Sex-Based Brain Differences and Emotional Harm

Technological advances have allowed neuroscientists to identify brain differences between women and men, which may lead to explanations for sex-biased population differences in behavior and brain-based disorders. Although the research is at its early stages, this is an appropriate time to examine some of the potential legal implications of these findings. This Article examines that question in the context of tort law, especially how scientific findings may affect the use of the reasonable person standard in emotional injury claims. Specifically, studies suggest that there may be distinct sex-based mechanisms involved in reactions to extreme stress, raising the question of whether women experience and process stress and trauma differently than men. This Article argues that these studies may eventually inform the use of the reasonableness standard for freestanding emotional harm claims. As science further develops, courts may either apply a reasonable woman standard in limited contexts or at least allow jurors to consider evidence of sex-based differences in applying a reasonable person standard. Recognizing these differences, courts have already begun to apply the reasonable woman standard to hostile workplace environment claims, and science may support broader use of that standard, especially for negligent and intentional infliction of emotional harm claims

Impact of X/Y genes and sex hormones on mouse neuroanatomy

Biological sex influences brain anatomy across many species. Sex differences in brain anatomy have classically been attributed to differences in sex chromosome complement (XX versus XY) and/or in levels of gonadal sex steroids released from ovaries and testes. Using the four core genotype (4CG) mouse model in which gonadal sex and sex chromosome complement are decoupled, we previously found that sex hormones and chromosomes influence the volume of distinct brain regions. However, recent studies suggest there may be more complex interactions between hormones and chromosomes, and that circulating steroids can compensate for and/or mask underlying chromosomal effects. Moreover, the impact of pre vs post-pubertal sex hormone exposure on this sex hormone/sex chromosome interplay is not well understood. Thus, we used whole brain high-resolution ex-vivo MRI of intact and pre-pubertally gonadectomized 4CG mice to investigate two questions: 1) Do circulating steroids mask sex differences in brain anatomy driven by sex chromosome complement? And 2) What is the contribution of pre- versus post-pubertal hormones to sex-hormone-dependent differences in brain anatomy? We found evidence of both cooperative and compensatory interactions between sex chromosomes and sex hormones in several brain regions, but the interaction effects were of low magnitude. Additionally, most brain regions affected by sex hormones were sensitive to both pre- and post-pubertal hormones. This data provides further insight into the biological origins of sex differences in brain anatomy

Sex-divergent effects on the NAD+-dependent deacetylase sirtuin signaling across the olfactory–entorhinal–amygdaloid axis in Alzheimer’s and Parkinson’s diseases

BackgroundSmell impairment is one of the earliest features in Alzheimer's (AD) and Parkinson's diseases (PD). Due to sex differences exist in terms of smell and olfactory structures as well as in the prevalence and manifestation of both neurological syndromes, we have applied olfactory proteomics to favor the discovery of novel sex-biased physio-pathological mechanisms and potential therapeutic targets associated with olfactory dysfunction.MethodsSWATH-MS (sequential window acquisition of all theoretical fragment ion spectra mass spectrometry) and bioinformatic workflows were applied in 57 post-mortem olfactory tracts (OT) derived from controls with no known neurological history (n = 6F/11M), AD (n = 4F/13M) and PD (n = 7F/16M) subjects. Complementary molecular analyses by Western-blotting were performed in the olfactory bulb (OB), entorhinal cortex (EC) and amygdala areas.Results327 and 151 OT differentially expressed proteins (DEPs) were observed in AD women and AD men, respectively (35 DEPs in common). With respect to PD, 198 DEPs were identified in PD women, whereas 95 DEPs were detected in PD men (20 DEPs in common). This proteome dyshomeostasis induced a disruption in OT protein interaction networks and widespread sex-dependent pathway perturbations in a disease-specific manner, among them Sirtuin (SIRT) signaling. SIRT1, SIRT2, SIRT3 and SIRT5 protein levels unveiled a tangled expression profile across the olfactory-entorhinal-amygdaloid axis, evidencing disease-, sex- and brain structure-dependent changes in olfactory protein acetylation.ConclusionsAlteration in the OT proteostasis was more severe in AD than in PD. Moreover, protein expression changes were more abundant in women than men independent of the neurological syndrome. Mechanistically, the tangled SIRT profile observed across the olfactory pathway-associated brain regions in AD and PD indicates differential NAD (+)-dependent deacetylase mechanisms between women and men. All these data shed new light on differential olfactory mechanisms across AD and PD, pointing out that the evaluation of the feasibility of emerging sirtuin-based therapies against neurodegenerative diseases should be considered with caution, including further sex dimension analyses in vivo and in clinical studies

COMT Val(158)Met genotypes differentially influence subgenual cingulate functional connectivity in healthy females

Brain imaging studies have cons stently shown subgenual Anterior Cingulate Cortical (sgACC) involvement in emotion processing. catechol-O-methyltransferase (COMT) Val(158) and Met(158) polymorphisms may influence such emotional brain processes in specific ways. Given that resting-state fMRI (rsfMRI) may increase our understanding on brain functioning, we integrated genetic and rsfMRI data and focused on sgACC functional connections. No studies have yet investigated the influence of the COMT Val(158)Met polymorphism (rs4680) on sgACC resting-state functional connectivity (rsFC) in healthy individuals. A homogeneous group of 61 Caucasian right-handed healthy female university students, all within the same age range, underwent isfMRI. Compared to Met158 homozygotes, Val(158) allele carriers displayed significantly stronger rsFC between the sgACC and the left parahippocampal gyrus, ventromedial parts of the inferior frontal gyrus (IFG), and the nucleus accumbens (NAc). On the other hand, compared to Val(158) homozygotes, we found in Met(158) allele carriers stronger sgACC rsFC with the medial frontal gyrus (MEG), more in particular the anterior parts of the medial orbitofrontal cortex. Although we did not use emotional or cognitive tasks, our sgACC rsFC results point to possible distinct differences in emotional and cognitive processes between Val(158) and Met(158) allele carriers. Hovvever, the exact nature of these directions remains to be determined

Sex Moderates the Relationship That Number of Professional Fights Has With Cognition and Brain Volumes.

Objective: Incidence of concussions and report of symptoms are greater among women across sports. While structural brain changes and cognitive declines are associated with repetitive head impact (RHI), the role of sex is not well-understood. This study aimed to determine if there is a moderating effect of sex on the relationship the number of professional fights has with cognitive functioning and regional brain volumes in a cohort of boxers, mixed martial artists, and martial artists. Methods: A total of 55 women were matched with 55 men based on age, years of education, ethnicity, and fighting style. Cognition was assessed via the CNS Vital Signs computerized cognitive battery and supplemental measures. Structural brain scans, demographic data, and number of professional fights (NoPF) were also considered. The matched pairs were compared via analysis of covariance, accounting for total brain volume. Within-subject moderation models were utilized to assess the moderating effect of sex on the relationship between NoPF and brain volumes and cognitive performance. Results: Men were observed to have poorer performance on measures of psychomotor speed when compared to women. On a series of analyses assessing the role of sex as a moderator of the relationship between NoPF and regional brain volumes/cognitive performance, a significant moderation effect was observed across multiple measures of cognitive functioning, such that men had poorer performance. Differences in numerous regional brain volumes were also observed, such that the relationship between NoPF and brain volumes was steeper among men. Conclusion: Sex was observed to be an important moderator in the relationship between NoPF, aspects of cognitive functioning, and volumes of numerous brain regions, suggesting that sex differences in neuroanatomic and cognitive response to RHI deserve further attention

Ageing: Not only an age-related issue

Developments in the last century have led to an unprecedented increase in life expectancy. These changes open opportunities for humans to grow and develop in healthy and adaptive ways, adding life to years as well as years to life. There are also challenges, however - as we live longer, a greater number of people will experience chronic illness and disability, often linked to lifestyle factors. The current paper advances an argument that there are fundamental biological sex differences which, sometimes directly and sometime mediated by lifestyle factors, underpin the marked differences in morbidity and mortality that we find between the sexes. Furthermore, we argue that it is necessary to consider sex as a key factor in research on healthy ageing, allowing for the possibility that different patterns exist between males and females, and that therefore different approaches and interventions are required to optimise healthy ageing in both sexes

Patterns of variation and allometry in sub-cortical structures of the human brain: an evaluation of sex differences and age

This research tests a series of research questions concerning relationships between size, shape (static adult scaling relations) and multivariate patterns of variation in brains of adult modern humans using in vivo measurements from magnetic resonance imaging (MRI) scans. The main research questions consider if patterns of adult human sub-cortical brain dimorphisms are driven by overall brain size differences between the sexes. Sex differences in absolute brain size in humans are well known. There is a general consensus that male brains are larger in absolute size than female brains. However, discrepancies among studies in the presence and extent of dimorphisms indicate uncertainty the degree to which sexual dimorphism (SD) is spread throughout the brain, particularly within sub-cortical structures. Therefore, to address the problem of SD, this project 1) tests brain size variation and scaling relationships in sub-cortical structures between adult human males and females, 2) tests these in younger and older age categories and 3) tests the degree to which sub-cortical brain components covary in size. This study includes two groups of right-handed, native English speakers recruited from the Champaign-Urbana community. These data represent 189 healthy individuals, consisting of four sex and age categories: younger men (n=18), younger women (n=23), older men (n=50), and older women (n=98). Younger individuals ages range from 18-35 years, and older individuals ages range from 50-80 years. The individuals involved in this project were originally recruited for a study on the effects of exercise and aging on cognition (Colcombe, 2004; Erickson et. al., 2004), and were screened for psychiatric illness prior to participation. The results presented here support the hypothesis that sex differences in sub-cortical structures relative to total brain volume are moderate to non-existent between males and females ii" " both in the younger and in the older age groups. Bivariate results indicate two possible patterns of allometry: significant positive allometry with the use of a reduced major axis regression, or allometry supporting a generally isometric to negatively allometric with the use of an ordinary least squares regression. Both results are described. Multivariate results (principal components analysis) of the combined sample indicate size plays a large role in explaining the variation in the data, with other factors offering substantial contributions. On explanation is that patterns of variation in the second and perhaps third principal components might be the result of developmental and functional relationships among sub-cortical structures. The main differences between the older and younger age categories is a higher correlation among regions in the younger category, lending some support to the idea that an extended human lifespan may lead to a breakdown in correlation structure as we age. Reduced major axis regression and ordinary least squares regression offer two alternatives to understanding scaling of sub-cortical structures in the brain. OLS results are in line with expectations of scaling patterns. Issues of sample size are important to the interpretation of results in this study, and are discussed. The effects of developmental processes on adult brain size are described throughout the thesis. In particular, gonadal hormones such as estrogen and testosterone have been hypothesized to result in larger or smaller structures in each of the sexes. The potential impact these hormones have on sex differences in the brain and on behavior support the idea that hormones may play a large role in determining differences in function, and that may or may not result in measurable differences in brain volumes. Finally, implications of this study and avenues for future research are discussed

Sex Bias in Autism

Autism is a neurodevelopmental disorder with unknown exact etiology. Interestingly, it affects males more than females in a striking ratio (4:1), respectively. This biased ratio served as a clue to search about the factors that are sex linked and hence sex hormones and X chromosomes were good candidates. Although understanding the basic sex dimorphism in male and female brains is essential to understand autism pathology. Theories regarding the biased sex ratio in autism have been raised, and some have been supported by evidence from human studies. Furthermore, sex-linked genetic dysregulation has also been reported in autism. In this chapter, an overview of what is known about sex bias in autism is reviewed, emphasizing the importance of carrying on in uncoding the sex bias in autism