The adult human brain weighs on average about 3lb (1.5 kg) [1] with a size of around 1130 cm³ in women and 1260 cm³ in men although there is substantial individual variation [2]. Male brains are about 10% larger than female brains and weigh 11-12% more than that of a woman. Men's heads are also about 2% bigger than women's. This is due to the larger physical stature of men. Male’s larger muscle mass and larger body size requires more neurons to control them. The brain weight is related to the body weight partly because it increases with increasing height [3]. This difference is also present at birth. A boy’s brain is between 12-20% larger than that of a girl. The head circumference of boys is also larger (2%) than that of girls. However, when the size of the brain is compared to body weight at this age, there is almost no difference between boys and girls. So, a girl baby and a boy baby who weigh the same will have similar brain sizes.

Sexual dimorphisms of adultbrain volumes were more evident in the cortex, with women havinglarger volumes, relative to cerebrum size, particularly in frontaland medial paralimbic cortices. Men had larger volumes, relative to cerebrum size, in frontomedial cortex, the amygdala and hypothalamus. There was greater sexual dimorphismin brain areas that are homologous with those identifiedin animal studies showing greater levels of sex steroid receptorsduring critical periods of brain development. These findingshave implications for developmental studies that would directlytest hypotheses about mechanisms relating sex steroid hormonesto sexual dimorphisms in humans [4].

Ratios of grey to white matter also differ significantly between the sexes in diverse regions of the human cortex [5]. Variations in the amount of white and grey matter in the brain remain significant [6-8]. Men have approximately 6.5 times more gray matter in the brain than women, and women have about 10 times more white matter than men do [3]. At the age of 20, a man has around 176,000 km and a woman, about 149,000 km of myelinated axons in their brains [9]. Men appear to have more gray matter, made up of active neurons, and women more of the white matter responsible for communication between different areas of the brain [10]. In women's brains, the neurons are packed in tightly, so that they're closer together. Some women even have as many as 12 percent more neurons than men do [10]. These neurons are densely crowded on certain layers of the cortex, namely the ones responsible for signals coming in and out of the brain, and these differences were present from birth [10]. When controlling for total cerebral volume, women had a higher percentage of grey matter than men, and men had a higher percentage of white matter [6, 8] and both gray and white matter volumes correlated with cognitive performance across sex groups. The average number of neocortical neurons was 19 billion in female brains and 23 billion in male brains, a 16% difference. In a study, which covered the age range from 20 years to 90 years, approximately 10% of all neocortical neurons are lost over the life span in both sexes. Sex and age were the main determinants of the total number of neurons in the human neocortex, whereas body size, per se, had no influence on neuron number [11]. Gender differences in precentral, cingulate, and anterior temporal white matter areas were also found, suggesting that microstructural white matter organization in these regions may have a sexual dimorphism [12].

Hypothalamus, where most of the basic functions of life are controlled, including hormonal activity via the pituitary gland also shows gender differences. The volume of a specific nucleus in the hypothalamus (third cell group of the interstitial nuclei of the anterior hypothalamus) is twice as large in heterosexual men as in women and homosexual men [13]. The preoptic area, involved in mating behavior, is about 2.2 times larger in men than in women and contains 2 times more cells. This enlargement is dependent on the amount of male sex hormones or androgens. Apparently, the difference in this area is only apparent after a person is 4 years old. At 4 years of age, there is a decrease in the number of cells in this nucleus in girls. The neuropil of the preoptic area is sexually dimorphic [14]. Gender-related differences were found in 2 cell groups in the preoptic-anterior hypothalamic area (PO-AHA) in human brain. Both nuclei were larger in male and appeared to be related in women to circulatingsteroid hormone levels [15]. The suprachiasmatic nucleus of the hypothalamus, involved with circadian rhythms and reproduction cycles, is different in shape in these two sexes. In males, this nucleus is shaped like a sphere whereas in females it is more elongated. However, the number of cells and volume of this nucleus are not different in men and women. It is possible that the shape of the suprachiasmatic nucleus influences the connections that this area makes with other areas of the brain, especially the other areas of the hypothalamus. In most hypothalamic areas that stain positively for androgen receptor (AR), nuclear staining in particular is less intense in young adult women than in men. The strongest sex difference is found in the lateral and medial mamillary nucleus [16]. The mamillary body complex is known to receive input from the hippocampus by the fornix and to be involved in cognition. In addition, a sex difference in AR staining is present in the horizontal diagonal band of Broca, the sexually dimorphic nucleus of the preoptic area, the medial preoptic area, the dorsal and ventral zone of the periventricular nucleus, the paraventricular nucleus, the supraoptic nucleus, the ventromedial hypothalamic nucleus and the infundibular nucleus. No sex differences were observed in AR staining in the bed nucleus of the stria terminalis, the nucleus basalis of Meynert and the island of Calleja [16].

It connects several regions of the frontal and temporal lobes and is 12 %, or 1.17mm² larger in women than in men [17].

A structure that crosses the third ventricle between the two thalami, was present in 78% of females and 68% of males. Among subjects with a massa intermedia, the structure was an average of 53.3% or 17.5 mm² larger in females than in males.Anatomical sex differences in structures that connect the two cerebral hemispheres may, in part, underlie functional sex differences in cognitive function and cerebral lateralization [17].

An area of the brain important for posture and balance, and the pons, a brain structure linked to the cerebellum that helps control consciousness, are larger in men than in women [18].

According to the majority of studies, men possess larger cerebra than women of the same age and health status, even if the body size differences are controlled statistically. Male brains were larger than female brains in all locations,though male enlargement was most prominent in the frontal andoccipital poles, bilaterally [19]. The male differentiated brain has a thicker right hemisphere. This may be the reason males tend to be more spatial, and mathematical. The left hemisphere, which is important to communication, is thicker in female oriented brains.

Men have 4% more neurons than women, and about 100 grams more of brain tissue. Women have a more developed neuropil, or the space between cell bodies, which contains synapses, dendrites and axons. This may explain why women are more prone to dementia (such as Alzheimer's disease) than men, because although both may lose the same number of neurons due to the disease, in males, the functional reserve may be greater as a larger number of nerve cells are present, which could prevent some of the functional losses [20]. In the temporal neocortex, a key part which is involved in both social and emotional processes and memory, men had a one third higher density than women of synapses, and had more brain cells, though the excess was slight compared with the excess in the number of synapses. Sexual dimorphism has been reported in the cortical volume of the Wernicke and Broca areas [21], as well as in the frontal and medial paralimbic cortices [5, 19, 22, 23]. Differences have been reported in the thickness and density of the grey matter in the parietal lobes [19] in the density of neurons [10, 11, 20, 24] and in the complexity of the dendritic arbors as well as in the density of dendritic spines in several cortical areas [25]. In female brains, the cortex is constructed differently, with neurons packed more closely together in layers 2 and 4 (which form the hard wiring for signals coming into the brain) of the temporal lobe, and in layers 3, 5 and 6 (which carry the wiring for outbound signals) of the prefrontal cortex [10]. Widespread areas of the cortical mantle are significantly thicker in women than in men [26]. Studies have shown greater cortical thickness in posteriortemporal and inferior parietal regions in females relative to males, independent of differences in brain or body size. Age-by-sexinteractions were not significant in the temporoparietal region,suggesting that sex differences in these regions are presentfrom at least late childhood and then are maintained throughout [19]. In a study it is shown that men have a significantly higher synaptic density than women in all cortical layers of the temporal neocortex [27]. Differences in brain anatomy have included the length of the left temporal plane, which is usually longer than the right. The sex differences in cellularity of the planum temporale involved an 11% larger density of neurons in several cortical layers of females, with no overlap between males and females [10].

The ratio between the orbitofrontal cortex, a region involved in regulating emotions, and the size of the amygdala, involved in producing emotional reactions, was significantly larger in women than men. One can speculate from these findings that women might on average prove more capable of controlling their emotional reactions. Women have larger orbital frontal cortices than men, resulting in highly significant difference in the ratio of orbital grey to amygdala volume. This may relate to behavioral evidence for sex differences in emotion processing [28].

Females have a more acute sense of smell, and on average, have a larger deep limbic system including hippocampus [4] and anterior commissure, a bundle of fibers which acts to interconnect the two amygdales [17], than males. Due to the larger deep limbic brain women are more in touch with their feelings, they are generally better able to express their feelings than men. They have an increased ability to bond and are connected to others. On the other hand larger deep limbic system leaves a female somewhat more susceptible to depression, especially at times of significant hormonal changes such as the onset of puberty, before menses, after the birth of a child and at menopause. Women attempt suicide three times more than men [29].

A large tract of neural fibers that allows the free flow of communication between both hemispheres of the brain is larger in women, compared to men [8, 30]. The larger corpus callosum allows more transmissions between the two hemispheres. Thus women use both hemispheres creating more synapses between the two sides of the brain. Although this discovery has been challenged in a volumetric study of the corpus callosum in Korean people in their 20s and 40s. It was shown that Korean men have larger corpus callosum as compared to women. There was no significant difference in corpus callosum volume between 20s and 40s.There was a positive relationship between body weight and corpus callosum for 20s, but not for 40s [31]. In another study a dramatic difference in the shape of corpus callosum was observed but there was no conclusive evidence of sexual dimorphism in the area of the corpus callosum or its subdivisions. The caudal portion of corpus callosum, the splenium was more of bulbous shaped in females and more tubular shaped in males. The maximum width of splenium was significantly greater in females than in males [5]. It has been reported that there is significant rightward asymmetries of callosal thickness predominantly in the anteriorbody and anterior third of the callosum, suggesting a more diffusefunctional organization of callosal projections in the righthemisphere. Asymmetries were increased in men, supporting theassumption of a sexually dimorphic organization of male andfemale brains that involves hemispheric relations and is reflectedin the organization and distribution of callosal fibers [32]. In Magnetic resonance imaging study, callosal measurements showed no significant effects of sex orhandedness, although subtle differences in callosal shape wereobserved in anterior and posterior regions between males andfemales and surface variability was increased in males [32]. It was found that in men the size of corpus callosum is related to handedness. The more left-handed a person was, the bigger the corpus callosum he had. Among women there was no difference between right-handers and left-handers [33].

It is significantly larger in men than in women[34]. More specifically, the left side IPL is larger than the right in men. In women, this asymmetry is reversed, although the difference between left and right sides is not as large as in men. This is the same area that was shown to be larger in the brain of Albert Einstein, as well as in other physicists and mathematicians [35]. It seems that the IPL correlates with the mathematical ability. The IPL lets the brain process input from the senses and aids in selective attention and perception. Studies have shown that the right IPL is linked to understanding spatial relationships and the ability to sense relationships between body parts [35]. The left on the other hand, is linked with perception of time and speed, and the ability to rotate 3-D figures in the brain. In general, the IPL allows the brain to process information from senses and help in selective attention and perception (for example, women are more able to focus on specific stimuli, such as a baby crying in the night).

A narrow band at the base of the frontal lobe, involved in social cognition and interpersonal judgment is about 10% bigger in women than in men [36] (men’s brains are about 10% larger than women’s brains, so measures were proportional). In addition, the size of the SG also correlated with a test of social cognition, so that people who scored higher in interpersonal awareness, male or female, had larger SGs. A similar study in children between 7 and 17 years of age showed different results. The SG was larger in boys as compared to girls. And this time, a smaller SG correlated with better “interpersonal awareness”—the opposite of the results were seen in adults. This could be due to a reduction in grey matter volume, or pruning, which generally happens to girls’ brains two years earlier than boys’. There does seem to be a relationship between SG size and social perception and femininity. Higher degrees of femininity were shown to be correlated with greater SG grey matter volume and surface area [36].

Sex differences exist in every brain lobe, including in many ‘cognitive’ regions such as the hippocampus, amygdala and neocortex [37]. Extensive evidence demonstrates that male and female hippocampi differ significantly in their anatomical structure, their neuroanatomic make-up and their reactivity to stressful situations [38]. Imaging studies consistently show that the hippocampus is larger in women than in men when adjusted for total brain size [4].

A rapidly growing body of evidence also documents the sexually dimorphic nature of the human amygdala [39, 40]. It is significantly larger in men than in women adjusted for total brain size [4]. Sex differences also exist in its structural relationship with the rest of the brain. In a study of a large sample of men and women, the patterns of covariance in the size of many brain structures were 'remarkably consistent' between men and women, except the amygdala, in particular, the left hemisphere amygdala, which showed several marked sex differences [41]. Magnetic resonance imaging (MRI) studies of the normally developing brain in childhood and adolescence showed that after correction for overall brain volume the caudate is relatively larger in girls, and the amygdala is relatively larger in boys [42]. The posterodorsal nucleus of the medial amygdala (MePD) has a greater volume in male rats than in females, but adult castration of male rats causes the volume to shrink to female values within four weeks, whereas androgen treatment of adult females for that period enlarges the MePD to levels equivalent to normal males. It was demonstrated that adult hormone manipulations can completely reverse a sexual dimorphism in brain regional volume in mammals. The extent of the MePD sexual dimorphism in rats in quite comparable to reported sexual dimorphisms in the human brain [10, 11, 43-46] and therefore supports the possibility that sexual dimorphisms of the human brain are caused solely by circulating steroids in adulthood. In addition, the regions of the brain with which the amygdala communicates while a subject is at rest are different in men and women. In men, the right amygdala is more active and shows more connectivity with brain regions such as the visual cortex and the striatum. Conversely, in women, the left amygdala is more active and is connected to regions such as the insular cortex and the hypothalamus. Many brain areas communi-cating with the amygdala in men are engaged with and responding to the external environment. For example, the visual cortex is responsible for vision, while the striatum coordinates motor actions. Conversely, many regions connected to the left-hemisphere amygdala in women control aspects of the environment within the body. Both the insular cortex and the hypothalamus, for example, receive strong input from the sensors inside the body. Several studies now report sex influences on amygdala function, including in the context of its well-known role in memory for emotional events. Evidence from animal research documents that the amygdala can modulate the storage of memory for emotional events, and does so through interactions with endogenous stress hormones released during stressful events [47]. This amygdala/stress hormone mechanism provides an evolutionarily adaptive way to create memory strength that is, in general, to memory importance. Both lesion and imaging studies have confirmed this conclusion in humans [48]. However, imaging studies have also revealed a sex-related hemispheric lateralization of amygdala function in relation to memory for emotional material. Specifically, the studies consistently indicate a preferential involvement of the left amygdala in memory for emotional material (generally visual images) in women, but a preferential involvement of the right amygdala in memory for the same material in men [49-51].In an intriguing parallel with the studies in humans, it was reported that stimulation of the right but not the left hemisphere amygdala modulates memory storage in male rats [52]. There is a distinct hemispheric relationship with sex in regards to the amygdala’s function in memory. Preferential activation occurred in the left amygdala in women and in the right amygdala in men. This implies sex-specific hemispheric lateralization of amygdala function, and possibly different ways of processing emotionally arousing memories. This hemispheric lateralization was also present in resting conditions, indicating a fundamental sex difference in how the amygdala functions [53].

The regions of the brain that play a key role in visual processing and in storing language and personal memories appear to differ between the sexes at the microscopic level. The frontal and the temporal areas of the cortex are more precisely organized in women, and are bigger in volume [54]. The density of synapses in the temporal neocortex was greater in men than in women. Fewer synapses to other regions may represent increasing specialization of the temporal cortex for language processing in females, and this may be related to their overall better performance on language tasks [27]. Sexes use different sides of their brains to process and store long-term memories [49] and a particular drug, propranolol, can block memory differently in men and women [55].

The two major areas related to speech, Broca, in the dorsolateral prefrontal cortex, Wernicke, in the superior temporal cortex were significantly larger in women. MRI studies showed that women had 23% in Broca's area, and 13% in Wernicke's area, more volume than men [45]. There is also a difference between men and women as to which part of the left hemisphere is responsible for speech and hand movements. In another study, the volume of the Wernicke's area was 18% larger in females compared with males, and the cortical volume of the Broca's area in females was 20% larger than in males [56]. In women, the frontal region is more important than the area at the back, so problems with speech are more likely to happen if the front part of the left hemisphere is damaged. In men, the areas contribute more equally, but if anything in the back part, especially the parietal region, is more important. The brains of women process verbal language simultaneously in the two sides (hemispheres) of the frontal brain, while men tend to process it in the left side only [57]. Studies have showed both that areas of the brain associated with language work harder in girls than in boys during language tasks, and that boys and girls rely on different parts of the brain when performing these tasks [58]. Femalesuse the posterior temporal lobes more bilaterally during linguistic processing of global structures in a narrative than males do [59]. fMRI on a conventional scanner for determining the anatomic substrate of language between subjects and between sexes showed activation changes in the left prefrontal cortex and right cerebellum and significantly decreased responses were seen in the posterior cingulate and over an extensive area of medial and dorsolateral parietal and superior temporal cortices. The male cohort showed a slight asymmetry of parietal deactivation, with more involvement on the right, whereas the female cohort showed a small region of activation in the right orbitofrontal cortex [60]. The male brain has its vocabulary making power seated only in the left hemisphere enabling him to develop a large vocabulary. The female brain becomes more proficient in the vocabulary she already has using her emotions and feelings for others to aid in the production of language.

Male oriented brains, hardly express feelings. It is due to the use of the right hemisphere only. Male brains separate language, in the left, and emotions in the right, while the female’s emotions are in both hemispheres. It helps explain why the male brain has a hard time expressing its feelings [54].

Men seem to think with their grey matter, which is full of active neurons. Women think with the white matter, which consists more of connections between the neurons. In this way, a woman's brain is a bit more complicated in setup, but those connections may allow a woman's brain to work faster than a man's [10]. The parts of the frontal lobe, responsible for problem-solving and decision-making, and the limbic cortex, responsible for regulating emotions, were larger in women. In men, the parietal cortex, which is involved in space perception, and the amygdala, which regulates sexual and social behavior, was large [61]. Men and women differ in accessing different sections of the brain for the same task. In one study, men and women were asked to sound out different words. Men relied on just one small area on the left side of the brain to complete the task, while the majority of women used areas in both sides of the brain [62]. However, both men and women sounded out the words equally well, indicating that there is more than one way for the brain to arrive at the same result.

Numerous studies report sex differences in neural activity despite no behavioral difference between the sexes. For example, Piefke et al. [63] examined the neural correlates of retrieval of emotional, autobiographical memories in men and women. Memory performance did not differ between the sexes, nor did the degree of emotion induced by retrieval. However, brain regions associated with retrieval in the two sexes differed significantly. In another study, the neural correlates of naming images were examined. Men and women performed the task equally well, but the patterns of brain activity associated with their performance differed significantly [64]. The cerebral network involved in semantic processing is significantly affected by sex and sex steroid hormones [65]. In performing a visuospatial abilities task and a phonological task, women and men showed no performance differences in accuracy but showed different brain activation patterns. Males exhibited more left-sided brain activation during the phonological task and greater bilateral activity during the visuospatial task. Females showed greater bilateral activity during the phonological task and had more right-sided brain activation during the visuospatial task [66]. Men outperformed women on a mental rotation task, and women outperformed men on a verbal fluency task. Comparable brain activation occurred in association with mental rotation and verbal fluency function, but with differential performance [67]. Women perform better on some phonological tasks and men on spatial tasks. ROI-based analysis documented the expected left-lateralized changes for the verbal task in the inferior parietal and planum temporal regions in both men and women, but only men showed right-lateralized increase for the spatial taskin these regions. Image-based analysis revealed a distributed network of cortical regions activated by the tasks, which consisted of the lateral frontal, medial frontal, mid-temporal, occipitoparietal, and occipital regions. The activation was more left lateralized for the verbal and more right for the spatial tasks, but men also showed some left activation for the spatial task, which was not seen in women. Increased task difficulty produced more distributed activation for the verbal and more circumscribed activation for the spatial task [68].

3-Tesla magnetic resonance imaging (MRI), including diffusion tensor imaging (DTI) in unsedated healthy newborns showed differences in male and female brains. The left ventricle was significantly larger than the right; females had significantly larger ventricles than males[69]. There was significant ventricular asymmetry at birth, with the left ventricle being larger than the right. This ventricle asymmetry is present in older children [46] and indicates that lateralization of the brain is present at birth. Interestingly, female newborns had larger lateral ventricles than males, even in the face of similar intracranial volumes and birth weights. Studies in older children have found no gender difference [46] or that males have larger ventricles than females [70].

From conception until the eighth week of gestation, men and women are almost exactly the same. The only difference is at the chromosomal level, deep inside the embryo’s cells. One pair of chromosomes determines whether the person is male or female. Except in the case of extremely rare abnormalities, a person with two X chromosomes is female, and a person with one X chromosome and one Y chromosome is male. Several studies have provided evidence that some sex differences do occur very early during development, before fetuses are exposed to endogenous sex steroid hormones. The genetic makeup of individuals tends to dictate physiological differences. Male and female brain cells carry a different complement ofsex chromosome genes and are influenced throughout life by adifferent mix of gonadal hormones. It is suggested thatbrain cells that differ in their genetic sex are not equivalent,and that difference may contribute to sex differences in brain function. XX and XY cells differentiate evenbefore they are influenced by gonadal hormones, and even ifthey are exposed to similar levels of gonadal steroids. Genes on the sex chromosomes probably determine the gender (sexually dimorphic phenotype) of the brain in two ways: by acting on the gonads to induce sex differences in levels of gonadal secretions that have sex-specific effects on the brain, and by acting in the brain itself to differentiate XX and XY brain cells [162]. A study in mice showed that sex chromosome genes contribute directlyto the development of a sex difference in thebrain [163]. Sexual identity is hard-wired and is determined before a person is even born. In a study, researchers performed two different genetic tests comparing the production of genes in male and female mice brains before the animal developed sex organs. They discovered 54 genes that were produced in different amounts in male and female brains--independent of hormonal influences. Of those 54 genes, 18 were produced in higher quantities in the male brain and 36 were found in higher quantities in the female brain [164]. Sex differences in dopaminergic neurons in rat fetuses had been demonstrated on day 14.5 post coitum (dpc) [165], while genomic study by [164] identified over 50 genes whose expression differed between male and female mouse brain on day 10.5 dpc well before gonads start to produce sex steroids. A study by Smith-Bouvier et al. [166], strongly suggests that sex chromosomes also play an important role in development of the differences between sexes in incidence and progression of autoimmune diseases. Animal experimental studies showed evidence for primary genetic control of sexual differentiation that does not involve sex hormones. Results obtained from cultures of embryonic rat brain indicate that dopaminergic neurons may develop morphological and functional sex differences in the absence of sex steroids [167]. Candidates for such hormone-independent effects are those genes located on the nonrecombining part of the Y chromosome and believed to be involved in primary sex determination of the organism. Two candidate genes are the two testis-determining factors, ZFY and the master switch for differentiation of a testis SRY; they are putative transcription factors. It was shown that SRY and ZFY are transcribed in the hypothalamus and frontal and temporal cortex of adult men, and not in women. It may well be possible that they function as sex-specific cell-intrinsic signals that are needed for full differentiation of a male human brain, and that continuous expression throughout life may be required to maintain sex-specific structural or functional properties of differentiated male neurons.

During the development of the embryo in the womb, circulating hormones have a very important role in the sexual differentiation of the brain. Depending on the type of hormone and the level of hormonal activity during the embryonic stage of development can produce brains with male or female traits. The presence of androgens in early life produces a “male” brain. In contrast, lack of androgens causes feminization, and the female sex is developed by default in a passive mechanism. However, studies have shown that estrogen plays an active role in differentiation of the female brain [168-173] and that the sensitive period for estrogen related processes occurs at a later time than that of testosterone related processes [174]. It is known, at least, in rodent brains, estradiol and not testosterone is responsible for the masculinization of the brain. Testosterone, secreted from the testes in male fetuses is transported into the brain, where it is converted into estradiol by cytochrome P450 aromatase, locally expressed in different parts of the brain [175, 176]. While female fetuses are not exposed to testosterone from their gonads, they are still exposed to estradiol from their mothers. To prevent masculinization of the female brain, large amounts of alpha-fetoprotein are present in the blood of female fetuses, which could bind estradiol and thus preventing it from entering into the brain [177].

In sexual differentiation of the human brain direct effects of testosterone seem to be of primary importance based upon evidence shown e.g. from subjects with mutations in the androgen receptor, estrogen receptor or in the aromatase gene [178]. In transsexuals, reversal of the sex difference in the central nucleus of the bed nucleus of the stria terminalis was observed. The size, type of innervation and neuron number agreed with their gender identity and not with their genetic sex [179, 180]. Various structural and functional brain differences related to sexual orientation have now also been reported [181-183]. Levels of circulating sex steroid hormones, during development and in adulthood, play a critical role in determining physiology and behavior in adulthood [184, 185]. Since the morphologic characteristics of neurons have been shown to influence the functional properties of the neurons [186-188], it is likely that these hormone-induced structural changes contribute significantly to the activation of neural circuits necessary for certain behaviors [189]. Recent findings suggest that manipulation of sex steroid hormone levels may induce dramatic macroscopic and microscopic structural changes in certain regions of the central nervous system, such as neurons of adult avian song system [190, 191], corpus callosum and anterior commissure [17, 192], bulbocavernosus spinal nucleus [193, 194], spinal motor neurons [195] rat Purkinje cell [196], sexual dimorphic nucleus of preoptic area of hypothalamus (SDN-POA) of hypothalamus [197], hippocampal pyramidal cells [198], bed nucleus of human stria terminalis [199], nigrostriatal dopamine neurons [200], rat arcuate nucleus [201-203], human median raphe nucleus [204], and substantia nigra [205]. Dorsal raphe nucleus (DRN) is the largest of all raphe nuclei in rat brain stem, and a part of serotonergic system [206]. Studies have also indentified many areas of the brain that are altered during development due to exposure to sex steroids, not only areas closely connected with reproduction, but also in the areas important for emotional responses such as amygdala and even other areas such as hippocampus and cerebellum [207, 208]. substantial evidence indicates that sex hormones influence learning and memory processes [209], and interact with stress hormones to do so. In humans, the menstrual cycle significantly influences performance on both verbal and spatial tasks [210], and modulates the neural circuitry associated with arousal [4]. Menstrual cycle influences have even been detected on the degree of hemispheric asymmetry associated with various cognitive tasks [211]. Menstrual cycle influences also exist on brain responsiveness to addictive drugs such as cocaine [212] and amphetamines [213], factors that will probably help to explain sex differences in addictive processes [214]. In addition, sex hormones such as oestrogen can alter the excitability of hippocampal cells [215] strongly influence their dendritic structure [216] and augment NMDA (N-methyl-D-aspartate) receptor binding [217]. Intrahippocampal oestrogen infusions modulate memory processes [218]. Finally, sex differences exist in hippocampal long-term potentiation [219], a phenomenon that is widely viewed to be related to memory processes. Human behavior is also subject to the activational effects of androgens. Transsexuals treated with cross-sex hormones display sex reversals in their cognitive abilities, emotional tendencies, and libido [220, 221], and sex offenders are sometimes treated with antiandrogens to reduce their sex drive [222].

Several studies have suggested that sex steroid hormones might not be the whole answer to sexual differentiation and that sex chromosomes could influence sex specific development. Sex hormones are crucial for many sex differences, but, equally, cannot explain all observed sex differences. For example, a recent study reported several sex differences in cocaine-seeking behavior in rats and, in addition, found that these differences were unaffected by oestrus state [223]. Many of such sex differences described in the human brain arise during development by an interaction of sex hormones and the developing neurons, although direct genetic effects are probably also involved [181]. Factors influencing structural [43] and functional [178, 181] sex differences in the brain are genetic factors like mutations or polymorphisms in the sex hormone receptors, abnormal prenatal hormone levels and compounds such as anticonvulsants, Diethylstilbestrol (an estrogen-like com-pound) and environmental endocrine disrupters. When given during pregnancy they interact with the action of sex hormones on the fetal brain.

The fundamental neurological substrate that forms the basis for complex cerebral asymmetries inHomo sapiens may have been established remarkably early in anthropoid evolution. In ancient times, both sexes had very defined role that helped ensure the survival of the species. Cave-men hunted while Cave-women gathered food near the home and cared for the children. Brain areas may have been sharpened to enable each sex to carry out their jobs. In evolutionary terms, developing superior navigation skills may have enabled men to become better suited to the role of hunter, while the development by females of a preference for landmarks may have enabled them to fulfill the task of gathering food closer to home [54]. The advantage of women regarding verbal skills also makes evolutionary sense. While men have the bodily strength to compete with other men, women use language to gain social advantage, such as by argumentation and persuasion [54]. Morning sickness, for example, which steers some women away from strong tastes and smells, may once have protected babies in utero from toxic items. Infidelity is a way for men to ensure genetic immortality [224]. Tendency toward cortical lateralization has been greatly elaborated in human evolution, such that at least 90% of extant humans are right-handed. Numerous data support an association of the left human hemisphere with time-sequencing, language skills, certain neurochemical asymmetries, and specific psychiatric disorders. The right hemisphere, on the other hand, is associated with holistic processing, visuospatial and musical abilities, emotional processing, and its own neurochemical and psychiatric properties. Significant sexual dimorphism in certain skills associated with cortical lateralization has been reported in humans. Females excel at language and fine motor skills, as well as emotional decoding and expression; males are relatively adept at composing music and exhibit visuospatial and mathematical skills [225]. Evolution can also produce adaptive sex differences in behavior and its neural substrate [226].

Postnatal social factors are generally presumed to be involved in the development of sexual orientation [227, 228]. Females of all ages are better at recognizing emotion or relationships than are men. These sex-determined differences appear in infancy and the gap widens as people mature. When such differences appear early in development, it can be assumed that these differences are programmed into our brains-“hardwired” to use a computer analogy. Sex differences that grow larger throughout childhood however, are probably shaped by culture, lifestyle and training. Studies of brain plasticity have shown us that experience changes our brains structure.

At birth, the human brain is still preparing for full operation. The brain's task for the first 3 years is to establish and reinforce connections with other neurons. As a child develops, the synapses become more complex, like a tree with more branches and limbs growing. After age 3, the creation of synapses slows until about age 10. Between birth and age 3, the brain creates more synapses than it needs. The synapses that are used a lot become a permanent part of the brain. The synapses that are not used frequently are eliminated. This is where experience plays an important role in wiring a young child's brain. The child’s experiences are the stimulation that sparks the activity between axons and dendrites and creates synapses. Clearly the social experience of a young baby is limited, but even then it is interacting, soaking up experience like a sponge. In an astonishingly short time it becomes proficient in a complicated, not entirely logical language. Even before an infant begins to talk, it understands sentences containing quite complex sequences. It is believed that nurturing one's brain can enhance what nature has provided. There is a lot of evidence that we build up our brain's representation of space by moving through it. Boys tend to get a lot more practice “moving through space” than girls do. This difference could possibly be erased if the girls are pushed out into the exploratory mode [97]. There is evidence that learning uses long-term potentiation (LTP) in the cerebral cortex as a way to strengthen synaptic connections between brain cells that are necessary to acquire and store new information [229]. Even with laboratory rats, it has been shown that those reared in a stimulating environment develop a much more intricate cerebral organization than those reared in nothing more than a bare cage. The more prominent sex differences were seen when the rearing environment was varied, with females showing less susceptibility to environmental influences in some neuronal populations [230].

Many CNS-related disorders show sex differences in their incidence and/or nature. These diseases include, but are not limited to, Alzheimer's disease (AD), post-traumatic stress disorder (PTSD) and other anxiety disorders, schizophrenia, stroke, multiple sclerosis, autism, addiction, fibromyalgia, attention deficit disorder, irritable bowel syndrome, Tourette's syndrome and eating disorders [231, 232]. Major depressive disorder, anxiety and eating disorders are much more prevalent in women, while schizophrenia, autism and attention deficit disorder are diagnosed more often in men [233]. The prefrontal cortex (PFC) performs important functions in the brain. It is rich in sex hormone receptors, and has among the highest concentration of oestrogen receptors in the human brain [234]. Sex differences in the neural substrate for working memory, a function, thought to depend on the prefrontal cortex (PFC), have been reported [235, 236]. The PFC is also associated with sex differences in its response to stress. [237, 238] and might develop at different rates in males and females [239]. The PFC is thought to be involved in decision making. Tranel et al. [240] present evidence that right hemisphere PFC lesions impair performance on this decision-making task in men but not women, whereas left hemisphere lesions impair performance in women but not men. It was also reported in an earlier brain imaging study of PFC function in normal subjects performing the decision-making task [241]. Certain diseases that cause neuronal loss in the cerebral cortex may be more detrimental to women due to their lower number of cortical neurons compared to men [242, 243]. The results of some studies suggest that Alzheimer’s disease (AD) disproportionately affects women [244]. There are growing indications that the disease pathology, and the relationship between pathology and behavioral disturbance, differs significantly between the sexes. AD-related neurofibrillary pathology associated with abnormally phosphorylated tau protein differs in the hypothalamus of men and women: up to 90% of older men show this pathology, whereas it is found in only 8–10% of age-matched women. An opposite sex difference occurs in the nucleus basalis of Meynert, the major source of cholinergic innervation to the neocortex. Here, the percentage of neurons containing pretangles with hyperphosphorylated tau protein is significantly higher in women than in men [245]. Other evidence indicates that the relationship of AD pathology to behavioral disruption also differs between the sexes. The presence of a single APOE^*E4 allele (an allele of a gene associated with an increased risk of AD) has been linked with significantly greater hippocampal atrophy and memory disruption in women than in men [246]. As another example, symptoms of depression significantly increase the risk of developing AD in men, but not in women [247]. Finally, Barnes et al. [244] showed that the relationship between the presence of cortical neurofibrillary tangles and a clinical diagnosis of AD differed dramatically between men and women. Using regression models, they found that each unit increase in pathology was associated with an approximately 3-fold increase in AD risk in men, but with a more than 20-fold increase in women.

Schizophrenia is another brain disease that differs in both incidence and nature between the sexes. Men and women differ on average in several clinical features of the disease, including its presentation, symptoms, age of onset, and the time course of the illness. Some patterns of brain morphology that are associated with the illness also differ between the sexes. Men with schizophrenia show significantly larger ventricles than do healthy men, whereas no such enlargement is seen in women with schizophrenia [248]. The ratio of the size of the amygdala to that of the orbitofrontal cortex, which is sexually dimorphic in healthy individuals, is increased in men with psychosis, but decreased in women with psychosis [249]. Results of studies from several laboratories [250] indicate that the normal patterns of hemispheric asymmetry seen in the brains of healthy individuals are reduced in schizophrenia, and that sex interacts with the changes in asymmetry. Sex differences even occur in the facial features of patients with schizophrenia: male patients display significantly less facial hemispheric asymmetry than do male controls, whereas female patients display marked facial asymmetries that are absent in female controls [251]. Significant interactive effects of sex and frontal lobe volume were found in regression analyses of the disorganization and suspicion-hostility symptom scales. In men, higher frontal lobe volume was associated with milder severity of disorganization but was not correlated with severity of suspicion-hostility. In women, higher frontal lobe volume was associated with more severe disorganization as well as more severe suspicion-hostility. No associations were found between brain volume and severity of negative or Schneiderian symptoms. These findings suggest that aspects of the neuropathological basis for some symptoms of schizophrenia may be sexually dimorphic [252].

It has been proposed that neuropsychiatricillnesses, such as schizophrenia, with a typical adolescentonset may be mediated by excess elimination of synapses [253, 254]. The rapid rate of periadolescent pruning in males may underliethe early age of onset and increased illness severity in maleschizophrenic patients [255, 256]. Previous studies in infants and older children find that white matter FA increases and ADC (apparent diffusion coefficient) decreases with age [257-259]. Gilmore et al. [260] observed a significant increase in FA in the genu and splenium of the corpus callosum, but not in other white matter tracts. This suggests that the white matter of the corpus callosum is undergoing significant maturation in the period after birth that may represent a window of vulnerability to perinatal insults that have been associated with neurodevelopmental disorders, including schizophrenia. Becker [261] has discovered clear sex differences in the levels of dopamine in several brain regions, as well as differences in the responsiveness of dopamine to stimulation by amphetamine and sex hormones. In humans, addiction differs between the sexes in important ways. Women, for example, are more sensitive than men to the reinforcing effects of psychostimulants (for example, amphetamine and cocaine), which may account for the more rapid progression from initial use to drug dependence in women compared with men [262].

Women and men tend to have different types of stress-related psychological disorders. Women have greater rates of depression and some types of anxiety disorders than men, while men have greater rates of alcohol-use disorders than women [263]. Based on neuroendocrine and behavioral evidence stress responses may be characterized by ‘fight-or-flight’ in men and ‘tend-and-be friend’ in women [264]. Under stressful situations, the ‘fight-or-flight’ response invokes resources that increase focus, alertness and fear, while inhibiting appetitive goals to cope with the threat or challenge [185, 265] In contrast, the female stress response primarily involves the limbic system including ventral striatum, putamen, insula and cingulate cortex. Both men and women’s brain activation lasted beyond the stress task, but the lasting response in the female brain was stronger. The asymmetric prefrontal activity in males was associated with a physiological index of stress responses-salivary cortisol, whereas the female limbic activation showed a lower degree of correlations with cortisol [266]. Women are more likely than men to focus on negative emotional aspects of stressful circumstances [263]. The female intelligence processing is more centralized in the brains frontal lobes [106]. Therefore the frontal lobe injuries can be more detrimental to cognitive performance in women than men. Among brain injury patients, after damage to the left hemisphere, long term speech difficulties occur three times more often in males.

In a study it was found that for females, areas in both the left and right sides of the brain were active during eye-hand co-ordination experiments. That occurred for men only when they were planning their most complex task: This gives insight to why different types of head injuries are more disastrous to one sex or the other. For example, in women 84 percent of grey matter regions and 86 percent of white matter regions involved in intellectual performance were located in the frontal lobes, whereas the percentages of these regions in a man's frontal lobes are 45 percent and zero, respectively. Clinical data shows that frontal lobe damage in women is much more destructive than the same type of damage in men. Rehabilitation after brain injuries such as stroke may need to be tailored to the sex of the person. The research findings suggest that if someone has a stroke on one side of the brain, in one of the areas that differs between males and females, it may be important to take into account the sex of the patient. If the stroke is only on one side of the brain, a woman may have rehabilitation options that the man may have more trouble with because the woman may be able to perform tasks using the other side of her brain, which is used to being fired up. Men may have more trouble with rehabilitation, and may need to be checked more carefully before they resume everyday activities. Boys also fall prey to learning disabilities, for example, dyslexia and attention deficit hyperactivity disorder (ADHD) are more frequently seen in boys than girls. The symptoms displayed by girls and boys with ADHD differ, too. Girls with ADHD usually exhibit inattention, while affected boys are prone to lack of impulse control [97].

There is a clear sex difference in psychiatric disorders such as depression: the prevalence, incidence and morbidity risk is higher in females than in males, which may be due to both organizing and activating effects of sex hormones on the hypothalamo-pituitary-adrenal-axis. Fluctuations in sex hormone levels are considered to be involved in the susceptibility to depression, seen e.g. in the premenstrual, ante-and postpartum period, during the transition phase to the menopause and during oral contraceptives treatment. It was found that about 40% of the activated corticotropin releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus in mood disorders expresses also the estrogen receptor (ER) [267]. Estrogen-responsive elements are found in the CRH gene promoter region, while estrogens stimulate CRH expression in animal studies. An androgen-responsive element in the CRH gene promoter region has also been identified, which initiates a suppressing effect on CRH expression [268]. Distinct liability for men and women to suffer from some psychiatric disorders responding to serotonergic agents may be related to differences in brain serotonin receptors.

Autoimmune diseases are more prevalent in women than in men. In multiple sclerosis (MS), a chronic inflammatory demyelinating disease of the central nervous system (CNS), there is a female-to-male preponderance approaching 2: 1 to 3: 1. The MS-associated HLA-DR2 allele is more frequent in women than in men with MS [269] and there is evidence that women develop MS at an earlier age than men [270]. Although MS is more common in women and may appear earlier, there is evidence that disease severity is worse in men. Male patients are somehow especially vulnerable to cognitive deficits [271]. Systemic lupus erythematosus (SLE) is nine times more common in women than in men, but men exhibit differences in clinical presentation, with an increased prevalence of SLE-associated renal disease, vascular thrombosis, pleuropericardial disease, peripheral neuropathy, and seizures as compared to women [272]. Hormonal shifts in pregnancy, menopause, and aging are associated with fluctuations in the course of autoimmune disease. Multiple sclerosis and rheumatoid arthritis, for example, improve during pregnancy, whereas lupus appears to worsen. Steroid receptors are found in immune cells and thus could provide a plausible pathway by which steroid hormones affect autoimmunity [273].

Sex differencesin brain development may be related to the prevalence, courseand treatment of several neuropsychiatric disorders, such asautism and attention deficit hyperactivity disorder [255, 256]. Autism and attention deficit show strong sexual dimorphism and are thought to originate from the dysfunction of cerebellum [207]. Males are at least four times more likely to develop autism, a highly heritable disorder, than females. Among relatives with a broader autistic phenotype, males predominate too.The threshold for phenotypic expression of many autistic characteristics is influenced by imprinted X-linked gene(s) [274]. Clinical samples of attention deficit hyperactivity disorder have been dominated by males. Gender differences in ADHD may be attributable to gender differences in dopamine receptor density. The rise of male, but not female, striatal dopamine receptors parallels the early developmental appearance of motor symptoms of ADHD. Transient lateralized D₂dopamine receptors in male striatum may increase vulnerability to ADHD [139].