Structural Differences in the Cerebral Cortex
of Healthy Female and Male Subjects:
An MRI Study
Thomas E. Schlaepfer, MD; Gordon J. Harris, PhD; Allen Y. Tien, MD;
Luon Peng; Seong Lee and Godfrey D. Pearlson; MD
Division of Psychiatric Neuroimaging
Department of Psychiatry
The Johns Hopkins Medical Institutions
PDF version for Internet Distribution
as published in Psychiatry Research-Neuroimaging 61:129-135, 1995
The copyright has been transferred to: Elsevier Science Ireland Ltd.
Address Correspondence To:
Thomas E. Schlaepfer, MD.
The Johns Hopkins Hospital
Department of Psychiatry / Meyer 3 - 166
600 N. Wolfe St.
Baltimore, MD 21287 - 7362
phone:
fax:
e-mail:
(410) 955 - 4725
(410) 614 - 3676
[email protected]
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ABSTRACT
There are both reproductive and non-reproductive behavioral differences between
men and women. Brain regions involved in determining sexual behavior have been
reported to differ between the sexes. Non-reproductive, cognitive functional
differences between sexes might be reflected in higher-order cortical structural
dimorphisms, which have not previously been studied. We hypothesized that
cortical regions involved in verbal behavior (which is sexually dimorphic) would
differ between sexes. Using magnetic resonance imaging we assessed gray matter
volumes in several cortical regions in 17 women and 43 men.
Women had 23.2% (dorsolateral prefrontal cortex) and 12.8% (superior temporal
gyrus) greater gray matter percentages (corrected for overall brain size and age)
than men in language-related, but not in a more visuo-spatially-related cortical
region (p<0.001). These data seem to establish sexually dimorphic structural
differences in the cerebral cortex, consistent with prior cerebral blood flow
reports.
Key Words. Heteromodal Association Cortex, gender dimorphism, cortical gray
matter volume, verbal fluency, magnetic resonance imaging
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INTRODUCTION
Men and women differ not only in their biology but also in their
reproductive and non-reproductive behavior. Brain regions involved in
controlling sexual behavior have been reported to differ between the sexes (Swaab,
et al., 1985). Non-reproductive, cognitive functional differences between sexes
might be reflected in higher-order cortical differences, which to our knowledge
have not previously been studied. The purpose of this study was to investigate
structural differences of cerebral cortex between men and women.
Sexually dimorphic behaviors include both reproductive and cognitive
elements. Neuropathological studies report gender differences in several human
brain regions related to reproductive behavior (Swaab, Fliers, et al., 1985; Allen, et
al., 1989). There are preliminary reports that homosexual men have subcortical
brain regions which resemble those of women more than those of heterosexual
men. For example, the suprachiasmatic nucleus of the hypothalamus was found to
be 1.7 times larger in heterosexual men than in men with homosexual orientation
(Swaab, et al., 1990). Another nucleus of the hypothalamus, INAH-3, which is
known to be smaller in women, was found to be smaller in homosexual than in
heterosexual men (LeVay, 1991).
It has been established that there are subtle sexual differences in human
cognitive functions (Maccoby, et al., 1974). A consistent finding is that males tend
to perform better in tasks requiring the mental ability to retain and manipulate
spatial and numeric data that cannot be solved verbally (Benbow, et al., 1980;
Holden, 1991), whereas females generally have greater verbal abilities (Bakan, et al.,
1974; Gladue, et al., 1990). This cognitive dimorphism should also be reflected in
functional and/or structural brain differences between the sexes, analogous to the
neuroanatomic dimorphism related to reproductive behavior.
Several such structural differences have been established in volumetric postmortem neuropathology studies. A recent study reported that handedness
correlated with anatomy of the Sylvian fissure in men but not in women (Witelson,
et al., 1992). It has also been reported that the caudal portions and the splenium of
the corpus callosum are larger in women than in men (de LaCoste-Utamsing, et al.,
1982). A similar study suggested that the anterior commissure is also larger in
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CORTICAL GENDER DIMORPHISM
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women, and even larger in homosexual men (Allen, et al., 1992). Functionally, a
cerebral blood flow study found higher cortical blood flow in women than in men
(Gur, et al., 1982), which was hypothesized to be related to increased gray matter
volume in women.
Such differences, if they exist, may well play an important role in cognitive
differences. However, to date there are no post-mortem or in-vivo volumetric
studies directly comparing regional cortical volumes in healthy women and men.
Since women perform better on verbal fluency tasks than men (Bakan and Putnam,
1974; Gladue, Beatty, et al., 1990), we hypothesized that cortical regions involved in
verbal fluency would show greater gray matter volume in women. Two cortical
areas, the superior temporal gyrus (STG) (Milner, 1971), and the dorsolateral
prefrontal cortex (DLPFC) (Luria, 1970), are closely linked to higher order verbal
function. We used magnetic resonance imaging (MRI) to study cortical gray
matter volumes in STG and DLPFC in healthy women and men. These regions
are both part of the heteromodal association cortex (HASC); a highly integrated
and reciprocally connected system, which is of importance in coordinating
sensory, motor, and behavioral activities (Flechsig, 1896; Mesulam, 1985; Gur, et al.,
1993; Schlaepfer, et al., 1994). A third region belonging also to the HASC system is
the inferior parietal lobule (IPL). This region is additionally to verbal function
mainly related to visuo-spatial processing (Fried, et al., 1982). Therefore IPL was
used to control for regional specificity.
MATERIAL AND METHODS
Subjects
Study subjects were 17 women (age 33.7 ± 9.1 years), and 43 men (30.7 ± 7.4
years) recruited from Johns Hopkins Hospital staff and the community. Age was
not significantly different between men and women. Subjects were screened for
mental disorders by a psychiatrist using the Structured Clinical Interview for
DSM-III-R (SCID) (Spitzer, et al., 1990). They had no history of current or past
substance abuse or neurological illness (including head trauma causing
unconsciousness greater than one hour), and no personal or family history of major
psychiatric illness. This project was approved by the Johns Hopkins Joint
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Committee on Clinical Investigations (JCCI), and written informed consent was
obtained from all subjects.
Equipment and Scan Protocol
Magnetic resonance images were acquired on a General Electric (Milwaukee,
WI) 1.5 Tesla Signa scanner. Contiguous, 5mm thick axial slices were acquired with
simultaneous T2 and proton sequences. The images extended from the base of the
cerebellum to the vertex, parallel to the anterior commissure-posterior
commissure (AC-PC) line. Scan parameters were TR = 2500, TE = 20/80. Number
of excitations was one. The analysis software described in this paper was developed
in-house in "C" and "XWindows" on a Digital Equipment Corp. (DEC, Nashua,
NH) DECstation 3100 workstation with color graphics monitor operating under
Ultrix-32 v.4.2. The images were archived on read/write magneto-optical disks (300
Mb per side).
Image analysis
We examined gray matter volume using quantitative MRI segmentation methods
(Harris, et al., 1991; Harris, et al., 1994) in STG and DLPFC regions in all subjects
(Figures 1 and 2), and compared these volumes among the two groups. We also
calculated IPL gray matter, total brain, cerebrospinal fluid (CSF), gray, and white
matter volumes, and computed all measures as a percentage of total brain volume
to correct for differences in brain size. The reliability and validity of the
segmentation method used in this study have been presented in detail previously
(Harris, Rhew, et al., 1991; Harris, Barta, et al., 1994).
We performed global gray-white-CSF segmentation on all slices. Regional
segmentation was done on ten selected slices ranging from the temporal lobe (three
slices below that one in which the frontal horns of the lateral ventricles were
closest together corresponding to Slice 8-9 of the Talairach atlas (Talairach, et al.,
1988)) to six slices above this frontal horn slice. Approximations to the three
heteromodal association cortex regions were defined as described earlier (Harris,
Barta, et al., 1994; Schlaepfer, Harris, et al., 1994). Superior temporal lobe area was
defined on the bottom two slices, in the second and third most anterior cortical
regions. The dorsolateral prefrontal cortex was defined on the fourth through
seventh slice from the bottom in the second most anterior cortical region. The
inferior parietal cortex was defined on the sixth and seventh slice from the bottom
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in the fourth most anterior cortical region. These cortical regions were defined as
the HASC areas for data analysis. We approximated definition of these regions
using a cortical profiling approach described previously (Harris, Barta, et al., 1994),
which defines a 2cm wide ring of cortex, which is divided into five equiangular
regions per hemisphere. A slicewise view of these regions is shown in Figure 1,
and an approximate surface projection of these regions on a volume rendered brain
is shown in Figure 2.
Data Analysis
Analysis of covariance was performed with the percentage of gray matter in
DLFPC, STG and IPL areas in relation to total brain volume as dependent variables
and age as covariate to account for age-related volume changes for all measures.
RESULTS
As shown in Table 1, women had significantly smaller brain volumes (F =
8.86, p < 0.001) than men. Gray matter percentages were calculated to correct for
the smaller brain size in women. Women had significantly higher gray matter
percentage than men in DLPFC (F = 21.9; p<0.0001), and STG (F = 7.8; p <
0.001)(Figure 3).
Women had 23.2% greater DLPFC, and 12.8% greater STG gray matter
percentage than did men. IPL gray matter percentage (F = 2.2, n.s.), and overall
gray matter (F = 0.9, n.s.), white matter (F = 2.1, n.s.) and CSF percentages (F = 0.2,
n.s.) were not significantly different between groups (Table 1).
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DISCUSSION
Our finding of a smaller total brain volume in healthy female subjects agrees
with previous findings (Dekaban, 1978; Ho, et al., 1980). Furthermore, increased
STG and DLPFC gray matter percentage in women is consistent with prior
reports of increased corpus callosum width in women (de LaCoste-Utamsing and
Holloway, 1982; Holloway, et al., 1986). Since women have relatively more cortical
gray matter, it would be necessary to have more axonal interconnections, hence
larger corpora callosi. Since females have smaller brains, the fact that our method
used a fixed cortical rim thickness (2 cm) may lead to a higher proportion of brain
being designated as cortical regions in females than males. However the
differences we detected were regional and not global.
Several groups have reported higher cerebral blood flow (CBF) for females
compared to men using methods like 133xenon inhalation (Gur, Gur, et al., 1982;
Shaw, et al., 1984; Devous, et al., 1986). It has been observed, that these differences
in CBF might be attributable to artifacts of the 133xenon technique like possible
male-female differences in the blood brain partition coefficient for xenon (Daniel,
et al., 1988). However, other groups found higher brain metabolic rates for glucose
in females in studies using positron emission tomography (Baxter, et al., 1987;
Yoshii, et al., 1988). We feel that the relatively higher gray matter volume of
dorsolateral prefrontal cortex (DLPFC) and superior temporal gyrus (STG) in
females might account for the findings of higher blood flow and higher metabolic
rates in females.
Since the cortex of the inferior parietal lobule (IPL) is involved in part in
processing visuo - spatial information (Fried, Mateer, et al., 1982) and men tend to
perform better on tasks involving visuo - spatial abilities (Benbow and Stanley,
1980; Holden, 1991), higher gray matter volumes in this region might have been
predicted for male subjects. There is also evidence that the region around the IPL
mediates short - term verbal memory (Ojemann, et al., 1979) and other language related functions (Ojemann, et al., 1989). We therefore hypothesize that in IPL a
tendency to higher relative gray matter volume in men related to the better visuo spatial abilities is counterbalanced by less gray matter due to poorer verbal abilities.
Schlaepfer et al.
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Despite the fact that we studied a relatively large number of subjects using a
method with proven reliability, this study has two important shortcomings: Since
we used cortical profiles with a predetermined thickness, our measurements likely
include slightly different structures in brains of different sizes, which could
conceivably lead to a systematic measuring bias. Any such effect of brain volume
on regional distribution of gray matter in he normally smaller-headed female
subjects would be expected to lead to the same significant decreases in
Heteromodal Association Cortex gray matter volume as those we documented
previously in a study of (smaller-headed) schizophrenic subjects (Schlaepfer et al.,
1994).
In fact the opposite was found in this study. An other shortcoming is that
the index regions of interest were only approximations of HASC regions. Gender
related differences might also involve MRI technical factors such as partial volume
effects, or between - group differences in gyral patterns or overall brain structural
relationships. However, our findings, although preliminary in nature, suggest that
there are localized structural gender-related differences in the cerebral cortex, in
regions involved in control of language functions.
The specificity of increased gray matter in women in higher order cortical centers
concerned with verbal function may be related to prior findings of sexually
disparate verbal cognitive performance (Bakan and Putnam, 1974; Benbow and
Stanley, 1980; Gladue, Beatty, et al., 1990; Holden, 1991).
Acknowledgments. This work was supported by a grant of the Swiss National
Science Foundation (Dr. Schlaepfer) and NIH grants MH40391, MH43775,
OPCRC-RR0722 (Dr. Pearlson).
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FIGURE CAPTIONS
Figure 1:
Seven gray/white/CSF segmented MRI slices are shown with regions of
interest approximating to dorsolateral prefrontal cortex (DLPFC, red stippling),
superior temporal gyrus (STG, blue stippling), and inferior parietal lobule (IPL,
black stippling).
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Figure 2:
Lateral view of brain surface in a three-dimensionally volume rendered
brain image. Approximate projected areas of dorsolateral prefrontal cortex
(DLPFC, red stippling), superior temporal gyrus (STG, blue stippling), and inferior
parietal lobule (IPL, black stippling), the regions described in Figure 1, are shown.
Selected slice planes are shown as white parallel lines.
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Figure 3:
Gray matter as percentage of total brain volume for dorsolateral prefrontal cortex
(DLPFC), superior temporal gyrus (STG), and inferior parietal lobule (IPL) are
displayed. Error bars represent the 95% confidence interval. Values for female
subjects are significantly different from male subjects for dorsolateral prefrontal
cortex (DLPFC, F = 21.9, p < 0.0001) and superior temporal gyrus (STG, F = 7.8, p
< 0.001). There was no difference for the inferior parietal lobule (IPL, F = 2.2, n.s).
Gray Matter (% of Brainvolume)
2
Male
Female
1
0
DLPFC
STG
IPL