Gender differences in the human cerebral cortex: more neurons in males; more processes in females

This study's objective was to investigate morphometric gender differences of the cerebral cortex in six males and five females, 12 to 24 years old. Though human brains lack sexual dimorphism on routine neuropathologic examinations, gender-specific brain weight, functional, and morphologic differences exist, suggesting that cortical differences may be found. Yet the cerebral cortex may be exempt from gender differences, as demonstrated by the fact that normal males and females perform comparably on intelligence tests. Stereologic morphometry on standardized histologic sections from 30 bilateral cortical loci determined cortical thickness, neuronal density, and derived neuronal number estimates. The mean +/- SD cortical thickness of the 60 loci examined was similar in males and females with right and left hemispheric gender ratios being balanced. In contrast, the average neuronal density of the same 60 loci was significantly higher in the male group than in the female group, and the corresponding mean male-to-female ratios were 1.18 in the right and 1.13 in the left hemisphere, which differ significantly from each other and from the balanced cortical thickness ratios. Estimates of neuronal numbers -- the product of neuronal thickness times density -- were 13% higher in males than in females, with mean male-to-female ratios of 1.13 in both hemispheres. The data provide morphologic evidence of considerable cerebral cortical dimorphism with the demonstration of significantly higher neuronal densities and neuronal number estimates in males, though with similar mean cortical thickness, implying a reciprocal increase in neuropil/neuronal processes in the female cortex.     

The human cerebral cortex: gender differences in structure and function

Most people are aware of subtle differences in cognitive functions between men and women. Psychometric tests confirm specific gender differences in a number of areas, the most robust being in spatial orientation and mathematical tasks which are better performed by males. Nonetheless, normal males and females perform comparably on intelligence tests and human brains lack sexual dimorphism on routine neuropathological exams--other than mean differences in weight and size. Even so, human brains demonstrate: 1) a sexually dimorphic nucleus in the hypothalamus with twofold neuronal numbers in males than in females; 2) the planum temporale/anterior Sylvian fissure on the left side are larger in males; 3) some studies reveal the posterior corpus callosum to be more bulbous in females while others fail to show this difference; and 4) a cytoarchitectural study demonstrates definite sexual dimorphism of cerebral cortex with significantly higher neuronal densities and neuronal number estimates in males and a reciprocal increase in neuropil/neuronal processes in female cortex as implied by the 2 sexes' similar mean cortical thicknesses. Such morphologic differences may provide the structural underpinning for the gender differences exhibited by the normal and diseased brain. Males manifest a higher prevalence of mental retardation and of learning disabilities than females which may reflect the male fetus' smaller overproduction of nerve cells. Such an inference is supported by the demonstration of 1) better functional recovery following early brain injury than after later insults, 2) substantially overproduced and secondarily reduced nerve cells in human cerebral cortex during gestation, 3) the demonstration of a similar neuronal production and a testosterone-dependent neuronal involution of the sexually dimorphic hypothalamic nucleus in rats, and 4) more cortical neurons present in the adult human male than female. If an overproduced nerve cell population is capable of compensating for pathologic nerve cell losses taking place during the process of neuronal involution, the magnitude of overproduced nerve cells may define the extent of the protection conveyed. Because male fetuses appear to involute fewer overproduced cortical neurons than females, this gender difference could explain in part the boys' greater functional impairments from early brain damage. Women, on the other hand, exhibit a higher incidence and prevalence of dementia than do men. Given the females' overall larger extent of cortical neuropil (neuronal processes) and lower neuronal numbers compared with men, any disease that causes neuronal loss could be expected to lead to more severe functional deficits in women due to their loss of more dendritic connections per neuron lost. In conclusion, superimposed on a strong background of functional and structural equality, human male and female cerebral cortex display distinct, sexually dimorphic features, which can begin to be linked to a complex array of gender-specific advantages and limitations in cognitive functions.     

Sexual dimorphism of vocal control nuclei in budgerigars (Melopsittacus undulatus) revealed with Nissl and NADPH-d staining

Nissl staining and nicotinamide adenine dinucleotide phosphate diaphorase (NADPH-d) histochemistry were used to explore the existence of sexual dimorphism in vocal control nuclei of adult budgerigars (Melopsittacus undulatus), a parrot species capable of lifelong vocal learning. Behavioral studies indicate that adult males possess larger vocal repertoires than adult females and learn new calls more quickly. The results of the present study show that the volumes of all vocal nuclei, as measured using both Nissl-stained and NADPH-d-stained material, as well as the total numbers of NADPH-d neurons, were 35-110% greater in males. Furthermore, all vocal nuclei exhibit conspicuous NADPH-d staining compared to surrounding fields in both adult males and females. Nevertheless, there were no significant gender differences in either the intensity of neuropil staining or the densities of NADPH-d neurons in vocal nuclei. Moreover NADPH-d neuron somal shapes were similar in males and females. Diameters of NADPH-d neurons in vocal nuclei were 8.5-32% larger in males than in females. Greater size of NADPH-d neuronal somata in males may be a general property of this cell type in budgerigars because a similar gender difference was found in a visual nucleus, the entopallium, which is not directly associated with the vocal control system and does not exhibit sexual dimorphism in total volume or total NADPH-d neuron numbers. Taken together, the results of the present study favor the hypothesis that superior lifelong vocal learning ability in male budgerigars rests largely on larger volumes of vocal control nuclei in males rather than on sexual dimorphism in the internal composition of vocal nuclei.     

Sex differences in neuron number in the binocular area of the rat visual cortex.

We have previously shown that the thickness of the binocular area of the primary visual cortex is sexually dimorphic in rats. In the present study, sex differences in the number of neurons in this cortical area were examined in nine littermate pairs of 90-day-old Long-Evans hooded rats. Cytoarchitectonic characteristics were used to define the binocular visual cortex, and its volume was estimated through three-dimensional reconstruction of serial coronal sections for each hemisphere. Neuronal and glial density as well as neuronal soma size were estimated from semithin sections through a stereological technique, the disector, in the same animals that were used to estimate volume. The volume of the binocular area was 19% greater in males than in females. While there were no sex differences in soma size or in neuronal density, the differences in the volume of the binocular area resulted in significant sex differences (male greater than female) in the number of neurons overall and in every layer, except layer IV. Glial density was not different between the sexes, but the total number of glial cells was higher in males than in females. These results demonstrate that the binocular visual cortex of the rat is sexually dimorphic in its volume and much of the difference is due to sex differences in the number of neurons and glial cells.     

Cerebral cortex: an MRI-based study of volume and variance with age and sex.

The aim of the present study was to examine quantitative differences in lobar cerebral cortical volumes in a healthy adult population. Quantitative volumetric MRI of whole brain, cerebral and cerebellar volumes was performed in a cross-sectional analysis of 97 normal volunteers, with segmented frontal, temporal, parietal and occipital cortical volumes measured in a subgroup of 60 subjects, 30 male and 30 female, matched for age and sex. The right cerebral hemisphere was larger than the left across the study group with a small (<1%) but significant difference in symmetry (P<0.001). No difference was found between volumes of right and left cerebellar hemispheres. Rightward cerebral cortical asymmetry (right larger than left) was found to be significant across all lobes except parietal. Males had greater cerebral, cerebellar and cerebral cortical lobar volumes than females. Larger male cerebral cortical volumes were seen in all lobes except for left parietal. Females had greater left parietal to left cerebral hemisphere and smaller left temporal to left cerebral hemisphere ratios. There was a mild reduction in cerebral volumes with age, more marked in males. This study confirms and augments past work indicating underlying structural asymmetries in the human brain, and provides further evidence that brain structures in humans are differentially sensitive to the effects of both age and sex.     

Influence of sex and estrus cycle on the sexual dimorphisms of the hypothalamic ventromedial nucleus: stereological evaluation and Golgi study

Neurons in the ventromedial nucleus of the hypothalamus (VMN) display structural and biochemical sex differences in response to estrogen. Despite this fact, reports on sex differences in the morphology of the VMN are restricted to its volume and synaptic patterning. The aim of this study was to characterize the neuroanatomical sexual dimorphisms in the VMN and to investigate whether endogenous changes in ovarian steroid secretion influence such dimorphisms. The VMN of adult male rats and intact, aged-matched female rats killed on proestrus and diestrus day 1 was examined by using stereological methods applied to conventionally stained sections and Golgi-impregnated material. The VMN contained 55,000 neurons in rats of both sexes, but its volume was, on average, 1.25 times larger in males than in females. The volume was greater in proestrus than in diestrus rats due to parallel changes in the neuronal somatic size. Unlike the dorsomedial division, neurons in the ventrolateral division had longer dendritic trees in proestrus than in diestrus females and males. The spine density was consistently higher in females than in males in both VMN divisions. In addition, in the ventrolateral part the magnitude of the sex differences varied across the estrus cycle, and reached the greatest value when females were in proestrus. The volume of the neuropil was significantly larger in males than in females, and was not affected by the estrus phase. Our results reveal that the magnitude of the neuroanatomical sex differences in the VMN vary across the estrus cycle due to the trophic influence of estrogen upon its neurons. They also show that the fundamental sex difference in the structure of the VMN is accounted for by the neuropil components.     

The importance of gender on the beneficial effects of posttraumatic hypothermia

The authors studied the importance of gender on the consequences of mild posttraumatic hypothermia following parasagittal fluid-percussion (F-P) brain injury in rats. After traumatic brain injury (TBI), brain temperature was maintained at normothermia (37 degrees C) or reduced to 33 degrees C for 4 h starting 30 min after the insult followed by a 1.5-h slow rewarming period. Animals (n = 48) were allowed to survive for 3 days before quantitative histopathological and immunocytochemical examination. As previously reported, contusion volume in normothermic animals (37 degrees C) was smaller (P < 0.05) in intact females compared to males. In addition, numbers of NeuN-positive cortical neurons were greater in females versus males after TBI. Posttraumatic hypothermia significantly reduced overall contusion volume in males (P < 0.05), while not significantly reducing contusion volume in females. Likewise, hypothermia protected against the loss of cortical neurons in males but had no effect in females. Ovariectomized females showed contusion volumes and neuronal cell counts comparable to those seen in males as well as a significant reduction in contusion volumes and greater neuronal counts following posttraumatic hypothermia. These data are the first to demonstrate that posttraumatic hypothermia (4 h) does not affect short-term histopathological outcomes in female rats. Potential mechanisms underlying this gender difference are discussed. Finally, these experimental findings may have important implications in terms of clinical trials using therapeutic hypothermia targeting patients with central nervous system (CNS) injury.     

Sex differences in postischemic neuronal necrosis in gerbils

Twenty-four hour postischemic neuronal necrosis was compared in male vs. female Mongolian gerbils subjected to a 3-h period of severe incomplete hemispheric ischemia produced by unilateral carotid occlusion. The incidence of stroke-prone males was 42.9% versus 26.7% for the females. Among the stroke-prone animals, the males displayed significantly greater neuronal necrosis at 24 h after ischemia compared to the females in the cerebral cortex and CA1 region of the hippocampus. In the CA1 region of the stroke-prone males, only 2.0% of the normal neuronal population remained by 24 h compared to 36.8% in the stroke-prone females (p less than 0.02). In the cerebral cortex, the males had only 19.9% of normal versus 58.2% in the females (p less than 0.05). In a second series of mechanistic experiments, no differences in cortical blood flow (CBF) were disclosed between preselected male and female stroke-prone animals before, during, or for 2 h after ischemia. As with the CBF, the extent of cortical extracellular hypocalcia during ischemia did not differ significantly. However, the degree of postischemic recovery of cortical extracellular calcium was significantly better in the females from 30 min to 2 h after reperfusion. In the same experiments, hemispheric vitamin E levels were measured at the 2 h time point as an index of postischemic brain lipid peroxidation. No difference in baseline vitamin E levels was observed between male and female sham-operated gerbils. In the males subjected to 3 h of ischemia plus 2 h of reperfusion, the hemispheric vitamin E decreased by 43.5% compared to the sham-operated males.(ABSTRACT TRUNCATED AT 250 WORDS)     

Gender effects on cortical thickness and the influence of scaling

Using magnetic resonance imaging and well-validated computational cortical pattern matching methods in a large and well-matched sample of healthy subjects (n = 60), we analyzed the regional specificity of gender-related cortical thickness differences across the lateral and medial cortices at submillimeter resolution. To establish the influences of brain size correction on gender effects, comparisons were performed with and without applying affine transformations to scale each image volume to a template. We revealed significantly greater cortical thickness in women compared to men, after correcting for individual differences in brain size, while no significant regional thickness increases were observed in males. The pattern and direction of the results were similar without brain size correction, although effects were less pronounced and a small cortical region in the lateral temporal lobes showed greater thickness in males. Our gender-specific findings support a dimorphic organization in male and female brains that appears to involve the architecture of the cortical mantle and that manifests as increased thickness in female brains. This sexual dimorphism favoring women, even without correcting for brain size, may have functional significance and possibly account for gender-specific abilities and/or behavioral differences between sexes.     

Relative medial and dorsal cortex volume in relation to sex differences in spatial ecology of a snake population

In non-avian reptiles the medial and dorsal cortices are putative homologues of the hippocampal formation in mammals and birds. Studies on mammals and birds commonly report neuro-ecological correlations between hippocampal volume and aspects of spatial ecology. We examined the relationship between putative homologous cortical volumes and spatial use in a population of the squamate reptile, Agkistrodon piscivorus, that exhibits sex differences in spatial use. Do male A. piscivorus that inhabit larger home ranges than females also have larger putative hippocampal volumes? Male and female brains were sectioned and digitized to quantify regional cortical volumes. Although sex differences in dorsal cortex volume were not observed, males had a significantly larger medial cortex relative to telencephalon volume. Similar to studies on mammals and birds, relative hippocampal or medial cortex volume was positively correlated with patterns of spatial use. We demonstrate volumetric sex differences within a reptilian putative hippocampal homologue.     

Regional Vulnerability after Traumatic Brain Injury: Gender Differences in Mice That Overexpress Human Copper, Zinc Superoxide Dismutase

Neuronal loss was quantified in both cortical and subcortical brain regions after traumatic brain injury in male and female nontransgenic (nTg) and transgenic (Tg) mice that overexpress human copper, zinc superoxide dismutase. Mice were euthanized at 7 days after a controlled cortical impact injury. Sections of brain were processed for immunolocalization of NeuN, a neuronal nuclear antigen, and the complement type 3 receptor, a marker of microglia/macrophages, and stained for iron. Cortical lesion volume and neuronal loss in the medial and/or lateral ventroposterior thalamic nuclei were significantly less in the nTg female compared to the nTg male (P = 0.0373 and P = 0.0023, respectively). In contrast, in CA3 of the hippocampus and laterodorsal thalamic nucleus (LD), there were no gender differences in neuronal loss between these nTg groups. Cortical lesion volume was significantly reduced in Tg males compared to nTg males (P = 0.0137) and was unchanged in the Tg females compared to the nTg females. Neuronal loss was attenuated in the CA3 and LD in the Tg females compared to the nTg females (P = 0.0252 and P = 0.0244, respectively). A similar protection was not observed in the Tg males. Microglial activation paralleled the pattern of neuronal loss and was most consistently aligned with iron deposition in the cortex and hippocampus. No overt differences were found in the pattern of microglial activation or iron staining between nTg and Tg mice nor between genders. Our findings demonstrate that neuroprotection, afforded by overexpression of copper, zinc superoxide dismutase, exhibits both regional and gender specificity.     

A Hypothesis Regarding the Pathogenesis and Epileptogenesis of Pediatric Cortical Dysplasia and Hemimegalencephaly Based on MRI Cerebral Volumes and NeuN Cortical Cell Densities

Summary:  This study compared MRI cerebral volumes and Neuronal-Nuclei (NeuN) cell densities in pediatric epilepsy surgery patients with cortical dysplasia (CD; n = 25) and hemimegalencephaly (HME; n = 14). Our purpose was to deduce possible mechanisms of pathogenesis and epileptogenesis based on an understanding of normal developmental corticoneurogenesis. We used MRI to measured cerebral hemisphere volumes, and NeuN staining to determine grey and white matter cell densities and cell sizes in the molecular layer, grey, and white matter. CD and HME surgical cases were compared with autopsy or non-CD cases (n = 20). Total MRI brain volumes were similar between non-CD, CD, and HME cases. However, in HME patients, the affected cerebral hemisphere was larger and the nonaffected side smaller than non-CD cases. Compared with autopsy cases, NeuN cell densities and cell sizes in CD and HME patients were increased in the molecular layer, upper grey matter, and white matter. In CD and HME cases, total cerebral hemisphere volumes were normal in size and there were more cortical neurons in upper layers than expected. The increase in cortical neuronal densities is consistent with the hypothesis that CD and HME pathogenesis involves increased neurogenesis in the late (not early) phases of cortical formation. In addition, more neurons in the molecular layer and white matter supports the concept that CD and HME pathogenesis also involves incomplete programmed cell death in the remnant cells occupying the preplate and subplate regions. Based on our anatomical and previous electrophysiological findings, we propose that in CD and HME seizure generation is the consequence of incomplete cerebral development with abnormal interactions between immature and mature cells and cellular networks.     

Sex and laterality differences in medial amygdala neurons and astrocytes of adult mice

The posterodorsal aspect of the medial amygdala (MePD) in rats is sexually dimorphic, being larger and containing more and larger neurons in males than in females. It is also highly lateralized, with the right MePD larger than the left in both sexes, but with the smaller left MePD actually containing more and larger neurons than the larger right. Astrocytes are also strikingly sexually differentiated, with male‐biased numbers and lateralized favoring the right in the rat MePD. However, comparable information is scant for mice where genetic tools offer greater experimental power. Hence, we examined the MePD from adult male and female C57Bl/6^J mice. We now report that the MePD is larger in males than in females, with the MePD in males containing more astrocytes and neurons than in females. However, we did not find sex differences in astrocyte complexity or overall glial number nor effects of laterality in either measure. While the mouse MePD is generally less lateralized than in rats, we did find that the sex difference in astrocyte number is only on the right because of a significant lateralization in females, with significantly fewer astrocytes on the right than the left but only in females. A sex difference in neuronal soma size favoring males was also evident, but only on the left. Sex differences in the number of neurons and astrocytes common to both rodent species may represent core morphological features that critically underlie the expression of sex‐specific behaviors that depend on the MePD. J. Comp. Neurol. 524:2492–2502, 2016. © 2016 Wiley Periodicals, Inc.     

Cerebral sex dimorphism and sexual orientation

The neurobiology of sexual orientation is frequently discussed in terms of cerebral sex dimorphism (defining both functional and structural sex differences). Yet, the information about possible cerebral differences between sex‐matched homo and heterosexual persons is limited, particularly among women. In this multimodal MRI study, we addressed these issues by investigating possible cerebral differences between homo and heterosexual persons, and by asking whether there is any sex difference in this aspect. Measurements of cortical thickness (Cth), subcortical volumes, and functional and structural resting‐state connections among 40 heterosexual males (HeM) and 40 heterosexual females (HeF) were compared with those of 30 homosexual males (HoM) and 30 homosexual females (HoF). Congruent with previous reports, sex differences were detected in heterosexual controls with regard to fractional anisotropy (FA), Cth, and several subcortical volumes. Homosexual groups did not display any sex differences in FA values. Furthermore, their functional connectivity was significantly less pronounced in the mesial prefrontal and precuneus regions. In these two particular regions, HoM also displayed thicker cerebral cortex than other groups, whereas HoF did not differ from HeF. In addition, in HoM the parietal Cth showed “sex‐reversed” values, not observed in HoF. Homosexual orientation seems associated with a less pronounced sexual differentiation of white matter tracts and a less pronounced functional connectivity of the self‐referential networks compared to heterosexual orientation. Analyses of Cth suggest that male and female homosexuality are not simple analogues of each other and that differences from heterosexual controls are more pronounced in HoM.     

Gender differences in the corpus callosum of neonates

The gender difference of corpus callosum is a long standing controversy. Some investigators have reported that adult females have a more bulbous splenium and larger area relative to brain size, but others failed to replicate this. Few studies have reported on sexual dimorphism during development. Midsagittal ultrasonographs were obtained through the anterior fontanelle of healthy Korean neonates (100 males, 100 females) and were analyzed with NIH Image. The total area of corpus callosum and sub-regions of corpus callosum showed no gender differences. However, the male corpus callosum had significantly more height than that of the female whereas there was no difference in width of the corpus callosum. The estimated average thickness of corpus callosum was greater in the female splenium.     

Partial demasculinization of several brain regions in adult male (XY) rats with a dysfunctional androgen receptor gene

The adult rat posterodorsal medial amygdala (MePD) is sexually dimorphic in regional volume and neuronal soma size, both of which are larger in males than in females. This sexual dimorphism is entirely dependent on adult circulating levels of testicular androgens, and both androgen and estrogen treatment can masculinize MePD structure. We examined male rats that are rendered androgen-insensitive by the testicular feminization mutation (tfm) of the androgen receptor (AR) gene to determine how a dysfunctional AR affects this and other brain sexual dimorphisms. In adult wild-type rats, the MePD in males had a greater regional volume, rostrocaudal extent, and soma size than in females. In genetic males, defective ARs affected some but not all of these indices: MePD volume and soma size in tfm males were intermediate between those of wild-type males and females, but the rostrocaudal extent of the MePD was unaffected by the mutation, being as great in tfm males as in wild-type males. Regional volume and soma size in the suprachiasmatic nucleus was reduced in tfm males compared with wild-type males, suggesting that AR normally affects this region in male rats. Interestingly, whereas volume of the sexually dimorphic nucleus of the preoptic area was unaffected by the tfm allele, soma size in this region was reduced in tfm males compared with wild-type males. Although estrogen receptor activation has been shown to be vital for masculinization of the rodent brain, our results indicate that ARs also contribute to this process in several brain regions.     

Sound-generating (sonic) motor system in a teleost fish (Porichthys notatus): sexual polymorphisms and general synaptology of sonic motor nucleus

The sonic motor nucleus of the plainfin midshipman, Porichthys notatus, is a midline nucleus located at the junction of the caudal medulla and rostral spinal cord. Its motoneurons innervate sonic "drumming" muscles that are attached to the lateral walls of the swimbladder. There are two classes of sexually mature males referred to as Type I and Type II. The Type I males are larger and generate sounds during the breeding season. The Type II males are smaller and, like adult females, have not yet been shown to generate sounds. This study examined possible sex differences in the size of sonic motoneurons, and the type and distribution of their afferent terminal boutons. The average soma diameter of motoneurons of Type I males is about 50% larger than that of Type II males and females. There is also a small but significant difference in soma diameter between Type II males and females; they are smaller in the former class. There were no sex differences in the presence or distribution of different classes of axosomatic and axodendritic terminal boutons, which included: (1) active zones with either clear, round, or pleomorphic vesicles, (2) active zones with both clear, round vesicles, and larger dense core vesicles, (3) "mixed synapses" with gap junctions and active zones usually associated with pleomorphic vesicles. The results are discussed within the context of sexual differentiation of vertebrate motor systems and the functional organization of the sonic motor system in fishes. Sex differences in soma diameter correlate with a number of sex differences in the gross and ultrastructural features that distinguish the sonic muscles of Type I males from those of Type II males and females, which are similar to each other. The absence of qualitative sex differences in synaptic morphology suggest that the central neuronal circuitry of the sonic motor system is similar among all three adult morphs.     

A biologically informed polygenic score of neuronal plasticity moderates the association between cognitive aptitudes and cortical thickness in adolescents

Although many studies of the adolescent brain identified positive associations between cognitive abilities and cortical thickness, little is known about mechanisms underlying such brain-behavior relationships. With experience-induced plasticity playing an important role in shaping the cerebral cortex throughout life, it is likely that some of the inter-individual variations in cortical thickness could be explained by genetic variations in relevant molecular processes, as indexed by a polygenic score of neuronal plasticity (PGS-NP). Here, we studied associations between PGS-NP, cognitive abilities, and thickness of the cerebral cortex, estimated from magnetic resonance images, in the Saguenay Youth Study (SYS, 533 females, 496 males: age=15.0 ± 1.8 years of age; cross-sectional), and the IMAGEN Study (566 females, 556 males; between 14 and 19 years; longitudinal). Using Gene Ontology, we first identified 199 genes implicated in neuronal plasticity, which mapped to 155,600 single nucleotide polymorphisms (SNPs). Second, we estimated their effect sizes from an educational attainment meta-GWAS to build a PGS-NP. Third, we examined a possible moderating role of PGS-NP in the relationship between performance intelligence quotient (PIQ), and its subtests, and the thickness of 34 cortical regions.In SYS, we observed a significant interaction between PGS-NP and object assembly vis-à-vis thickness in male adolescents (p = 0.026). A median-split analysis showed that, in males with a ‘high’ PGS-NP, stronger associations between object assembly and thickness were found in regions with larger age-related changes in thickness (r = 0.55, p = 0.00075). Although the interaction between PIQ and PGS-NP was non-significant (p = 0.064), we performed a similar median-split analysis. Again, in the high PGS-NP males, positive associations between PIQ and thickness were observed in regions with larger age-related changes in thickness (r = 0.40, p = 0.018). In the IMAGEN cohort, we did not replicate the first set of results (interaction between PGS-NP and cognitive abilities via-a-vis cortical thickness) while we did observe the same relationship between the brain-behaviour relationship and (longitudinal) changes in cortical thickness (Matrix reasoning: r = 0.63, p = 6.5e-05). No statistically significant results were observed in female adolescents in either cohort. Overall, these cross-sectional and longitudinal results suggest that molecular mechanisms involved in neuronal plasticity may contribute to inter-individual variations of cortical thickness related to cognitive abilities during adolescence in a sex-specific manner.     

Development of cortical and subcortical brain structures in childhood and adolescence: a structural MRI study

The purpose of the present study was to describe in greater anatomical detail the changes in brain structure that occur during maturation between childhood and adolescence. High-resolution MRI, tissue classification, and anatomical segmentation of cortical and subcortical regions were used in a sample of 35 normally developing children and adolescents between 7 and 16 years of age (mean age 11 years; 20 males, 15 females). Each cortical and subcortical measure was examined for age and sex effects on raw volumes and on the measures as proportions of total supratentorial cranial volume. Results indicate age-related increases in total supratentorial cranial volume and raw and proportional increases in total cerebral white matter. Gray-matter volume reductions were only observed once variance in total brain size was proportionally controlled. The change in total cerebral white-matter proportion was significantly greater than the change in total cerebral gray-matter proportion over this age range, suggesting that the relative gray-matter reduction is probably due to significant increases in white matter. Total raw cerebral CSF volume increases were also observed. Within the cerebrum, regional patterns varied depending on the tissue (or CSF) assessed. Only frontal and parietal cortices showed changes in gray matter, white matter, and CSF measures. Once the approximately 7% larger brain volume in males was controlled, only mesial temporal cortex, caudate, thalamus, and basomesial diencephalic structures showed sex effects with the females having greater relative volumes in these regions than the males. Overall, these results are consistent with earlier reports and describe in greater detail the regional pattern of age-related differences in gray and white matter in normally developing children and adolescents.     

Cortical neuronal densities and lamination in focal cortical dysplasia

Focal cortical dysplasia (FCD) is considered to represent a malformation due to abnormal cortical development (MCD) and is an important cause of focal epilepsy. The histopathological features include abnormal laminar architecture, the presence of hypertrophic and dysmorphic neurones in FCD type IIA and additional balloon cells in FCD type IIB. The events causing these sporadic lesions are unknown, but abnormal progenitor cell proliferation occurring late in corticogenesis has been proposed. FCD-like lesions have, however, also been described following a cerebral injury early in life. We carried out a stereological assessment on 15 cases of FCD on NeuN- and Nissl-stained sections from patients with a wide age range, and identified a significant reduction in the neuronal density in all cases in the region of dysplasia compared to the adjacent unaffected cortex (mean neuronal densities 19.2×10³/mm³ in the region of dysplasia; 42.8×10³/mm³ in the adjacent cortex). Relative differences in neuronal density and size in FCD cases between the superficial (layer I and II) and deep cortical laminae (layer V and VI) were similar to that observed in other pathologies including mild MCD, temporal neocortex adjacent to hippocampal sclerosis as well as in a non-epilepsy surgical control group. The lower overall neuronal densities observed in FCD may reflect neuropil expansion, a local failure of neuronal migration, proliferation or secondary neuronal loss. The preservation of relative differences in neuronal densities between cortical layers and laminar patterns of neurofilament staining in FCD would support the view that the temporal sequence of lamination is not affected.