1088
Symposium
Sex differences in brain structure and function, although subtle, might have important implications for understanding the biological basis of differences in the prevalence and expression of psychiatric disorders. Interdisciplinary approaches are necessary to examine sex differences and sex-specific effects across multiple scales of brain organization, from microstructure to functional networks, while accounting for interactions with other biological and environmental factors including genetics, hormones, social norms, and life experiences. This system-level perspective importantly acknowledges that the brain is itself an organized system embedded within broader biological and social systems, each of which exhibits sex differences and uniquely interacts with brain organization. Large datasets in combination with computational methods are required to disentangle the complex relationships between brain, sex, and health outcomes.
This symposium highlights cutting-edge research using advanced methods and large-scale open datasets to study sex differences in multiscale human brain organization, with talks spanning multiple levels of biological analysis across the lifespan, addressing both health and disease. Dr. Sarah Whittle (professor) will focus on the adolescent period and will present work investigating environmental and pubertal contributors (both physical and hormonal) to sex differences in brain structure and function using the Adolescent Brain Cognitive Development dataset. Ms. Bianca Serio (doctoral candidate) will present findings on adult variability and sex differences in computationally derived low-dimensional representations of functional brain organization, integrating multimodal data from the Human Connectome Project with densely sampled individual data, and using a sex-specific design to explore neuroendocrine influences on brain function. Dr. Claudia Barth (senior researcher) will focus on female brain health in aging, presenting findings from large datasets, including the UK Biobank, and using machine learning approach and causal modeling techniques such as Mendelian randomization to assess the impact of female-specific factors on the aging brain and risks for depression and Alzheimer's disease. Finally, Dr. Armin Raznahan (tenured senior investigator) will present work using multimodal mapping techniques that integrate neuroimaging and transcriptomics to provide a detailed view of sex differences in brain anatomy, activity, and gene expression.
Throughout this session, attendees will be exposed to innovative applications of computational and multimodal research methods. Attendees will also learn to appreciate the critical role of large interdisciplinary research and collaborative study consortia to advance our understanding of sex differences in brain organization across the lifespan.
The learning objectives of this symposium are for attendees to gain an understanding of:
1) The general relevance of studying sex differences to all neuroimagers
2) The importance of taking an interdisciplinary and multiscale approach when studying sex differences in brain organization across the lifespan, in health and disease
3) The promise of innovative computational approaches, large-scale open datasets and collaborative study consortia for the study of sex differences
The importance of considering sex differences in neuroscientific research is being increasingly recognized, with leading journals raising the standards for reporting on sex and gender in research and requiring compliance to the Sex and Gender Equity in Research (SAGER) guidelines. As such, this symposium will be valuable to all OHBM attendees. Methodologically, this symposium will also be of particular interest to researchers integrating multimodal and interdisciplinary measures as well as using large-scale open datasets. Conceptually, the symposium will further be particularly relevant to researchers interested in studying health and disease, specific stages of the lifespan (i.e., childhood/adolescence, adulthood, ageing), as well as sex differences and sex specificity.
Presentations
Adolescence is a period of marked brain development, with sex differences in brain developmental trajectories thought to be influenced in part by sex-specific pubertal processes. Increased neural plasticity during this time is thought to contribute to the adolescent brain being particularly susceptible to effects of the social environment, in ways that differ based on sex and pubertal stage. In this talk, I will present research that investigates the complex role of pubertal stage, pubertal hormones, and the social environment in shaping sex-specific patterns of brain structure and function in large samples (Ns>3000) of adolescents (aged 9-14 years) from the US-based Adolescent Brain Cognitive Development Study. I will highlight two specific studies. First, I will present a longitudinal study investigating whether pubertal stage (i.e., Tanner stage) moderates the impact of adverse experiences on emotional brain function in males and females. Findings suggest that certain Tanner stages are associated with increased sensitivity to the effects of adverse experiences on emotional brain function, particularly in subcortical regions, with findings differing for males and females. Second, I will hone in on the female adolescent brain, and present exploratory work investigating associations between pubertal hormones (estradiol, testosterone, dehydroepiandrosterone) and brain phenotypes derived from multiple imaging modalities in female adolescents. Using elastic-net regression with cross-validation, both unique and overlapping neural correlates of these hormones are found, suggesting neural mechanisms by which pubertal hormones impact specific behaviours and functioning in females. In summary, this research sheds new light on the role of puberty in shaping sex-specific patterns of brain development, and engendering sex-specific neural sensitivity to the effects of the social environment.
Relevant recent publications:
- Khetan, M., Vijayakumar, N., Tian, Y. E., Herting, M. M., O'Connell, M., Seal, M., & Whittle, S. (2024). Pubertal hormones and the early adolescent female brain: a multimodality brain MRI study. bioRxiv, 2024.2011.2027.625122. https://doi.org/10.1101/2024.11.27.625122.
- Cheng, T. W., Magis-Weinberg, L., Guazzelli Williamson, V., Ladouceur, C. D., Whittle, S. L., Herting, M. M., ... & Pfeifer, J. H. (2021). A Researcher’s Guide to the Measurement and Modeling of Puberty in the ABCD Study® at Baseline. Frontiers in endocrinology, 12, 608575.
- Rakesh, D., Seguin, C., Zalesky, A., Cropley, V., & Whittle, S. (2021). Associations between neighborhood disadvantage, resting-state functional connectivity, and behavior in the adolescent brain cognitive development study: the moderating role of positive family and school environments. Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 6(9), 877-886.
Presenter
Sarah Whittle, Unversity of Melbourne Melbourne, Victoria
Australia
Although patterns of functional connectivity are considered to be largely stable, trait-like features of the human brain, they also exhibit a remarkable variability, both within and between individuals. This talk will present multimodal and interdisciplinary research exploring variability and sex differences in functional brain organization across population-level and individual scales, revealing both shared and sex-specific effects. First, in a large sample (N = 1000) from the Human Connectome Project, we investigated sex differences in functional cortical organization using the sensory-association (S-A) axis, a low-dimensional representation of functional brain organization. Our findings demonstrated widespread sex differences in the S-A axis that were not systematically explained by cortical morphometry (i.e., brain size, microstructural organization, nor the mean geodesic distance of functional connectivity profiles). Instead, these effects reflected sex-specific variations in network topology and functional connectivity profiles, suggesting that sex differences in functional cortical organization extend beyond sex differences in cortical morphometry. Second, at the individual level, data from two densely sampled individuals (one female, one male) revealed dynamic intra-individual variability in the S-A axis over 20–30 consecutive days of testing. Daily variability was greatest in temporal limbic and ventral prefrontal regions in both participants, but was more strongly pronounced in the male subject. Beyond shared patterns of effects, the female and male participants further revealed subtle and unique associations between neuroendocrine fluctuations and intra-individual variability along the S-A axis. These findings point to neuroendocrine factors as possible modulators of intra-individual variability in functional brain organization. Together, these studies bridge population- and individual-level perspectives, uncovering both similarities and differences in macroscale functional brain organization across sexes and exploring their interdisciplinary underpinnings. This talk underscores the importance of considering sex differences when studying functional brain organization, as well as examining variability across scales to study both group-level generalizable effects and individual-specific mechanisms, for a better understanding of functional variability in health and disease.
Relevant recent publications:
- Serio, B., Hettwer, M. D., Wiersch, L., Bignardi, G., Sacher, J., Weis, S., ... & Valk, S. L. (2024). Sex differences in functional cortical organization reflect differences in network topology rather than cortical morphometry. Nature Communications, 15(1), 7714.
- Serio, B., Yilmaz, D., Pritschet, L., Grotzinger, H., Jacobs, E. G., Eickhoff, S. B., & Valk, S. L. (2024). Exploring sex-specific neuroendocrine influences on the sensorimotor-association axis in single individuals. bioRxiv, 2024-05.
Presenter
Bianca Serio, Max Planck School of Cognition Leipzig, Saxony
Germany
Estradiol is the predominant sex steroid in females and has been implicated in the development of depression and Alzheimer’s disease – two disorders that disproportionately affect females compared to males. Despite well-established sex differences in these brain disorders, there has been a limited focus on the effects of endocrine aging on brain health and mental health in females. If studied at all, research commonly relies on small datasets, emphasizing the need for big data studies and concerted consortia efforts to increase power, reproducibility, and generalizability of female brain health studies. In my talk, I will spotlight female brain health by informing on the role of estradiol and factors related to estradiol exposure on the aging female brain and risk for depression and Alzheimer’s disease. First, I will present our work on studying these associations using large-scale population-based datasets and machine learning tools within a conventional observational framework relying on cross-sectional data. Second, I will move from an observational to a causal framework by showcasing our work using Mendelian randomization (MR), a computational method which uses genetic variants to test for causal exposure-outcome relationships in a large female-only sample. Lastly, I will conclude the talk by introducing our recently launched ENIGMA Neuroendocrinology Working Group which aims at pooling datasets globally to explore the effects of hormonal transition periods on female brain health. In summary, by using large-scale, female-only samples, and state-of-the-art methods in observational as well as causal frameworks, our research provides a unique contribution to our current understanding of potential effects of sex steroids on female brain and mental health.
Funding: The work is supported by the South-Eastern Norway Regional Health Authority (PI CB: 2023037, 2022103) and the European Research Council (PI CB: 101163765).
Relevant recent publications:
- Barth, C., Galea, L. A., Jacobs, E. G., Lee, B. H., Westlye, L. T., & de Lange, A. M. G. (2024). Menopausal hormone therapy and the female brain: leveraging neuroimaging and prescription registry data from the UK Biobank cohort. eLife 13:RP99538.
- Heller, C., Barth, C., Silk, T. J., Vijayakumar, N., Carmona, S., Martínez-García, M., ... & Petersen, N. (2024). The ENIGMA-Neuroendocrinology working group to bridge gaps in female mental health research. Nature Mental Health, 2(4), 348-350.
- Barth, C., Crestol, A., de Lange, A. M. G., & Galea, L. A. (2023). Sex steroids and the female brain across the lifespan: insights into risk of depression and Alzheimer's disease. The Lancet Diabetes & Endocrinology.
- Oppenheimer, H., van der Meer, D., Schindler, L., Crestol, A., Westlye, L. T., de Lange, A. M. G., & Barth, C. No Causal Links Between Lifetime Estradiol Exposure and Female’s Brain and Mental Health–A Mendelian Randomization Study. preprint
Humans show sex-differences in numerous mental health outcomes - likely reflecting the complex interaction of biological, psychological and social factors. Mapping sex-differences in human brain organization through in vivo neuroimaging may help to unravel this complexity. However, there remains controversy regarding the extent and nature of sex-biased human brain organization from neuroimaging, and we lack information on potential cellular underpinnings of those neuroimaging sex-differences that have been reported. This talk will present new work that (1) charts reproducible structural and functional sex-differences in the human brain using multiple large-scale datasets encompassing up to ~35k individuals, and then (2) conducts single nucleus RNAseq of >1.5M cells in 180 cortical samples from 30 individuals (15 male) to resolve cell-type specific sex differences at neuroimaging hotspots of sex-biased brain anatomy. We find that humans show reproducible sex differences in regional brain volume that: exist above and beyond sex-differences in overall brain size; show a consistent spatial patterning (r~0.8) within and across samples; are small-medium in absolute effect size and orthogonal to co-occurring sex differences in brain activation; and include regions implicated in multiple psychiatric disorders. Single nucleus RNAseq at hotspots of sex-biased brain volume find similar cellular proportions in males and females (p>0.05) but extensive cell-type specific sex-differences in gene expression (FDR q<0.05) that are most prominent for glial cells and enriched for genes implicated in diverse sex-biased psychiatric conditions. This work nominates numerous anatomical and molecular brain systems that show sex-biased organization in humans – identifying potential pathways for sex-differences in psychiatric risk. These pathways represent empirically prioritized targets for sex-specific modulation of mental health outcomes.
Relevant recent publications:
- Liu, S., Seidlitz, J., Blumenthal, J. D., Clasen, L. S., & Raznahan, A. (2020). Integrative structural, functional, and transcriptomic analyses of sex-biased brain organization in humans. Proceedings of the National Academy of Sciences, 117(31), 18788-18798.
- DeCasien, A. R., Guma, E., Liu, S., & Raznahan, A. (2022). Sex differences in the human brain: a roadmap for more careful analysis and interpretation of a biological reality. Biology of Sex Differences, 13(1), 43.
- Shafee, R., Moraczewski, D., Liu, S., Mallard, T., Thomas, A., & Raznahan, A. (2024). A sex-stratified analysis of the genetic architecture of human brain anatomy. Nature Communications, 15(1), 8041.