Sex Differences in Brain

Structure, Function, and

Chemistry
Hamidreza Chegini
ICSS_2010
Difference Between Sex and Gender
Sex: distinctions in biology between
men and women,
Gender: is rooted in biology and
shaped by environment and describes
ones self-representation as male or
female
Introduction
Evaluate the literature on sex differences in
brain structure, chemistry, and function
using in vivo imaging methodologies,
SPECT, PET, MRI and fMRI
Postmortem studies
Evaluation of brain sex differences in
neuropsychiatric disorders.
Animal models studies
Sex
Differences
in the Brain
are
Structural

A major biological sex difference is the
menstrual cycle
Menstrual cycle is associated with variations in
female sex steroid hormones over a 28- to 32-day
period.(1- early follicular, with low levels of
estrogen and progesterone; 2- later follicular,
with significantly elevated levels of estrogen
only and 3- mid-luteal, with significantly
elevated levels of progesterone only)
Estrogen : involved in cognition and
neuroprotection.
Estrogen : involved in the sexual differentiation
of the brain (morphology and neurochemistry).


Chemistry of Brain
Brain chemicals: receptors and transporters are
measured using radiotracers and imaged using
a PET or SPECT camera.
sites for specific radiotracers
1. Serotonin transporter, 5-HT1A, and 5-HT2A
2. Dopamine :D1 & D2 receptors, DA
transporter;
3. GABA A-benzodiazepine receptors
4. Nicotinic acetylcholine receptors
5. mu opioid receptors
Tracers are currently under development for
other chemical sites in brain including, but
not limited:
1. Amyloid,
2. NMDA receptors,
3. Muscarinic Ach receptors,
4. 5-HT1B, 5-HT6 and 5-HT7
5. Cannabinoid receptors that will be available
soon to explore sex differences in brain
neurochemistry.
The majority of studies reporting
sex differences in brain chemistry
have focused on
serotonin and dopamine systems
and emerging evidence also
suggests differences in
GABA systems.
Sex Differences
in
Brain structure

It has been long known that women have
smaller brain volumes than men, which is
explained in part by their smaller stature.
Average brain volumes (excluding cerebral
spinal fluid , meninges, and other non brain
tissue)
Women 1130 cc
Men 1260 cc
Gray and white matter volumes also
vary by sex
Women have a higher percentage of gray matter,
whereas men have a higher percentage of white
matter and CSF .

The gray/white matter ratio was consistently
higher in frontal, temporal, parietal, and occipital
lobes; cingulate gyrus; and insula in women versus
men.

Men have greater brain volume ,
greater CSF volume or lateral
ventricles , and greater sulcal
volume compared with women.

Neuronal sizes
The authors reported that females had
more overall neuropil (neuronal and
astrocytes sizes) than males, but the males
had higher neuronal densities (more
synaptic contacts /mm3).
The men had smaller but more numerous
units, while women had larger cells,
especially in the left hemisphere (women
are more frequently right handed and have
better language abilities).
Goldstein et al. (2001) showed that when
relative difference in overall brain size is taken
into consideration, while the female hippocampus
is larger than that of the male, males have a
bigger volume of the CA1 field and larger
neurons than females.
Females with very high levels of estrogen
during their menstrual cycle are more likely to
suffer from catamenial epilepsy; this could be due
to the greater sensitivity of the female
hippocampal cells to neurotransmitters,
glucocorticoids, and NMDA receptor binding.
Males had higher numbers of astrocytes than
females in the CA3 area of the hippocampus, but
the females had higher numbers of those cells in
the CA1 region.
Recently, Cerghet et al. (2006) reported that the
density of oligodendrocytes and the expression of
myelin proteins in the corpus callosum, fornix
and spinal cord are 2040% greater in male
compared to female rats.
But in the corpus callosum, the generation of
new glia and their apoptotic loss is twice as great
in females as in males.
IQ Correlation with brain lobs
In men, IQ correlates with gray matter
volume in the frontal and parietal lobes,
In women, IQ correlates with gray matter
volume in the frontal lobe and Brocas area.
Suggesting that men and women use
different brain areas to achieve a similar IQ.
Age-related brain volume
In adult men with age increased: volume
loss in frontal and temporal lobes.
whereas in women with age increased:
volume loss in hippocampus and parietal
lobes.
In adult men and women, global gray
matter decreases linearly with age with a
steeper decline in men .finding has been
confirmed postmortem.
Young girls have larger hippocampal volume ,
whereas the amygdala is larger in boys.
Interestingly, enzymes for estrogen synthesis and
estrogen receptor messenger have been localized
to the hippocampus ,
Whereas androgen receptors are more prevalent
in the amygdala.
The reasons for these differences are not clear but
may be related to the female sex steroids.
Sex Differences in Whole Brain
and Selected Brain Regions
from in vivo MRI Studies
Men > Women
Total Volume
White Matter
CSF
Total Corpus
Callosum
Cerebellum



Pons
putamen
Amygdala
Hypothalamus
Frontomedial
Cortex
Women > Men
Caudate
Hippocampus
Fronto-orbital Cortex
Brocas area
Right parietal lobe
Ant. commissure
Superior Frontal and Lingual Gyri
Sex Differences in
Brain chemistry

Serotonin
There is a wealth of preclinical and clinical
evidence supporting sex differences in
serotonin neurotransmission.
Whole blood 5-HT levels are higher in
women compared with men , which appears
to be genetically determined.
Men synthesize serotonin significantly
faster than women.
Serotonin: coordinate complex sensory and
motor patterns during a variety of behavioral
states and implicated in the pathology of mood
disorders, sleep and eating disorders, and
schizophrenia.

Sex differences in 5-HT function may underlie
the gender difference in the prevalence of
depression and may impact pharmacological
treatments that target 5-HT neurotransmission.
Healthy women have higher 5-HT
transporter availability in the diencephalon
and brainstem compared with men.

5-HT transporters are selectively decreased
in an age-specific manner in depressed
women but not in depressed men.
5-HT transporter functions to regulate 5-HT
neurotransmission
Baseline 5-HT function may be higher in women
versus men
Dysregulation of this function in young
depressed women may explain sex specific
pathophysiological mechanism underlying
depressed mood in young women
It has been suggested that young women may be
more responsive to SSRIs versus tricyclic
compared with older women and men.
Figure 1. Proposed sex differences in a 5-HT synapse, with
higher 5-HT reuptake transporters, neurotransmission, and
5HT1A receptors in women versus men.

Women have higher 5-HT1A receptor numbers
than men in certain brain regions,
While a sex difference in 5-HT2A receptors has
been reported , there is substantial evidence
supporting no difference in receptor levels but a
difference in radiotracer metabolism that may give
the appearance of higher 5-HT2 receptor number.
Dopamine
DA function is enhanced in women compared to
men.
DA is important for reward processes including
the reinforcing effects of most drugs of abuse
and has been implicated in a variety of
neuropsychiatric disorders including Parkinsons
disease, which is more prevalent in men than
women, and schizophrenia, for which sex
differences exist in the onset and course of the
disorder.
Amphetamine- induced DA release in the
right globus pallidus and right inferior
frontal gyrus was higher in women
compared with men.
The DA transporter, which functions to
regulate synaptic DA availability, is higher
in women compared with men.
Healthy women have higher presynaptic
DA tone in striatum and higher extrastriatal
DA receptor density compared with men.



These results have implications for the many
disease states in psychiatry, such as
schizophrenia, that are associated with
disturbances in DA neurotransmission and show
differences by sex in rate and course.

Specifically, higher dopaminergic tone in
women may protect against the development of
schizophrenia, alcoholism, and other diseases
with established disturbances in DA function.



Notably, estrogen may possess neuroprotective
qualities in its interaction with the DA system,
especially with regard to schizophrenia.

A second increase in the incidence of
schizophrenia in women between the ages of 45
and 54 may be attributed to menopause and
decreasing sex steroid hormone levels.
If women have higher dopaminergic tone,
antidopaminergic treatment drugs may be
more effective in women versus men.

In early Parkinsons disease, a robust sex
difference in prefrontal monoaminergic
activity may be associated with observed
clinical sex differences, such that men have
more severe parkinsonian motor problems than
women , which DA likely underlies.
Cholinergic system
Cholinergic system (which is involved
in memory and cognition):
Imaging the vesicular acetylcholine
transporter, a marker of cholinergic
synaptic density, demonstrated that
women have higher concentrations of
cholinergic synaptic terminals.
The length of hormone therapy in postmenopausal
women was positively correlated with the
concentrations of cholinergic synaptic terminals in
cortical areas and the posterior cingulate ,
suggesting that hormone therapy may positively
influence the survival of cholinergic cells in
postmenopausal women.

Women also express higher numbers of cortical
muscarinic Ach receptors.
GABAergic system
Women have higher cortical GABA levels than men as
measured with magnetic resonance spectroscopy
(MRS) .
GABA levels in healthy and unmedicated women with
premenstrual dysphoric disorder (PMDD) vary across
the menstrual cycle such that cortical GABA levels
declined between the follicular and luteal phase in
healthy women and increased between the follicular
and luteal phase in women with PMDD.
This indicates that GABA neurotransmission in tightly
regulated by the menstrual cycle.
Opioid system
Higher mu-opioid binding in women versus men
has been reported throughout cortical and
subcortical regions.

Women in the follicular phase of their menstrual
cycle appear to have a negative correlation
between fluctuating estradiol and mu-opioid
receptor availability in the amygdala and
hypothalamus.
Serotonin
Neurotransmission
Brain Regions
5-HT Transporter Brainstem
F > M
5-HT1A Receptor
Amygdala,
hippocampus,
cingulate, medial and
orbital prefrontal cortex
F > M
5-HT2A Receptor
Frontal, cingulate cortex
F > M

Dopamine
Neurotransmission
DA Transporter Striatum,Caudate
nucleus
F > M

DA Synthesis Caudate, putamen
F > M
D2 Receptor Striatum
Frontal cortex
F > M affinity
F <M binding potential

GABA
Neurotransmission
Occipital cortex F > M cortical GABA
Sex diff. in other parameters
Sex differences has reported in NO(specially
nNOS=neuron Nitric Oxide Synthesis),
BDNF(Brain Derived Neurotrophic Factor) ,
CREB(Cyclic AMP Response Element Binding
Protein) in animal models.
Sex Differences in Brain
Function

Cerebral Blood Flow
A majority of studies have demonstrated
that women consistently have higher global
cerebral blood flow (CBF) compared with
men during rest and cognitive activity
regardless of the brain imaging modality.
Cerebral Metabolic Rate of glucose
utilization (CMRglu) tends to be higher in
women versus men , particularly in the orbital
frontal area , although not consistently.

Global CMRglu may be inversely correlated
with brain size such that individuals with
smaller brains have higher CMRglu.
Cerebral Metabolic Rate of
glucose utilization
Regional CMRglu varied significantly with
menstrual cycle phase, suggesting that there are
acute hormonal effects on brain glucose
metabolism .

These findings cast doubt on the interpretations
of studies that did not control for menstrual cycle
phase or hormone levels and highlight the
importance for future studies to control biological
parameters known to affect cerebral blood flow,
such as the menstrual cycle.
The direct implications of sex
differences in global cerebral blood
flow on psychiatric disorders are
unclear; however, increased blood flow
in the brains of women may lead to a
better distribution of psychotropic
drugs in the brain.
There is some evidence in postmenopausal
women that estrogen increases regional
cerebral blood flow.
Estrogen may account for some of the
variability in blood flow and metabolism
between men and women.
These differences may explain why some
drugs are more effective for treating
neuropsychiatric disorders in women versus
men.

Hormones may modulate arousal circuitry in
women.
Circulating estrogen has been shown to reduce
arousal in women via the hypothalamic-
pituitary-adrenal axis .
Postmenopausal women had decreased
arousal compared with premenopausal women
in response to erotic videos, which was
reversed with the administration of estradiol.
Cognition
Sex differences in cognition have been
well documented women perform
better on verbal and memory tasks,
wherease men excel in spatial tasks.

Men outperform
women
Women
outperform Men
Affect and Emotion
Sex differences have also been observed in affect
and emotion processing. Women perform better
in speeded emotion recognition tasks and are
more expressive.

Regarding emotional experience, women are
more prone to clinical depression, mood
fluctuation associated with phases of the
menstural cycle have been documented, and such
phase-associated hormonal changes may relate to
cognitive performance.
Aggression
However, perhaps the most salient
difference between men and women in
emotional behavior, is the discrepancy
in aggression.
Emotion
Several studies have shown that female and
male subjects process emotions differently, with
women being more emotionally expressive and
showing stronger psychophysiological responses
to emotional stimuli than men.
Overall, in women the processing of emotion
more frequently activated midline limbic
structures, including the subcallosal anterior
cingulate, thalamus, midbrain and cerebellum,
whereas males showed more activation in left
inferior frontal and posterior cortices.
Emotional decision task
Shirao et al. (2005) found that the bilateral
caudate nuclei and left putamen were more
strongly activated in women than in men while
performing an emotional decision task with
unpleasant words concerning interpersonal
relationships,
while the paralimbic area was activated only in
women and the left medial prefrontal cortex was
activated only in men while performing an
emotional decision task with unpleasant words
concerning body image.
Semantic Processing
The authors suggested that semantic
processing in women is more susceptible
to influences from emotional prosody
than is semantic processing in men.
Spatial memory task
Healthy men and women received fMRI
scans while performing a spatial memory
task in a virtual environment.
Although the men and women performed
the task equally well, the left hemisphere
hippocampus was activated in women
performing the task, whereas the right
hemisphere amygdala was activated in men.
Mood Induction
Using fMRI, Women showed significantly
greater activation in the right posterior cingulate,
the left putamen and the left cerebellum during
positive mood induction, and in bilateral superior
temporal gyri and cerebellar vermis during
negative mood induction, compared to men.

Furthermore , perception of emotions would
lead to a greater activation of the basal ganglia in
females.

Orbitofrontal-to-amygdala size ratio
Gur et al. (2004) reported that the relative size of the
orbitofrontal compared to amygdala regions is significantly
greater in women compared to men , possibly pointing
toward a differential ability to exert emotional control in
the sexes.

Interestingly, the ratio between the two structures is
differentially altered in schizophrenia:
the orbitofrontal-to-amygdala size ratio is increased in
schizophrenic relative to healthy men, yet it is decreased in
schizophrenic relative to healthy women.

The amygdala is considered to be primary
involved in excitatory aspects of emotional
behavior while the orbito-frontal region is
implicated in modulation.
Assuming that volume is associated with
increased brain functional capacity , the
lower incidence of violent behavior in
women would lead to the prediction that
women have higher orbito-frontal relative to
amygdala volume than men.
It is noted that studies reporting amygdala
effects predominantly on the right side of
the brain involved only male subjects,
whereas studies reporting amygdala effects
predominantly on the left side of the brain
involved only female subjects.

This finding suggested that subject sex
might be one determinant of the
hemispheric lateralization of amygdala
function.

Sex-related hemispheric lateralization of
amygdala function in long-term memory for
emotionally arousing films.




Men> Women



Women>Men
These results are consistent with the view
that, under emotionally arousing conditions,
activation of right amygdala/hemisphere
function produces a relative enhancement
of memory for central information in males,
and activation of left amygdala/ hemisphere
function in females produces a relative
enhancement of memory for peripheral
details in women.
Verbal episodic memory task
There are a number of studies reporting that
women perform at a higher level than do men on
episodic memory tasks.
For example sex differences in favoure of
women are found in word recall, word
recognition, story recall, name recognition and
recognition of concrete pictures and objects.
Women also surpass men on verbal production
tasks, such as rapid word retrieval (i.e.,verbal
fluency).
Visuospatial episodic memory tasks
As men typically perform at a higher level
than do women on visuospatial tasks-for
instance, understanding what an irregular figure
looks like when it is rotated in space men can
be expected to perform at a higher level than
women on episodic memory tasks, requiring
visuospatial processing.
Face Recognition
Many studies have shown that women
outperform men on face recognition tasks.
Although face recognition cannot readily be
assumed to rely on verbal processing, we
hypothesized that women could utilize their
greater verbal abilities to encode faces, by
verbalizing the face : a dark, blue-eyed
handsome man.

The results also revealed that the female
recognition advantage was magnified for female
faces. The tendency for female to remember for
faces of their own sex than faces of the opposite
sex(e.g., own sex effect) is found across age.
Both young girls and adult women
remember more female faces , irrespective
of the age of the faces (e.g., faces of young
girls and adult women), and across ethnicity
(e.g.,ethnically familiar or unfamiliar faces).

In contrast, men tend to remember male
and female faces equally well.
we suggest that women allocate more attention
to female than to male faces.

A study on infants has shown that infant girls
devote more attention to faces than infant boys
do.

Speculatively, the attention that infant girls
devote to faces may form the basis of womens
superior face recognition ability.
Thank You