1 Harvard Medical School Department of Psychiatry at Massachusetts Mental Health Center, Boston, MA 02115, , 2 Harvard Medical School Department of Psychiatry at Brockton/West Roxbury VA Medical Center, Brockton, MA and Massachusetts General Hospital, Boston, MA, , 3 Harvard Institute of Psychiatric Epidemiology and Genetics, Boston, MA 02115, , 4 Boston University Schools of Public Health (Department of Epidemiology and Biostatistics) and Medicine, Boston, MA, , 5 Harvard Medical School Departments of Neurology and Radiology Services, Center for Morphometric Analysis, Massachusetts General Hospital, Boston, MA 02129 and , 6 Harvard School of Public Health, Department of Epidemiology, Boston, MA 02115, USA
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Abstract |
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Introduction |
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In vivo imaging and postmortem studies of sexual dimorphisms in humans report that the cerebrum is larger in men than women by ~810% (Filipek et al., 1994; Witelson et al., 1995
; Passe et al., 1997
; Rabinowicz et al., 1999
; Nopoulos et al., 2000
), a finding that is not wholly attributed to body size. However, regionally specific sex differences, relative to size of cerebrum, have been reported, and the direction of the sex effects differs depending on the brain region. These studies have reported, in women, relative to cerebrum size, greater cortical gray matter volume (Gur et al., 1999
), larger volumes of regions associated with language functions [e.g. Broca's area (Harasty et al., 1997
)] and superior temporal cortex, in particular planum temporale (Jacobs et al., 1993
; Schlaepfer et al., 1995
; Harasty et al., 1997
)], and larger volumes of the hippocampus (Filipek et al., 1994
; Giedd et al., 1996
; Murphy et al., 1996
), caudate (Filipek et al., 1994
; Murphy et al., 1996
), thalamic nuclei (Murphy et al., 1996
), anterior cingulate gyrus (Paus et al., 1996
), dorsolateral prefrontal cortex (Schlaepfer et al., 1995
), right inferior parietal lobe (Nopoulos et al., 2000
), and white matter involved in interhemispheric connectivity (Allen and Gorski, 1987
; Witelson, 1989
; Highley et al., 1999
; Nopoulos et al., 2000
). Cell packing density, or number of neurons per unit volume, in the planum temporale was also greater in women than men (Witelson et al., 1995
).
Compared to women, men have been found to have larger volumes, relative to cerebrum size, or differences in neuronal densities in other limbic and paralimbic regions [i.e. amgydala (Giedd et al., 1996), hypothalamus (Swaab and Fliers, 1985
; Allen et al., 1989
; Zhou et al., 1995
) and paracingulate gyrus (Paus et al., 1996
)], larger genu of the corpus callosum (Witelson, 1989
) and overall white matter volume (Passe et al., 1997
; Gur et al., 1999
), and greater cerebrospinal fluid [lateral ventricles (Agartz et al., 1992
; Kaye et al., 1992
) or sulcal volume (Gur et al., 1999
)]. Some have argued that men have more neurons across the entire cortex (Pakkenberg and Gundersen, 1997
; Rabinowicz et al., 1999
) and women, more neuropil (Jacobs et al., 1993
; Rabinowicz et al., 1999
). However, these findings are inconsistent with others (Witelson et al., 1995
; Harasty et al., 1997
), and suggest that sex differences in neuronal characteristics depend on the brain region and/or cortical layer assessed (Witelson et al., 1995
). Thus, the consistency and etiology of sexual dimorphisms in the human brain remain unresolved.
One potential factor involved in human sexual dimorphisms may be the effects of sex steroid hormones on brain development. However, for the most part, this has been demonstrated only in animals (McEwen, 1983; Tobet et al., 1993
; Pilgrim and Hutchison, 1994
; Park et al., 1996
; Gorski, 2000
). Although there are species-specific mechanisms, there may be some that are shared, given recent work demonstrating that the spatial organization of estrogen receptors in human adults in particular brain regions was similar to homologous regions in several other mammalian species (Donahue et al., 2000
).
Although the relative roles of testosterone and estrogen on the sexual differentiation of the human brain are as yet unclear, most likely both will contribute.
One mechanism well-studied in animals is the role of aromatization on sexual differentiation [reviewed by Kawata (Kawata, 1995)]. During critical periods of early development, testosterone is, in part, converted to estradiol by the enzyme aromatase. Estradiol has been found to enhance neuronal density and size, maturation and migration, neurite growth and synaptogenesis (McEwen, 1983
; Miranda and Toran-Allerand, 1992
), and masculinize the rat brain. During early brain development in rodents, ferrets and monkeys (MacLusky et al., 1987
; Clark et al., 1988
; Miranda and Toran-Allerand, 1992
; Tobet et al., 1993
; Park et al., 1996
), aromatase activity has been found in the hypothalamus and amygdala, where there is the highest concentration of sex steroid receptors, and the hippocampus, thalamic nuclei, specific cortical regions, and the corpus callosum and optic tract (MacLusky et al., 1987
). In animals, cortical regions show high concentrations of these receptors only during fetal and early postnatal development, which then recede postnatally (MacLusky et al., 1987
; Miranda and Toran-Allerand, 1992
), although not completely (Clark et al., 1988
). Animal studies have shown a significant association between the drop in cortical estrogen receptors postnatally and levels of messenger RNA, suggesting that estradiol may modulate cortical differentiation (Miranda and Toran-Allerand, 1992
; Toran-Allerand, 1996
). Further, animal studies have demonstrated the relationship between differential localization of androgen and estrogen receptors during critical periods of development and brain morphology and behavior (McEwen, 1983
; Sandhu et al., 1986
), suggesting that specific neurons may be more affected than others at the local level where aromatization takes place (Roselli and Resko, 1986
; MacLusky et al., 1987
; Clark et al., 1988
; Miranda and Toran-Allerand, 1992
; Pilgrim and Hutchison, 1994
).
In this study, we present a comprehensive examination of sexual dimorphisms in cortical and subcortical regions of the adult human brain using in vivo magnetic resonance imaging. We provide a preliminary step in indirectly examining the hypothesis that sex steroid hormones may be associated with sexual dimorphisms in the human brain. We tested the hypothesis that homologous brain regions in humans, identified in animal studies to have high levels of sex steroid receptors during early brain development, would be more likely to retain sexual dimorphisms in adulthood than brain regions that have not been so identified.
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Materials and Methods |
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The sample for this study was recruited through advertisements in the Boston area, and consisted of males (n = 27) and females (n = 21) selected to be comparable based on age, ethnicity, parental socioeconomic status (SES), reading ability and handedness (all but four were right-handed). [These normal subjects were recruited as comparison subjects for two studies of psychosis [NIMH. MH56956 (J.M.G.); MH43518 and MH46318 (M.T.T.)]. Subjects were excluded if they had a current or lifetime history of any medical illness affecting central nervous system function, current psychopathology or lifetime history of major psychiatric disorders. Evidence of significant psychopathology was indicated by any T-Scale (except Masculinity-Femininity) elevations above 70 on the short form of the Minnesota Multiphasic Personality Inventory (MMPI) (Vincent et al., 1984), evidence of substance abuse within the past 6 months, history of psychosis or psychiatric hospitalizations, and family history of psychosis. However, in order to avoid the risk of selecting a super-normal group, subjects were not screened for a lifetime history of psychopathology or neuropsychological dysfunction. All psychiatric evaluations were conducted by masters-level clinical interviewers with extensive diagnostic interviewing experience. All clinical material was evaluated by diagnostic experts (J.M.G., L.J.S.) who assessed whether a subject should be considered a normal comparison subject. In five previous publications on the neuropsychological status of these subjects, subjects were shown to be in the higher end of the average range for cognitive functioning in normal populations (Faraone et al., 1995
).
Subjects had a mean age of 39.8 years, were 93% Caucasian, with 14.4 ± 2.3 years of education, had an average IQ of 106.9 ± 12.2, and were predominantly from middle SES backgrounds. [SES was assessed using the two-factor Hollingshead and Redlich scale (Hollingshead and Redlich, 1958), a well-established rating scale based on weighting parental education and occupation into social classes IV.] There were no statistically significant or substantively meaningful differences between the characteristics of the men and the women (see Table 1
) [see also Goldstein et al. (Goldstein et al., 1999
)]. All subjects gave informed consent and were paid for their participation. All procedures were approved by the Institutional Review Boards for Human Subjects at Harvard Medical School, Massachusetts Mental Health Center, and Massachusetts General Hospital.
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MRI scans were acquired at the NMR Center of the Massachusetts General Hospital (MGH) with a 1.5 T General Electric Signa scanner. Contiguous 3.1 mm coronal spoiled-gradient echo images of the entire brain were obtained using the parameters: TR = 40 ms, TE = 8 ms, flip angle = 50°, field of view = 30 cm, matrix = 256 x 256, and averages = 1. MR images were processed and analyzed at the MGH Center for Morphometric Analysis (CMA). Images were positionally normalized by imposing a standard three-dimensional coordinate system on each three-dimensional MR 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 (nondeformation) transformation (Filipek et al., 1994; Caviness et al., 1996b
). Positional normalization overcomes potential problems caused by variation in head position across subjects during scanning. Scans were then resliced into the 3.1 mm coronal scans.
Each slice of the T1-weighted, positionally normalized threedimensional coronal scans was segmented into gray and white matter and ventricular structures using a semi-automated intensity contour mapping algorithm and signal intensity histogram distributions. This technique, described in detail elsewhere (Rademacher et al., 1992; Filipek et al., 1994
; Caviness et al., 1996b
; Goldstein et al., 1999
) yields separate compartments of neocortex, subcortical gray nuclei, white matter and ventricular system subdivisions, generally corresponding to the natural tissue boundaries distinguished by signal intensities in the T1-weighted images. The neocortex, defined by the graywhite matter segmentation procedure, was subdivided or parcellated into bilateral parcellation units, based on the system originally described by Caviness et al. (Caviness et al., 1996b
) and applied by Goldstein et al. (Goldstein et al., 1999
) on a subsample of the subjects reported here. This is a comprehensive system for neocortical subdivision, designed to approximate architectonic and functional subdivisions, and based on specific topographical anatomic landmarks present in virtually all brains [see original studies for details on the anatomic definitions (Rademacher et al., 1992
; Caviness et al., 1996b
)].
Segmentation and cortical parcellation are conducted by extensively trained, BA-level MR technicians who have had some college-level background in neuroanatomy or behavioral neuroscience. They are trained and supervised on these procedures on an ongoing basis by our neuroanatomist (N.M.). MR technicians are blind to any sociodemographic or clinical characteristics of the subjects, including their sex. Very good reliability of the cortical and subcortical regions has been established in several previous studies, including for the sample presented in this study (Caviness et al., 1996b; Goldstein et al., 1999
; Seidman et al., 1999
). Volumes, measured in cm3, were calculated for each brain region by multiplying the slice thickness by the area measurement of the region on each slice, and then summing over all slices on which the region appeared.
Data Analytic Approach
Sex differences in volumes of brain regions were tested using proportional volumes, relative to cerebrum size. This approach is consistent with methods used by other imaging studies (Filipek et al., 1994), and is necessary to compare men and women, given that men tend to have larger cerebrums than women. Total volumes of brain regions were analyzed for the hypothesis presented here. Effect sizes were calculated based on the adjusted mean female brain volume minus the adjusted mean male brain volume, divided by the pooled standard deviation of male and female volumes. (Analyses of covariance, controlling for cerebrum size, were also conducted to ensure that results were consistent across methods.)
We hypothesized that one potential reason for sexual dimorphisms across brain regions may be related to the impact of sex steroid hormones during brain development. In an indirect test of this association, we a priori divided the 45 brain regions into two groups. One group consisted of 30 homologous brain regions in humans, that were identified in rat, ferret and monkey studies to have a high density of estrogen and androgen receptors during early development (Pfaff and Keiner, 1973; MacLusky et al., 1987
; Clark et al., 1988
; Sibug et al., 1991
). The other group consisted of 15 other brain regions, for which a developmentally high concentration of sex steroid receptors has not been identified in the animal literature. The groups were independently created by an expert neuroanatomist (N.M.) and the principal author (J.M.G.) to ensure reliability. The high receptor-density group included: superior and middle frontal gyri, frontomedial and frontoorbital cortices (MacLusky et al., 1987
; Clark et al., 1988
; Simerly et al., 1990
; Kolb and Stewart, 1991
); basal forebrain (Pfaff and Keiner, 1973
); primary motor cortex (MacLusky et al., 1987
; Simerly et al., 1990
) (precentral gyrus); supplementary motor cortex (Clark et al., 1988
); anterior, posterior and paracingulate gyri (Pfaff and Keiner, 1973
; Clark et al., 1988
; Shughrue et al., 1990
; Kolb and Stewart, 1991
; Sibug et al., 1991
); agranular insular cortex (Kolb and Stewart, 1991
; Sibug et al., 1991
) (insula); parahippocampal gyrus (Clark et al., 1988
; Sibug et al., 1991
); posterior parietal cortex (MacLusky et al., 1987
; Clark et al., 1988
) (angular and supramarginal gyri); primary somatosensory (MacLusky et al., 1987
; Clark et al., 1988
; Simerly et al., 1990
) (postcentral gyrus); primary visual cortex (MacLusky et al., 1987
; Clark et al., 1988
) (lingual gyrus, occipital pole and superior calcarine sulcus); primary auditory cortex (Simerly et al., 1990
; Yokosuka et al., 1995
) (Heschl's gyrus); and subcortical regions: amygdala (Clark et al., 1988
; Simerly et al., 1990
), hypothalamus (Pfaff and Keiner, 1973
; MacLusky et al., 1987
; Clark et al., 1988
; Simerly et al., 1990
; Tobet et al., 1993
; Park et al., 1996
); hippocampus (MacLusky et al., 1987
); thalamic nuclei (Pfaff and Keiner, 1973
; Simerly et al., 1990
), the nucleus accumbens (Pfaff and Keiner, 1973
), and the caudate, putamen, globus pallidum (Sibug et al., 1991
).
In order to conduct a two-group comparison across multiple brain regions, a normalized summary measure, the absolute value of the t-statistic, was calculated for each brain area, estimating the mean magnitude of difference in proportions between female and male subjects (see t-statistics in Table 2). For each of the areas, the critical values for the t-statistics were 2.01 at the
= 0.05 level and 1.68 at the
= 0.10 level. A permutation test (Good, 1994
) was conducted to examine whether the distribution of these 45 standardized scores (t-statistics) significantly differed based on the dichotomous grouping by developmental level of estrogen and androgen receptor-concentration. Specifically, a difference in the means of the absolute values of the t-statistics was calculated using the observed 45 scores. The magnitude of this difference was compared to 20 000 iterations in which the brain regions were randomly regrouped. Under the null hypothesis that there is no relation between sexual brain dimorphism and developmental estrogen and androgen receptorconcentration level, the observed difference in the means of the absolute values of the t-statistics is not expected to be extreme when compared to the permutation distribution.
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Results |
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The permutation test (Good, 1994), which compares regions that, according to the animal literature, have developmentally high levels of estrogen and androgen receptors with other regions that do not, showed that only 120 of 20 000 iterations yielded a more extreme value than the observed data (P = 0.006, SE P = 0.00055, 95% CI = 0.0049, 0.0071). Thus, there was a significantly greater magnitude of adult sexual dimorphism among the group of brain areas with developmentally high levels of sex steroid hormone receptors than among the other regions. We investigated whether size of area accounted for the results by plotting the t-values and absolute t-values by size of region. There was no evidence that size of region accounted for the association between level of receptor density and magnitude of sexual dimorphism.
Region-specific sex differences can be seen in Table 2, in which brain regions were rank-ordered by effect size (ES), i.e. from the largest positive ES, which represented women with larger relative volumes than men, to the largest negative ES, which represented men with larger relative volumes than women. As seen in Table 2
, represented as positive ESs, women had larger cortical volumes, relative to cerebrum size, than men in the majority of the frontal and medial paralimbic brain regions. Significantly larger volumes in women than men (P < 0.05) were seen in the precentral gyrus, frontoorbital cortex, superior frontal and lingual gyri. Significance levels for sexual dimorphisms (P
0.10) were in the middle frontal, cingulate and posterior supramarginal gyri. Represented in Table 2
as large negative ESs, men had larger volumes, relative to cerebrum size, in frontomedial cortex and the hypothalamus (P = 0.11) and the amygdala and angular gyrus. Figure 1
illustrates that the brain regions with the largest positive and negative sexual dimorphism effect sizes, seen in Table 2
, fell into the group of regions designated as having developmentally high levels of sex steroid receptors.
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Discussion |
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Although in our study, the locations of sex steroid receptors were extrapolated from animal studies, there are only a few studies in humans, of which we are aware, that have reported mapping estrogen and androgen receptors in the brain (Rance et al., 1990; Sarrieau et al., 1990
; Puy et al., 1995
; Donahue et al., 2000
; Fernández-Guasti et al., 2000
). The studies were in human adults, i.e. not during development, although there was one study of brain tissue from five adolescent epileptic patients (Puy et al., 1995
). Further, the only cortical regions examined in these studies were temporal cortex (Sarrieau et al., 1990
; Puy et al., 1995
) and the basal forebrain (Donahue et al., 2000
). Finally, the most recent study (Donahue et al., 2000
) demonstrated that the spatial organization of estrogen receptors in human adults in the hypothalamus, basal forebrain, basal ganglia and amygdala were similar to homologous regions in several other mammalian species (Donahue et al., 2000
). This suggested that there are some similarities across mammalian species in the location of sex steroid receptors, even though animal studies have reported differences across species as well.
The interpretation that our findings implicate fetal and early postnatal factors is underscored by the significant specific cortical sexual dimorphisms, since the density of cortical gonadal receptors recedes dramatically after early postnatal development, as demonstrated in rats and monkeys (McEwen, 1983; MacLusky et al., 1987
; Clark et al., 1988
; Toran-Allerand, 1996
). Further, early postnatal effects in rats and monkeys are analogous to fetal timing in humans. Finally, we know from previous animal studies that during early critical periods of brain development, the effects of sex steroid hormones can potentially be irreversible (Pilgrim and Hutchison, 1994
; Gorski, 2000
). This was suggested in a recent study of Turner's syndrome women, i.e. women with chromosomal (XO) and hormonal abnormalities that affect early brain development (Murphy et al., 1993
). In vivo brain imaging studies of these women in adulthood demonstrated genetic and early hormonal effects on adult temporo-parietal and hippocampal volumes respectively (Murphy et al., 1993
). Although our study presents a more comprehensive examination of the cerebrum than previously reported, the validity of our findings is underscored by their consistency, in part, with previous in vivo human imaging studies that found similar normal sexual dimorphisms using different methods to assess brain volumes [e.g. cingulate gyrus (Paus et al., 1996
) middle frontal gyrus (Schlaepfer et al., 1995
), caudate (Filipek et al., 1994
) and overall cortical gray matter (Gur et al., 1999
)]. Further, sexual dimorphisms found in this study did not appear to be explained by size of region, functional type of cortical tissue (e.g. unimodalheteromodal) or cortical subcortical divisions.
There are a number of study limitations that raise questions about the interpretation of our results. First, we are making inferences about associations between early developmental factors and adult brain outcomes 40 years later. There are many changes that affect the emergence of adult sexual dimorphisms that are unaccounted for here. These include circulating androgens in adulthood, as indicated by recent work demonstrating morphometric changes in specific amygdaloid nuclei in the adult rat that were wholly controlled by circulating androgens (Cooke et al., 1999; McEwen, 1999
), and hormonal actions affecting structural plasticity of the adult brain during life experience (McEwen, 1999
). Second, morphometric analyses of MR images are only an approximation of the architectonically defined brain regions evaluated in animal studies. Thus, further work is required to demonstrate the translation from animal to human brain areas. Third, this study was not a study of developmental mechanisms, which would be necessary in order to actually test the hypothesis that hormonal activity early in development is associated with adult human brain volumes. Nevertheless, we do find region-specific, volumetric sexual dimorphisms of the adult human brain. Further, we suggest, in a preliminary step, that they may be, in part, associated with sex steroid activity early in development.
There is precedence for this idea suggested by the animal literature. For example, animal studies have demonstrated that aromatase activity is one of the primary causes of sexual differentiation (Shughrue et al., 1990; Pilgrim and Hutchison, 1994
; Kawata, 1995
). Aromatase activity is due to epigenetic hormonal factors, e.g. secretion of testicular testosterone, and sex-specific genetic programs affecting early brain development (Beyer et al., 1993
, 1994
) [reviewed by Kawata (Kawata, 1995
)], that are enhanced or modified by gonadal steroids later in development. These latter studies, as well as others (Tobet et al., 1993
; Park et al., 1996
), suggest that dimorphic determination may, in part, begin during neurogenesis and/or migration, which may have important implications for understanding the determinants of the postmigratory neuronal effects of sex steroid receptor activity (Tobet et al., 1993
; Park et al., 1996
). In addition, other developmental mechanisms responsible for sexual differentiation may include direct effects of testosterone, differential apoptotic cell death which has been found to be, in part, regulated by androgens and activational effects of circulating hormones, occurring later in development, e.g. during puberty, which can potentiate neural circuits laid down during early development (Pilgrim and Hutchison, 1994
; Kawata, 1995
).
Animal studies have demonstrated a sex difference in the density of estrogen or androgen receptors in different brain regions [reviewed by Kawata (Kawata, 1995)]. However, sex differences in morphology may not be accounted for by differential densities of receptors, since others have shown similar availability of these receptors (Simerly et al., 1990
; Sibug et al., 1991
), but sex differences in the level of aromatase enzymes, the structure of the aromatase-containing neurons, or the level of proteins such as
-fetoprotein that may protect the female brain from the masculinizing effects of aromatization (Shughrue et al., 1990
; Shinoda et al., 1993
, 1994
; Pilgrim and Hutchison, 1994
; Kawata, 1995
). The latter studies suggest that the potential for sexual dimorphisms may be the same in males and females, and determined more by factors affecting enzymatic activity. In addition, the co-localization of gonadal receptors with neurotransmitters, such as the monoamines (Canick et al., 1987
; Reisert et al., 1990
; Beyer et al., 1991
; Stewart et al., 1991
) and
-aminobutyric acid (GABA) (O'Connor et al., 1988
; Tobet et al., 1999
), and growth factors, such as insulin and nerve growth factor (Kawata, 1995
; Toran-Allerand, 1996
), may mediate the relationship between receptor density and dimorphism. These findings in animals raise hypotheses about potential mechanisms to test in human studies.
Although our findings do not provide a test of a developmental mechanism, they have implications for testing hypotheses about the timing of sexual dimorphisms in human brain development, which can lead to hypotheses about developmental mechanisms. The findings may also have implications for understanding sex differences in particular cognitive domains (Goldman et al., 1974; Collaer and Hines, 1995
), since studies have demonstrated that early exposure to gonadal hormones affects brain morphology and cognition (Murphy et al., 1993
; Collaer and Hines, 1995
; Wilson, 1999
). Normal population studies have identified small, but significant, sex differences in aspects of verbal fluency, perceptual speed, olfaction and visualspatial skills (Collaer and Hines, 1995
; Toomey and Goldstein, 2000
). Our findings regarding sexual dimorphisms in prefrontal regions (e.g. middle, inferior and orbital prefrontal), and posterior parietal and occipital cortices may contribute to explaining some of these effects. In fact, human and animal studies have demonstrated significant associations between sex differences in brain morphology and specific cognitive domains, such as verbal and visualspatial skills (Goldman et al., 1974
; Andreasen et al., 1993
; Raz et al., 1998
; Gur et al., 1999
). Thus, our findings may have important implications for understanding sex differences in brain and behavioral abnormalities in neurodevelopmental disorders with fetal origins.
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Notes |
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Address correspondence to Jill M. Goldstein, Ph.D., Massachusetts Mental Health Center, Harvard Institute of Psychiatric Epidemiology and Genetics, 74 Fenwood Rd, Boston, MA 02115. Email: jill_goldstein{at}hms.harvard.edu.
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