covariates included sex, group (relatives, controls), the interaction between sex and group, handedness, ethnicity, parental education, and IQ. The left hippocampus was significantly associated with immediate verbal memory (z = 3.66, P<.001); the right hippocampus was not (z = −1.86, P= .06). The left hippocampus was significantly associated with delayed verbal memory (z = 3.15, P = .001). Group (relatives, controls), the sex × group interaction, and ethnicity remained significant in these models for immediate and delayed verbal memory. The right hippocampus remained nonsignificant. Hippocampal volumes did not significantly predict percent retention.

To help in understanding the magnitude of the relationship between hippocampal volumes and the residual verbal memory scores, we calculated Pearson correlations, partialling out the confounders described above. For the entire sample, immediate verbal memory was more strongly associated with left (r = 0.32) than right (r = 0.14) hippocampal volumes. Similarly, delayed verbal memory was more strongly associated with left (r = 0.27) than right (r= 0.12) hippocampus. Within-group analyses showed that the relationship between left hippocampus and memory seemed to be strongest in the multiplex relatives(Table 4).

Table Graphic Jump LocationTable 4. Correlations Between Hippocampal Volumes and Verbal Memory Performance in Controls and Relatives of Patients With Schizophrenia*
EFFECTS OF PATIENTS AND THEIR RELATIVES ON HIPPOCAMPAL VOLUMES COMPARED WITH CONTROLS

Groups did not differ significantly on age, sex, parental socioeconomic status, parents' education, ethnicity, handedness, and drug or alcohol use(Table 5). There were expected significant differences in education and estimated IQ involving the patients.

Table Graphic Jump LocationTable 5. Demographic Variables for Controls, Patients With Schizophrenia, and Their Nonpsychotic Relatives*72,56,55

There were no significant differences in total cerebral volume among groups (Table 6) or between patients vs relatives (χ21 = 2.97, P= .10). There was a significant overall group effect for the left, but not the right hippocampus. Patients (β [SE] = −.4819 [.1141], P<.001) and relatives (β [SE] = −.4046 [.1010], P<.001) had significantly smaller left hippocampi than controls, whereas there were no significant differences for the right hippocampus(Figure 2B). There were no significant differences between patients and relatives for the right hippocampus (χ21 = 0.27, P = .61) or the left hippocampus (χ21 = 0.64, P= .43).

Table Graphic Jump LocationTable 6. Brain Volumes in Controls, Patients With Schizophrenia, and Their Nonpsychotic Relatives*

We found strong support for our hypotheses regarding hippocampal volumes and verbal declarative memory deficits as manifestations of vulnerability to schizophrenia. First, nonpsychotic relatives, primarily those from multiplex families, had significantly smaller left hippocampi than controls. Second, there was a linear trend indicating smaller left hippocampi in multiplex as compared with simplex relatives and controls, and significantly smaller left hippocampi in multiplex as compared with simplex relatives. Third, the positive association between verbal memory function and left hippocampal volumes suggests that smaller hippocampi are related to important cognitive dysfunctions. Fourth, patients with schizophrenia had smaller left but not right hippocampal volumes than controls, which is identical to the pattern seen in relatives. While the effect in probands was marginally larger than in nonpsychotic relatives from the same families, there were no significant differences in left hippocampal volumes between them. These results are consistent with the hypothesis that increased genetic liability to schizophrenia affects brain structure73 and verbal memory,40 supporting the hypothesis that a smaller left hippocampus and verbal memory deficits are associated vulnerability indicators for schizophrenia.

Our statistical analysis allowed us to adjust for the evaluation of more than one relative per family. Results were equally robust when controlling for psychiatric diagnosis. These findings are virtually identical to our previous reports of no significant effect of psychiatric diagnosis on brain volumes in a smaller sample of mainly simplex relatives13 and on neuropsychological dysfunction in relatives.34 Because there were no differences between the controls, relatives, or patients in substance use, these factors cannot account for volumetric differences between relatives and controls. Thus, psychopathology in relatives does not explain their smaller left hippocampi. Because we controlled for demographic features and IQ, these cannot account for the results.

We found comparable effects in relatives who have passed through the peak age of risk for schizophrenia. This suggests that our findings cannot be accounted for by people who will develop schizophrenia. Others have demonstrated significant reductions in N-acetyl-aspartate in the hippocampus of unaffected adult siblings of patients with schizophrenia.74 Smaller hippocampal volumes, especially in the left hemisphere, have been reported in adolescents and young adults (aged 15-25 years) at risk for schizophrenia,11 suggesting that hippocampal abnormalities are already present by midadolescence.

The absence of a significant difference in left hippocampal volume between nonpsychotic relatives (mainly siblings) and patients with schizophrenia is striking. This argues against the idea that secondary effects of psychosis or its treatment cause smaller hippocampi. Longitudinal studies of first-episode patients with schizophrenia do not demonstrate changes in hippocampal volumes over time.7577 These data together point to processes affecting hippocampal volume preceding the onset of illness.

Our study demonstrates an association between left hippocampal volumes and verbal declarative memory in relatives and controls. The association was strongest in multiplex relatives. However, because the sample sizes were small, we have to interpret these correlations cautiously. Nevertheless, the convergence of 2 deficits, theoretically and empirically linked in the broader literature on brain-behavior relationships, provides strong support for the construct validity of our findings.

The cause of these abnormalities is unknown, but our finding of smaller hippocampi in multiplex compared with simplex relatives implicates genes. The distribution of impairment among families is consistent with multifactorial models of familial transmission. Presumably, multiplex families harbor more schizophrenia genes than simplex families, putting relatives at greater risk for both schizophrenia and genetically related deficits. Our results, however, do not address the genetic vs environmental causes of hippocampal deficits, given the inferential limitations of family studies that do not include twins or adoptive relatives.78 Nor do our data rule out other causes affecting left hippocampi in nonpsychotic relatives, such as acquired brain injury79 or effects of psychosocial stress on the hippocampus,80 which could interact with genetic vulnerability. Currently, there are no published studies demonstrating either association in relatives of patients with schizophrenia. It is possible that the hippocampal abnormalities originate from subtle brain injuries similar to those occurring in schizophrenia81 that are caused by obstetric complications82 or viruses.83 There is some support for slightly elevated rates of obstetric complications in nonpsychotic relatives of patients with schizophrenia.8486 We also cannot rule out the possibility of later-occurring alterations in developmental processes such as abnormal synaptic pruning or myelination, which could account for the abnormal hippocampus. However, consistent with the occurrence of earlier abnormal brain development, children at risk for schizophrenia show signs of neurological, cognitive, and socioaffective maladjustment as early as the preschool years.4

The nature of the subtle memory problems observed in relatives suggests several points worthy of follow-up research. Unlike patients with schizophrenia61 or patients with amnestic disorders,23 the relatives do not have abnormal rates of forgetting as compared with controls.34,35,40 Thus, their memory deficits suggest defects in the acquisition or retrieval, rather than storage, of information. Such difficulties have been linked to posterior hippocampus and other associated structures such as the parahippocampal gyrus,87 as well as the prefrontal cortex.88 Further research can determine whether defects in related processes of working memory, encoding, or attention explain the memory impairments, and whether associated brain regions important for memory are impaired in relatives.

Our results must be interpreted in light of some limitations. It would have been optimal to have diagnosed controls in the same way as relatives. Nevertheless, the groups were comparable on demographic factors and did not differ in substance or psychotropic medication use, Moreover, psychiatric diagnoses were not associated with hippocampal abnormalities in relatives. In addition, the smaller left hippocampi in patients with schizophrenia are comparable to those reported by others.18 Although we did not administer an extensive family history diagnostic interview to the controls, the absence of this information would not bias our findings. This mitigates against the idea that our control group is "super normal." Nevertheless our screening method using elevations on the MMPI could have resulted in a psychiatrically clean control group.

In summary, these results provide support for the hypothesis that expressions of the liability to schizophrenia include a smaller left hippocampus and inefficient verbal declarative memory. Because both genetic factors and obstetric complications have been suggested as risk factors for schizophrenia and for hippocampal dysfunction,8991 it is important to investigate the possibility that independent or interactive aspects of these causes may result in left hippocampal abnormalities in relatives. This work also helps to differentiate between vulnerability factors and factors associated with schizophrenic psychosis per se, which is an important distinction for improved treatment and prevention of schizophrenia.92

Submitted for publication May 21, 2001; final revision received September 7, 2001; accepted October 1, 2001.

We thank the following people for their contributions to this project: Mimi Braude, MSW, Deborah Catt, Joanne Donatelli, Elizabeth Hoge, MD, Lynda Jacobs, Jennifer Koch, Genichi Matsuda, MD, Camille McPherson, Catherine Monaco, PhD, James Myers, John Pepple, PhD, Anne Shore, Jason Tourville, Michael Ward, PhD, Heidi Wencel, PhD, Judith Wides, and Andrew Worth, PhD.

This article was supported in part by grants from the Theodore and Vada Stanley Foundation, Bethesda, Md, and the National Association for Research in Schizophrenia and Affective Disorders (NARSAD), Great Neck, NY (Dr Seidman); grants SDA K21 MH 00976 and MH 56956 from the National Institute of Mental Health, Bethesda (Dr Goldstein); a grant from NARSAD (Dr Makris); a grant from the Fairway Trust, Kingston Upon Thames, England (Dr Kennedy); and the NARSAD Distinguished Investigator Award and grants MH 43518 and 46318 from the National Institute of Mental Health (Dr Tsuang).

This work was presented, in part, at the Annual Meeting of the American College of Neuropsychopharmacology, Acapulco, Mexico, December 13, 1999, and the Annual Meeting of the Society of Biological Psychiatry, Chicago, Ill, May 11, 2000.

Corresponding author: Larry J. Seidman, PhD, Neuropsychology Laboratory, Massachusetts Mental Health Center, 74 Fenwood Rd, Boston, MA 02115 (e-mail: larry_seidman@hms.harvard.edu).

Lewis  SWMurray  RM Obstetric complications, neurodevelopmental deviance, and risk for schizophrenia. J Psychiatr Res. 1987;21413- 421
Link to Article
Weinberger  DR Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry. 1987;44660- 669
Link to Article
Zubin  JSpring  B Vulnerability: a new view of schizophrenia. J Abnorm Psychol. 1977;86103- 126
Link to Article
Olin  SSMednick  SA Risk factors of psychosis: identifying vulnerable populations premorbidly. Schizophr Bull. 1996;22223- 240
Link to Article
Faraone  SVGreen  AISeidman  LJTsuang  MT "Schizotaxia": clinical implications and new directions for research. Schizophr Bull. 2001;271- 18
Link to Article
Seidman  LJ Clinical neuroscience and epidemiology of schizophrenia. Harv Rev Psychiatry. 1997;3338- 342
Link to Article
Tsuang  MTSeidman  LJFaraone  SV New approaches to the genetics of schizophrenia: neuropsychological and neuroimaging studies of nonpsychotic first degree relatives of people with schizophrenia. Gattaz  WFHafner  Heds.Balance of the Century. Berlin, Germany Springer Berlin Inc1999;191- 207The Fourth Symposium on the Search for the Causes of Schizophrenia; 4
Seidman  LJWencel  HEMcDonald  CMurray  RTsuang  MT Neuroimaging studies of non-psychotic first degree relatives of people with schizophrenia: towards a neurobiology of vulnerability to schizophrenia("schizotaxia"). Stone  WSFaraone  SVTsuang  MTeds.Early Clinical Intervention and Prevention of Schizophrenia Totowa, NJ Humana PressIn press,
Keshavan  MSMontrose  DMPierri  JNDick  ELRosenberg  DTalagala  LSweeney  JA Magnetic resonance imaging and spectroscopy in offspring at risk for schizophrenia: preliminary studies. Prog Neuropsychopharmacol Biol Psychiatry. 1997;211285- 1295
Link to Article
Screiber  HBaur-Seack  KKornhuber  HHWallner  BFriedrich  JMDe Winter  I-MBorn  J Brain morphology in adolescents at genetic risk for schizophrenia assessed by qualitative and quantitative magnetic resonance imaging. Schizophr Res. 1999;4081- 84
Link to Article
Lawrie  SMWhalley  HCAbukmeil  SSKestelman  JNDonnelly  LMiller  PBest  JJKCunningham-Owens  DGJohnstone  EC Brain structure, genetic liability, and psychotic symptoms in subjects at high risk of developing schizophrenia. Biol Psychiatry. 2001;49811- 823
Link to Article
Seidman  LJFaraone  SVGoldstein  JMGoodman  JMKremen  WSMatsuda  GHoge  EAKennedy  DMakris  NCaviness  VSTsuang  MT Reduced subcortical brain volumes in nonpsychotic siblings of schizophrenic patients: a pilot MRI study. Am J Med Genet. 1997;74507- 514
Link to Article
Seidman  LJFaraone  SVGoldstein  JMGoodman  JMKremen  WSToomey  RTourville  JKennedy  DMakris  NCaviness  VSTsuang  MT Thalamic and amygdala-hippocampal volume reductions in first-degree relatives of patients with schizophrenia: an MRI-based morphometric analysis. Biol Psychiatry. 1999;46941- 954
Link to Article
Staal  WGHulshoff  HESchnack  HVan der Schot  ACKahn  RS Partial volume decrease of the thalamus in relatives of patients with schizophrenia. Am J Psychiatry. 1998;1551784- 1786
Sharma  TLancaster  ELee  DLewis  SSigmundsson  TTakei  NGurling  HBarta  PPearlson  GMurray  R Brain changes in schizophrenia: volumetric MRI study of families multiply affected with schizophrenia: the Maudsley Family Study, 5. Br J Psychiatry. 1998;173132- 138
Link to Article
Cannon  TDVan Erp  TGMHuttunen  MLonnqvist  JSalonen  OValanne  L Regional gray matter, white matter, and cerebrospinal fluid distributions in schizophrenic patients, their siblings, and controls. Arch Gen Psychiatry. 1998;551084- 1091
Link to Article
Nelson  MDSaykin  AJFlashman  LARiordan  HJ Hippocampal volume reduction in schizophrenia as assessed by magnetic resonance imaging: a meta-analytic study. Arch Gen Psychiatry. 1998;55433- 440
Link to Article
Wright  ICRabe-Hesketh  SWoodruff  PWRDavid  ASMurray  RMBullmore  ET Meta-analysis of regional brain volumes in schizophrenia. Am J Psychiatry. 2000;15716- 25
McCarley  RWWible  CGFrumin  MHirayasu  YLevitt  JJFischer  IAShenton  ME MRI anatomy of schizophrenia. Biol Psychiatry. 1999;451099- 1119
Link to Article
Harrison  PJ The neuropathology of schizophrenia: a critical review of the data and their interpretation. Brain. 1999;122593- 624
Link to Article
Weinberger  DR Cell biology of the hippocampal formation in schizophrenia. Biol Psychiatry. 1999;45395- 402
Link to Article
Benes  FM Evidence for altered trisynaptic circuitry in schizophrenic hippocampus. Biol Psychiatry. 1999;46589- 599
Link to Article
Squire  LRZola-Morgan  S The medial temporal lobe memory system. Science. 1991;2531380- 1386
Link to Article
Papez  JW A proposed mechanism of emotion. Arch Neurol Psychiatry. 1937;38725- 743
Link to Article
Maclean  PD The Triune Brain in Evolution: Role in Paleocerebral Functions.  New York, NY Plenum Press1990;
Shenton  MEKikinis  RJolesz  FAPollak  SDLeMay  MWible  CGHokama  HMartin  JMetcalf  DColeman  MMcCarley  RW Abnormalities of the left temporal lobe and thought disorder in schizophrenia: a quantitative magnetic resonance imaging study. N Engl J Med. 1992;327604- 612
Link to Article
Crow  TJBall  JBloom  SRBrown  RBruton  CJColter  NFrith  CDJohnstone  ECOwens  DGRoberts  GW Schizophrenia as an anomaly of development of cerebral asymmetry: a postmortem study and a proposal concerning the genetic basis of the disease. Arch Gen Psychiatry. 1989;461145- 1150
Link to Article
Heinrichs  RWZakzanis  KK Neurocognitive deficit in schizophrenia: a quantitative review of the evidence. Neuropsychology. 1998;12426- 445
Link to Article
Aleman  AHijman  Rde Haan  EHFKahn  RS Memory impairment in schizophrenia: a meta-analysis. Am J Psychiatry. 1999;1561358- 1366
Eichenbaum  H The hippocampal system and declarative memory in humans and animals: experimental analysis and historical origins. Schacter  DTulving  Eeds.Memory Systems Cambridge, Mass MIT Press1994;147- 201
Tsuang  MTFaraone  SVLyons  MJ Identification of the phenotype in psychiatric genetics. Eur Arch Psychiatr Neurol Sci. 1993;243131- 142
Link to Article
Coon  HPlaetke  RHolik  JHoff  MMyles-Worsley  MWaldo  MFreedman  RByerly  W Use of a neurophysiological trait in linkage analysis of schizophrenia. Biol Psychiatry. 1993;34277- 289
Link to Article
Tsuang  MTStone  WSFaraone  SV Schizophrenia: a review of genetic studies. Harv Rev Psychiatry. 1999;7185- 207
Link to Article
Faraone  SVSeidman  LJKremen  WSPepple  JRLyons  MJTsuang  MT Neuropsychological functioning among the nonpsychotic relatives of schizophrenic patients: a diagnostic efficiency analysis. J Abnorm Psychol. 1995;104286- 304
Link to Article
Faraone  SVSeidman  LJKremen  WSToomey  RPepple  JRTsuang  MT Neuropsychological functioning among the nonpsychotic relatives of schizophrenic patients: a four-year follow-up study. J Abnorm Psychol. 1999;108176- 181
Link to Article
McGue  MGottesman  IIRao  DC The transmission of schizophrenia under a multifactorial threshold model. Am J Hum Genet. 1983; 351161- 1178
Gottesman  IIMcGue  M Mixed and mixed-up models for the transmission of schizophrenia. Cichetti  Ded.Thinking Clearly about Psychology: Essays in Honor of Paul E. Meehl Minneapolis University of MinnesotaPress1990;
Gottesman  II Schizophrenia Genesis: The Origin of Madness.  New York, NY WH Freeman Publishers1991;
Faraone  SVTsuang  MT Quantitative models of the genetic transmission of schizophrenia. Psychol Bull. 1985;9841- 66
Link to Article
Faraone  SVSeidman  LJKremen  WSToomey  RPepple  JRTsuang  MT Neuropsychological functioning among the nonpsychotic relatives of schizophrenic patients: the effect of genetic loading. Biol Psychiatry. 2000;48120- 126
Link to Article
Griffiths  TDSigmundsson  TTakei  NRowe  DMurray  RM Neurological abnormalities in familial and sporadic schizophrenia. Brain. 1998;121191- 203
Link to Article
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition.  Washington, DC American Psychiatric Association1987;
Spitzer  REndicott  J Schedule for Affective Disorders and Schizophrenia(SADS).  New York New York State Psychiatric Institute1978;
Nurnberger  JIBlehar  MCKaufmann  CAYork-Cooler  CSimpson  SGHarkavy-Friedman  JSevere  JBMalaspina  DReich  TMiller  MBowman  ESDePaulo  JRCloninger  CRRobinson  GMoldin  SGershon  ESMaxwell  EGuroff  JJKirch  DWynne  DBerg  KTsuang  MTFaraone  SVPepple  JRRitz  AL Diagnostic interview for genetic studies: rationale, unique features, and training. Arch Gen Psychiatry. 1994;51849- 859
Link to Article
Spitzer  RLWilliams  JBWGibbon  M Structured Clinical Interview for DSM-III-R Personality Disorders (SCID-II).  New York New York State Psychiatric Institute1987;
Stangl  DZimmerman  S Structured Interview for DSM-III Personality Disorders.  Iowa City University of Iowa1983;
Seidman  LJGoldstein  JMMakris  NKennedy  DNKremen  WSToomey  RCaviness  VSFaraone  SVTsuang  MT Subcortical brain abnormalities in patients with schizophrenia: an MRI morphometric study. Biol Psychiatry. 2000;4724S
Link to Article
Goldstein  JMSeidman  LJO'Brien  LMHorton  NJKennedy  DNMakris  NCaviness  VSFaraone  SVTsuang  MT Impact of normal sexual dimorphisms on sex differences in structural brain abnormalities in schizophrenia assessed by magnetic resonance imaging. Arch Gen Psychiatry. 2002;59154- 164
Link to Article
Vincent  KRCastillo  IMHauser  RIZapata  JAStuart  HJCohn  CKO'Shanick  GJ MMPI-168 Codebook.  Norwood, NJ Ablex Publishing Corp1984;
Buckley  PO'Callaghan  ELarkin  CWaddington  JL Schizophrenia research: the problem of controls. Biol Psychiatry. 1992;32215- 217
Link to Article
Shastel  DLGur  REMozley  DRichards  JTaleff  MMHeimberg  CGallacher  FGur  RC Volunteers for biomedical research: recruitment and screening of normal controls. Arch Gen Psychiatry. 1991;481022- 1025
Link to Article
Thaker  GKMoran  MLahti  AAdami  HTamminga  C Psychiatric morbidity in research volunteers. Arch Gen Psychiatry. 1990;47980
Link to Article
Kendler  KS The super-normal control group in psychiatric genetics: Possible artifactual evidence for coaggregation. Psychiatr Genet. 1990;145- 53
Tsuang  MTFleming  JAKendler  KSGruenberg  AM Selection of controls for family studies: biases and implications. Arch Gen Psychiatry. 1988;451006- 1008
Link to Article
Jastak  JFJastak  S Wide Range Achievement Test–Revised.  Wilmington, Del Jastak Assoc1985;
Wechsler  D Wechsler Adult Intelligence Scale–Revised Manual.  New York, NY Psychological Corp1981;
Brooker  BHCyr  JJ Tables for clinicians to use to convert WAIS-R short forms. J Clin Psychol. 1986;42983- 986
Link to Article
Kremen  WSSeidman  LJFaraone  SVPepple  JRLyons  MJTsuang  MT The "3 Rs" and neuropsychological function in schizophrenia: an empirical test of the matching fallacy. Neuropsychology. 1996;1022- 31
Link to Article
Annett  M A classification of hand preference by association analysis. Br J Psychol. 1970;61303- 321
Link to Article
Wechsler  D Wechsler Memory Scale–Revised Manual.  San Antonio, Tex Psychological Corp1987;
Seidman  LJStone  WSJones  RHarrison  RHMirsky  AF Comparative effects of schizophrenia and temporal lobe epilepsy on memory. J Int Neuropsychol Soc. 1998;4342- 352
Filipek  PAKennedy  DNCaviness  VSRossnick  SLSpraggins  TAStarewicz  PM MRI-based brain morphometry: development and application to normal controls. Ann Neurol. 1989;2561- 67
Link to Article
Filipek  PRichelme  CKennedy  DNCaviness  VS The young adult human brain: an MRI-based morphometric analysis. Cereb Cortex. 1994;4344- 360
Link to Article
Kennedy  DNFilipek  PACaviness  VS Anatomic segmentation and volumetric calculations in nuclear magnetic resonance imaging. IEEE Trans Med Imaging. 1989;81- 7
Link to Article
Makris  NMeyer  JWBates  JFYeterian  EHKennedy  DNCaviness  VS MRI-based topographic parcellation of human cerebral white matter and nuclei, II: rationale and applications with systematics of cerebral connectivity. Neuroimage. 1999;918- 45
Link to Article
Caviness  VSMakris  NMeyer  JKennedy  D MRI-based parcellation of human neocortex: an anatomically specified method with estimate of reliability. J Cogn Neurosci. 1996;8566- 588
Link to Article
Rosene  DLvan Hoesen  GW The hippocampal formation of the primate brain: A review of some comparative aspects of cytoarchitecture and connections. Jones  EGPeters  Aeds.Cerebral Cortex 6 New York, NY Plenum Press1987;345- 456
Liang  KYZeger  SL Longitudinal data analysis using generalized linear models. Biometrika. 1986;7313- 22
Link to Article
Zeger  SLLiang  KY Longitudinal data analysis for discrete and continuous outcomes. Biometrics. 1986;42121- 130
Link to Article
Lipsitz  SRFitzmaurice  GMOrav  EJLaird  NM Performance of generalized estimating equations in practical situations. Biometrics. 1994;50270- 278
Link to Article
Sutradhar  BCDas  K On the efficiency of regression estimators in generalised linear models for longitudinal data. Biometrika. 1999;86459- 465
Link to Article
Hollingshead  AB Four Factor Index of Social Status.  New Haven, Conn Yale University Press1975;
Cannon  TDMednick  SAParnas  JSchulsinger  FPraestholm  JVestergaard  A Developmental brain abnormalities in the offspring of schizophrenic mothers: contributions of genetic and perinatal factors. Arch Gen Psychiatry. 1993;50551- 564
Link to Article
Callicott  JHEgan  MFBertolino  AMattay  VSLangheim  FJPFrank  JAWeinberger  DR Hippocampal N-acetyl aspartate in unaffected siblings of patients with schizophrenia: a possible intermediate neurobiological phenotype. Biol Psychiatry. 1998;44941- 950
Link to Article
DeLisi  LESakuma  MTew  WKushner  MHoff  ALGrimson  R Schizophrenia as a chronic active brain process: a study of progressive brain structural change subsequent to the onset of schizophrenia. Psychiatry Res. 1997;74129- 140
Link to Article
Gur  RECowell  PTuretsky  BIGallacher  FCannon  TBilker  WGur  RC A follow-up magnetic resonance imaging study of schizophrenia: relationship of neuroanatomical changes to clinical and neurobehavioral measures. Arch Gen Psychiatry. 1998;55145- 152
Link to Article
Lieberman  JChakos  MWu  HAlvir  JHoffman  ERobinson  DBilder  R Longitudinal study of brain morphology in first episode schizophrenia. Biol Psychiatry. 2001;49487- 499
Link to Article
Faraone  SVTsuang  DTsuang  MT Genetics of Mental Disorders: A Guide for Students, Clinicians and Researchers.  New York, NY Guilford Press1999;
Stefanis  NFrangou  SYakeley  JSharma  TO'Connell  PMorgan  KSigmudssonTaylor  MMurray  R Hippocampal volume reduction in schizophrenia: effects of genetic risk and pregnancy and birth complications. Biol Psychiatry. 1999;46697- 702
Link to Article
McEwen  BSMagarinos  AM Stress effects on morphology and function of the hippocampus. Ann N Y Acad Sci. 1997;821271- 284
Link to Article
Suddath  RLChristison  GWTorrey  EFCasanova  MFWeinberger  DR Anatomical abnormalities in the brains of monozygotic twins discordant for schizophrenia. N Engl J Med. 1990;322789- 794
Link to Article
McNeil  TF Perinatal risk factors and schizophrenia: selective review and methodological concerns. Epidemiol Rev. 1995;17107- 112
Torrey  EFPeterson  MR Schizophrenia and the limbic system. Lancet. 1974;2942- 946
Link to Article
Sacker  ADone  DJCrow  TJ Obstetric complications in children born to parents with schizophrenia: a meta-analysis of case-control studies. Psychol Med. 1996;26279- 287
Link to Article
Rosso  IMCannon  TDHuttunen  THuttunen  MOLonnqvist  JGasperoni  TL Obstetric risk factors for early-onset schizophrenia in a Finnish birth cohort. Am J Psychiatry. 2000;157801- 807
Link to Article
Cannon  TDRosso  IMHollister  JMBearden  CESanchez  LEHadley  T A prospective cohort study of genetic and perinatal influences in the etiology of schizophrenia. Schizophr Bull. 2000;26351- 366
Link to Article
Schacter  DLWagner  AD Medial temporal lobe activations in fMRI and PET studies of episodic encoding and retrieval. Hippocampus. 1999;97- 24
Link to Article
Wagner  AD Working memory contributions to human learning and remembering. Neuron. 1999;2219- 22
Link to Article
Tsuang  MTFaraone  SV The case for heterogeneity in the etiology of schizophrenia. Schizophr Res. 1995;17161- 175
Link to Article
Buka  SLGoldstein  JMSeidman  LJZornberg  GLDonatelli  JATsuang  MT Impacts of perinatal hypoxia and genetic vulnerability on schizophrenia: the New England longitudinal studies of schizophrenia. Psychiatr Ann. 1999;29151- 156
Link to Article
Jones  PBMurray  RM The genetics of schizophrenia is the genetics of neurodevelopment. Br J Psychiatry. 1991;158615- 623
Link to Article
Tsuang  MTStone  WSSeidman  LJFaraone  SVZimmet  SWojcik  JKelleher  JPGreen  AI Treatment of nonpsychotic relatives of patients with schizophrenia: four case studies. Biol Psychiatry. 1999;451412- 1418
Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Method of segmentation of the hippocampus (observed in radiological convention) as performed in our study(under the supervision of Nikos Makris, MD, PhD). Identification of the hippocampus is achieved using a cross-referencing tool,66 which allows visualization of the structure in 3 coregistered cardinal views(coronal, axial, and sagittal). A-F, Dotted lines (b, c, e, f) on sagittal slices (A) and (D) indicate where coronal slices (B and E) and axial slices(C and F) lie. D presents a more medial view compared with A, while the image in F is more superior to that in C, and the image in E is more posterior than that of B. Colored outlines separating the hippocampus from its neighboring structures are shown. Colored lines distinguish the structures. Specifically, 2 lines were drawn to demarcate the boundary between the anterior hippocampus and amygdala (A, B, and C) and the boundary between the hippocampus and posterior thalamus (D, E, and F). G-J, Segmentation of the hippocampus is shown in 4 representative coronal sections, which is determined by outlines previously drawn in sagittal (A and D) and axial (C and F) planes. G, Coronal slice in the anterior tip of the hippocampus (where it borders amygdala). H, Coronal slice is in the middle of the hippocampus. I, Coronal slice is in the posterior hippocampus (where it borders posterior thalamus). J, Coronal slice in the tail of the hippocampus. K, Dotted vertical lines g, h, i, and j indicate the corresponding coronal planes.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Left and right hippocampal volumes proportionally adjusted for total cerebral volume in control subjects, relatives of schizophrenics, and patients with schizophrenia. A, Comparison of controls and nonpsychotic relatives. B, Comparison of controls, nonpsychotic relatives, and patients with schizophrenia. Percent of total cerebral volume indicates hippocampal volume/total cerebral volume × 100; SEs are corrected for intrafamilial correlation.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Demographic Variables for Controls and Relatives of Patients With Schizophrenia*72,56,55,57
Table Graphic Jump LocationTable 2. Brain Volumes and Verbal Memory Performance in Controls and Relatives of Patients With Shizophrenia*40
Table Graphic Jump LocationTable 3. Regression Models for Left Hippocampus Analyzing Different Subsets of Relatives vs Controls*
Table Graphic Jump LocationTable 4. Correlations Between Hippocampal Volumes and Verbal Memory Performance in Controls and Relatives of Patients With Schizophrenia*
Table Graphic Jump LocationTable 5. Demographic Variables for Controls, Patients With Schizophrenia, and Their Nonpsychotic Relatives*72,56,55
Table Graphic Jump LocationTable 6. Brain Volumes in Controls, Patients With Schizophrenia, and Their Nonpsychotic Relatives*

References

Lewis  SWMurray  RM Obstetric complications, neurodevelopmental deviance, and risk for schizophrenia. J Psychiatr Res. 1987;21413- 421
Link to Article
Weinberger  DR Implications of normal brain development for the pathogenesis of schizophrenia. Arch Gen Psychiatry. 1987;44660- 669
Link to Article
Zubin  JSpring  B Vulnerability: a new view of schizophrenia. J Abnorm Psychol. 1977;86103- 126
Link to Article
Olin  SSMednick  SA Risk factors of psychosis: identifying vulnerable populations premorbidly. Schizophr Bull. 1996;22223- 240
Link to Article
Faraone  SVGreen  AISeidman  LJTsuang  MT "Schizotaxia": clinical implications and new directions for research. Schizophr Bull. 2001;271- 18
Link to Article
Seidman  LJ Clinical neuroscience and epidemiology of schizophrenia. Harv Rev Psychiatry. 1997;3338- 342
Link to Article
Tsuang  MTSeidman  LJFaraone  SV New approaches to the genetics of schizophrenia: neuropsychological and neuroimaging studies of nonpsychotic first degree relatives of people with schizophrenia. Gattaz  WFHafner  Heds.Balance of the Century. Berlin, Germany Springer Berlin Inc1999;191- 207The Fourth Symposium on the Search for the Causes of Schizophrenia; 4
Seidman  LJWencel  HEMcDonald  CMurray  RTsuang  MT Neuroimaging studies of non-psychotic first degree relatives of people with schizophrenia: towards a neurobiology of vulnerability to schizophrenia("schizotaxia"). Stone  WSFaraone  SVTsuang  MTeds.Early Clinical Intervention and Prevention of Schizophrenia Totowa, NJ Humana PressIn press,
Keshavan  MSMontrose  DMPierri  JNDick  ELRosenberg  DTalagala  LSweeney  JA Magnetic resonance imaging and spectroscopy in offspring at risk for schizophrenia: preliminary studies. Prog Neuropsychopharmacol Biol Psychiatry. 1997;211285- 1295
Link to Article
Screiber  HBaur-Seack  KKornhuber  HHWallner  BFriedrich  JMDe Winter  I-MBorn  J Brain morphology in adolescents at genetic risk for schizophrenia assessed by qualitative and quantitative magnetic resonance imaging. Schizophr Res. 1999;4081- 84
Link to Article
Lawrie  SMWhalley  HCAbukmeil  SSKestelman  JNDonnelly  LMiller  PBest  JJKCunningham-Owens  DGJohnstone  EC Brain structure, genetic liability, and psychotic symptoms in subjects at high risk of developing schizophrenia. Biol Psychiatry. 2001;49811- 823
Link to Article
Seidman  LJFaraone  SVGoldstein  JMGoodman  JMKremen  WSMatsuda  GHoge  EAKennedy  DMakris  NCaviness  VSTsuang  MT Reduced subcortical brain volumes in nonpsychotic siblings of schizophrenic patients: a pilot MRI study. Am J Med Genet. 1997;74507- 514
Link to Article
Seidman  LJFaraone  SVGoldstein  JMGoodman  JMKremen  WSToomey  RTourville  JKennedy  DMakris  NCaviness  VSTsuang  MT Thalamic and amygdala-hippocampal volume reductions in first-degree relatives of patients with schizophrenia: an MRI-based morphometric analysis. Biol Psychiatry. 1999;46941- 954
Link to Article
Staal  WGHulshoff  HESchnack  HVan der Schot  ACKahn  RS Partial volume decrease of the thalamus in relatives of patients with schizophrenia. Am J Psychiatry. 1998;1551784- 1786
Sharma  TLancaster  ELee  DLewis  SSigmundsson  TTakei  NGurling  HBarta  PPearlson  GMurray  R Brain changes in schizophrenia: volumetric MRI study of families multiply affected with schizophrenia: the Maudsley Family Study, 5. Br J Psychiatry. 1998;173132- 138
Link to Article
Cannon  TDVan Erp  TGMHuttunen  MLonnqvist  JSalonen  OValanne  L Regional gray matter, white matter, and cerebrospinal fluid distributions in schizophrenic patients, their siblings, and controls. Arch Gen Psychiatry. 1998;551084- 1091
Link to Article
Nelson  MDSaykin  AJFlashman  LARiordan  HJ Hippocampal volume reduction in schizophrenia as assessed by magnetic resonance imaging: a meta-analytic study. Arch Gen Psychiatry. 1998;55433- 440
Link to Article
Wright  ICRabe-Hesketh  SWoodruff  PWRDavid  ASMurray  RMBullmore  ET Meta-analysis of regional brain volumes in schizophrenia. Am J Psychiatry. 2000;15716- 25
McCarley  RWWible  CGFrumin  MHirayasu  YLevitt  JJFischer  IAShenton  ME MRI anatomy of schizophrenia. Biol Psychiatry. 1999;451099- 1119
Link to Article
Harrison  PJ The neuropathology of schizophrenia: a critical review of the data and their interpretation. Brain. 1999;122593- 624
Link to Article
Weinberger  DR Cell biology of the hippocampal formation in schizophrenia. Biol Psychiatry. 1999;45395- 402
Link to Article
Benes  FM Evidence for altered trisynaptic circuitry in schizophrenic hippocampus. Biol Psychiatry. 1999;46589- 599
Link to Article
Squire  LRZola-Morgan  S The medial temporal lobe memory system. Science. 1991;2531380- 1386
Link to Article
Papez  JW A proposed mechanism of emotion. Arch Neurol Psychiatry. 1937;38725- 743
Link to Article
Maclean  PD The Triune Brain in Evolution: Role in Paleocerebral Functions.  New York, NY Plenum Press1990;
Shenton  MEKikinis  RJolesz  FAPollak  SDLeMay  MWible  CGHokama  HMartin  JMetcalf  DColeman  MMcCarley  RW Abnormalities of the left temporal lobe and thought disorder in schizophrenia: a quantitative magnetic resonance imaging study. N Engl J Med. 1992;327604- 612
Link to Article
Crow  TJBall  JBloom  SRBrown  RBruton  CJColter  NFrith  CDJohnstone  ECOwens  DGRoberts  GW Schizophrenia as an anomaly of development of cerebral asymmetry: a postmortem study and a proposal concerning the genetic basis of the disease. Arch Gen Psychiatry. 1989;461145- 1150
Link to Article
Heinrichs  RWZakzanis  KK Neurocognitive deficit in schizophrenia: a quantitative review of the evidence. Neuropsychology. 1998;12426- 445
Link to Article
Aleman  AHijman  Rde Haan  EHFKahn  RS Memory impairment in schizophrenia: a meta-analysis. Am J Psychiatry. 1999;1561358- 1366
Eichenbaum  H The hippocampal system and declarative memory in humans and animals: experimental analysis and historical origins. Schacter  DTulving  Eeds.Memory Systems Cambridge, Mass MIT Press1994;147- 201
Tsuang  MTFaraone  SVLyons  MJ Identification of the phenotype in psychiatric genetics. Eur Arch Psychiatr Neurol Sci. 1993;243131- 142
Link to Article
Coon  HPlaetke  RHolik  JHoff  MMyles-Worsley  MWaldo  MFreedman  RByerly  W Use of a neurophysiological trait in linkage analysis of schizophrenia. Biol Psychiatry. 1993;34277- 289
Link to Article
Tsuang  MTStone  WSFaraone  SV Schizophrenia: a review of genetic studies. Harv Rev Psychiatry. 1999;7185- 207
Link to Article
Faraone  SVSeidman  LJKremen  WSPepple  JRLyons  MJTsuang  MT Neuropsychological functioning among the nonpsychotic relatives of schizophrenic patients: a diagnostic efficiency analysis. J Abnorm Psychol. 1995;104286- 304
Link to Article
Faraone  SVSeidman  LJKremen  WSToomey  RPepple  JRTsuang  MT Neuropsychological functioning among the nonpsychotic relatives of schizophrenic patients: a four-year follow-up study. J Abnorm Psychol. 1999;108176- 181
Link to Article
McGue  MGottesman  IIRao  DC The transmission of schizophrenia under a multifactorial threshold model. Am J Hum Genet. 1983; 351161- 1178
Gottesman  IIMcGue  M Mixed and mixed-up models for the transmission of schizophrenia. Cichetti  Ded.Thinking Clearly about Psychology: Essays in Honor of Paul E. Meehl Minneapolis University of MinnesotaPress1990;
Gottesman  II Schizophrenia Genesis: The Origin of Madness.  New York, NY WH Freeman Publishers1991;
Faraone  SVTsuang  MT Quantitative models of the genetic transmission of schizophrenia. Psychol Bull. 1985;9841- 66
Link to Article
Faraone  SVSeidman  LJKremen  WSToomey  RPepple  JRTsuang  MT Neuropsychological functioning among the nonpsychotic relatives of schizophrenic patients: the effect of genetic loading. Biol Psychiatry. 2000;48120- 126
Link to Article
Griffiths  TDSigmundsson  TTakei  NRowe  DMurray  RM Neurological abnormalities in familial and sporadic schizophrenia. Brain. 1998;121191- 203
Link to Article
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition.  Washington, DC American Psychiatric Association1987;
Spitzer  REndicott  J Schedule for Affective Disorders and Schizophrenia(SADS).  New York New York State Psychiatric Institute1978;
Nurnberger  JIBlehar  MCKaufmann  CAYork-Cooler  CSimpson  SGHarkavy-Friedman  JSevere  JBMalaspina  DReich  TMiller  MBowman  ESDePaulo  JRCloninger  CRRobinson  GMoldin  SGershon  ESMaxwell  EGuroff  JJKirch  DWynne  DBerg  KTsuang  MTFaraone  SVPepple  JRRitz  AL Diagnostic interview for genetic studies: rationale, unique features, and training. Arch Gen Psychiatry. 1994;51849- 859
Link to Article
Spitzer  RLWilliams  JBWGibbon  M Structured Clinical Interview for DSM-III-R Personality Disorders (SCID-II).  New York New York State Psychiatric Institute1987;
Stangl  DZimmerman  S Structured Interview for DSM-III Personality Disorders.  Iowa City University of Iowa1983;
Seidman  LJGoldstein  JMMakris  NKennedy  DNKremen  WSToomey  RCaviness  VSFaraone  SVTsuang  MT Subcortical brain abnormalities in patients with schizophrenia: an MRI morphometric study. Biol Psychiatry. 2000;4724S
Link to Article
Goldstein  JMSeidman  LJO'Brien  LMHorton  NJKennedy  DNMakris  NCaviness  VSFaraone  SVTsuang  MT Impact of normal sexual dimorphisms on sex differences in structural brain abnormalities in schizophrenia assessed by magnetic resonance imaging. Arch Gen Psychiatry. 2002;59154- 164
Link to Article
Vincent  KRCastillo  IMHauser  RIZapata  JAStuart  HJCohn  CKO'Shanick  GJ MMPI-168 Codebook.  Norwood, NJ Ablex Publishing Corp1984;
Buckley  PO'Callaghan  ELarkin  CWaddington  JL Schizophrenia research: the problem of controls. Biol Psychiatry. 1992;32215- 217
Link to Article
Shastel  DLGur  REMozley  DRichards  JTaleff  MMHeimberg  CGallacher  FGur  RC Volunteers for biomedical research: recruitment and screening of normal controls. Arch Gen Psychiatry. 1991;481022- 1025
Link to Article
Thaker  GKMoran  MLahti  AAdami  HTamminga  C Psychiatric morbidity in research volunteers. Arch Gen Psychiatry. 1990;47980
Link to Article
Kendler  KS The super-normal control group in psychiatric genetics: Possible artifactual evidence for coaggregation. Psychiatr Genet. 1990;145- 53
Tsuang  MTFleming  JAKendler  KSGruenberg  AM Selection of controls for family studies: biases and implications. Arch Gen Psychiatry. 1988;451006- 1008
Link to Article
Jastak  JFJastak  S Wide Range Achievement Test–Revised.  Wilmington, Del Jastak Assoc1985;
Wechsler  D Wechsler Adult Intelligence Scale–Revised Manual.  New York, NY Psychological Corp1981;
Brooker  BHCyr  JJ Tables for clinicians to use to convert WAIS-R short forms. J Clin Psychol. 1986;42983- 986
Link to Article
Kremen  WSSeidman  LJFaraone  SVPepple  JRLyons  MJTsuang  MT The "3 Rs" and neuropsychological function in schizophrenia: an empirical test of the matching fallacy. Neuropsychology. 1996;1022- 31
Link to Article
Annett  M A classification of hand preference by association analysis. Br J Psychol. 1970;61303- 321
Link to Article
Wechsler  D Wechsler Memory Scale–Revised Manual.  San Antonio, Tex Psychological Corp1987;
Seidman  LJStone  WSJones  RHarrison  RHMirsky  AF Comparative effects of schizophrenia and temporal lobe epilepsy on memory. J Int Neuropsychol Soc. 1998;4342- 352
Filipek  PAKennedy  DNCaviness  VSRossnick  SLSpraggins  TAStarewicz  PM MRI-based brain morphometry: development and application to normal controls. Ann Neurol. 1989;2561- 67
Link to Article
Filipek  PRichelme  CKennedy  DNCaviness  VS The young adult human brain: an MRI-based morphometric analysis. Cereb Cortex. 1994;4344- 360
Link to Article
Kennedy  DNFilipek  PACaviness  VS Anatomic segmentation and volumetric calculations in nuclear magnetic resonance imaging. IEEE Trans Med Imaging. 1989;81- 7
Link to Article
Makris  NMeyer  JWBates  JFYeterian  EHKennedy  DNCaviness  VS MRI-based topographic parcellation of human cerebral white matter and nuclei, II: rationale and applications with systematics of cerebral connectivity. Neuroimage. 1999;918- 45
Link to Article
Caviness  VSMakris  NMeyer  JKennedy  D MRI-based parcellation of human neocortex: an anatomically specified method with estimate of reliability. J Cogn Neurosci. 1996;8566- 588
Link to Article
Rosene  DLvan Hoesen  GW The hippocampal formation of the primate brain: A review of some comparative aspects of cytoarchitecture and connections. Jones  EGPeters  Aeds.Cerebral Cortex 6 New York, NY Plenum Press1987;345- 456
Liang  KYZeger  SL Longitudinal data analysis using generalized linear models. Biometrika. 1986;7313- 22
Link to Article
Zeger  SLLiang  KY Longitudinal data analysis for discrete and continuous outcomes. Biometrics. 1986;42121- 130
Link to Article
Lipsitz  SRFitzmaurice  GMOrav  EJLaird  NM Performance of generalized estimating equations in practical situations. Biometrics. 1994;50270- 278
Link to Article
Sutradhar  BCDas  K On the efficiency of regression estimators in generalised linear models for longitudinal data. Biometrika. 1999;86459- 465
Link to Article
Hollingshead  AB Four Factor Index of Social Status.  New Haven, Conn Yale University Press1975;
Cannon  TDMednick  SAParnas  JSchulsinger  FPraestholm  JVestergaard  A Developmental brain abnormalities in the offspring of schizophrenic mothers: contributions of genetic and perinatal factors. Arch Gen Psychiatry. 1993;50551- 564
Link to Article
Callicott  JHEgan  MFBertolino  AMattay  VSLangheim  FJPFrank  JAWeinberger  DR Hippocampal N-acetyl aspartate in unaffected siblings of patients with schizophrenia: a possible intermediate neurobiological phenotype. Biol Psychiatry. 1998;44941- 950
Link to Article
DeLisi  LESakuma  MTew  WKushner  MHoff  ALGrimson  R Schizophrenia as a chronic active brain process: a study of progressive brain structural change subsequent to the onset of schizophrenia. Psychiatry Res. 1997;74129- 140
Link to Article
Gur  RECowell  PTuretsky  BIGallacher  FCannon  TBilker  WGur  RC A follow-up magnetic resonance imaging study of schizophrenia: relationship of neuroanatomical changes to clinical and neurobehavioral measures. Arch Gen Psychiatry. 1998;55145- 152
Link to Article
Lieberman  JChakos  MWu  HAlvir  JHoffman  ERobinson  DBilder  R Longitudinal study of brain morphology in first episode schizophrenia. Biol Psychiatry. 2001;49487- 499
Link to Article
Faraone  SVTsuang  DTsuang  MT Genetics of Mental Disorders: A Guide for Students, Clinicians and Researchers.  New York, NY Guilford Press1999;
Stefanis  NFrangou  SYakeley  JSharma  TO'Connell  PMorgan  KSigmudssonTaylor  MMurray  R Hippocampal volume reduction in schizophrenia: effects of genetic risk and pregnancy and birth complications. Biol Psychiatry. 1999;46697- 702
Link to Article
McEwen  BSMagarinos  AM Stress effects on morphology and function of the hippocampus. Ann N Y Acad Sci. 1997;821271- 284
Link to Article
Suddath  RLChristison  GWTorrey  EFCasanova  MFWeinberger  DR Anatomical abnormalities in the brains of monozygotic twins discordant for schizophrenia. N Engl J Med. 1990;322789- 794
Link to Article
McNeil  TF Perinatal risk factors and schizophrenia: selective review and methodological concerns. Epidemiol Rev. 1995;17107- 112
Torrey  EFPeterson  MR Schizophrenia and the limbic system. Lancet. 1974;2942- 946
Link to Article
Sacker  ADone  DJCrow  TJ Obstetric complications in children born to parents with schizophrenia: a meta-analysis of case-control studies. Psychol Med. 1996;26279- 287
Link to Article
Rosso  IMCannon  TDHuttunen  THuttunen  MOLonnqvist  JGasperoni  TL Obstetric risk factors for early-onset schizophrenia in a Finnish birth cohort. Am J Psychiatry. 2000;157801- 807
Link to Article
Cannon  TDRosso  IMHollister  JMBearden  CESanchez  LEHadley  T A prospective cohort study of genetic and perinatal influences in the etiology of schizophrenia. Schizophr Bull. 2000;26351- 366
Link to Article
Schacter  DLWagner  AD Medial temporal lobe activations in fMRI and PET studies of episodic encoding and retrieval. Hippocampus. 1999;97- 24
Link to Article
Wagner  AD Working memory contributions to human learning and remembering. Neuron. 1999;2219- 22
Link to Article
Tsuang  MTFaraone  SV The case for heterogeneity in the etiology of schizophrenia. Schizophr Res. 1995;17161- 175
Link to Article
Buka  SLGoldstein  JMSeidman  LJZornberg  GLDonatelli  JATsuang  MT Impacts of perinatal hypoxia and genetic vulnerability on schizophrenia: the New England longitudinal studies of schizophrenia. Psychiatr Ann. 1999;29151- 156
Link to Article
Jones  PBMurray  RM The genetics of schizophrenia is the genetics of neurodevelopment. Br J Psychiatry. 1991;158615- 623
Link to Article
Tsuang  MTStone  WSSeidman  LJFaraone  SVZimmet  SWojcik  JKelleher  JPGreen  AI Treatment of nonpsychotic relatives of patients with schizophrenia: four case studies. Biol Psychiatry. 1999;451412- 1418
Link to Article

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 166

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles
Recent advances in the biological study of personality disorders. Psychiatr Clin North Am 2008;31(3):441-61, vii.
JAMAevidence.com