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Left Hippocampal Volume as a Vulnerability Indicator for Schizophrenia
A Magnetic Resonance Imaging Morphometric Study of Nonpsychotic First-Degree Relatives
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
Arch Gen Psychiatry. 2002;59:839-849.
ABSTRACT
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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.
INTRODUCTION
CURRENT perspectives on the cause of schizophrenia have focused attention
on neurobiological vulnerability to the illness.1-3
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.6-8 Both younger9-11 and older12-16
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.17-19
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,20-22
especially because of its role in learning and memory.23-25
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.5-7
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, 36-39
The multifactorial model of schizophrenia has found some, although not complete,
support.33, 36-39
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 AND METHODS
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.50-52
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 x 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 x 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).
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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.
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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
RESULTS
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).
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Table 1. Demographic Variables for Controls and Relatives of Patients
With Schizophrenia*
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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.
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Table 2. Brain Volumes and Verbal Memory Performance in Controls and
Relatives of Patients With Shizophrenia*
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Table 3. Regression Models for Left Hippocampus Analyzing Different
Subsets of Relatives vs Controls*
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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 x 100; SEs are corrected for
intrafamilial correlation.
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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  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 ( 22 = 7.7, P<.02). A test of linear trend was also significant (21 = 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 (21 = 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 x 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).
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Table 4. Correlations Between Hippocampal Volumes and Verbal Memory
Performance in Controls and Relatives of Patients With Schizophrenia*
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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.
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Table 5. Demographic Variables for Controls, Patients With Schizophrenia,
and Their Nonpsychotic Relatives*
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There were no significant differences in total cerebral volume among
groups (Table 6) or between patients
vs relatives (21 = 2.97, P
= .10). There was a significant overall group effect for the left, but not
the right hippocampus. Patients ( [SE] = -.4819 [.1141], P<.001) and relatives ( [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 (21 = 0.27, P = .61) or the left
hippocampus (21 = 0.64, P
= .43).
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Table 6. Brain Volumes in Controls, Patients With Schizophrenia, and
Their Nonpsychotic Relatives*
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COMMENT
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.75-77
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.84-86
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,89-91
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
AUTHOR INFORMATION
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{at}hms.harvard.edu).
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).
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