Gabriel Allan Devenyi

Neuroimaging studies often derive and discuss structural covariance (SC) as a representation of underlying brain circuitry that reflects coordinated maturation, anatomical connectivity, transcriptional similarity, and shared genetic influences. These associations motivate its use to study brain organization across development, aging, and disease. However, the algorithms used to derive SC networks impose constraints that may shape their biological interpretation. To understand the impact of algorithm choice, we used the thalamocortical system as an example and compared five common representations of voxelwise SC, namely, principal component analysis (PCA), independent component analysis (ICA), non-negative matrix factorization (NMF), orthogonal projective NMF (OPNMF), and k -means clustering, in 755 participants aged 8–22 years from the Philadelphia Neurodevelopmental Cohort (PNC). SC networks derived from deformation-based morphometry (DBM) were evaluated against three complementary biological benchmarks: age-related individual differences, fractional-anisotropy (FA)-based microstructural connectivity of regionally-specific thalamocortical connections, and Allen Human Brain Atlas gene expression. Each algorithm demonstrated underlying sensitivity to differing aspects of neurobiology: PCA and OPNMF showed the strongest associations between participant-level component weights and age. NMF, OPNMF, and k -means showed greater spatial overlap between positive cortical SC and tractography-derived projections. ICA and PCA showed stronger correspondence between thalamic and cortical gene-expression profiles across the transcriptome, whereas NMF, OPNMF, and k -means more often identified thalamic components with relatively high core-matrix gene expression. This study emphasizes that algorithmic constraints effectively act as biological priors and decomposition methods do not provide neutral compression of the data. We conclude that it is critical to consider whether the algorithmic objective matches the representational geometry of the neurobiology being studied. Overall, our findings suggest that SC studies should select and justify algorithms according to the biological question, explicitly considering whether their constraints favour distributed gradients, overlapping regional parts, or discrete clusters. Meanwhile, interpretations of SC findings could also be informed by the specific algorithmic constraints used to derive them.

International data privacy regulations impede the pooling of research data for collaborative analysis. We introduce Neurobagel, a federated network enabling cohort discovery across locally governed, access-controlled datasets. Through intuitive graphical tools and a decentralized query infrastructure, Neurobagel facilitates harmonization, control, and discovery of data according to local regulations. Today, Neurobagel is deployed by consortia and data platforms in Europe, North America, Asia, and Australia, supporting diverse and evolving regulatory frameworks.

The existence and mechanistic bases of sex effects on human subcortical anatomy remain unclear. To address these gaps, we combined structural neuroimaging of sex differences in subcortical volume and shape across three independent cohorts (combined N=2,886) with neuroimaging maps of sex chromosomal and endocrine effects from three clinical cohorts (combined N=313, including sex chromosome aneuploidies and isolated gonadotropin-releasing hormone deficiency). We found that human subcortical anatomy shows focal sex differences of moderate-strong effect size during young adulthood (male-biased surface area overlying lateral/ventral putamen and pallidum, nucleus accumbens, ventral posterior complex of thalamus, anterior hippocampus, and medial and central nuclei of amygdala; female-biased surface area overlying caudate head, posterior/dorsal pallidum, mediodorsal, lateral dorsal, lateral geniculate, and medial geniculate nuclei of thalamus, posterior hippocampus, and basolateral and lateral nuclei of amygdala). These regional sex differences show strong within-sample reproducibility at modest sample sizes (N≥200) and are replicable in a fully independent mid-adulthood cohort. Strikingly, we find that the topography of adult subcortical sex differences is already established by pre/early puberty (age 9 years), and the same holds for cortical sex differences. Comparison with neuroimaging data from rare disorder cohorts reveals that subcortical sex differences show a statistically significant spatial and directional congruence with the anatomical effects of X-chromosome dosage in the striatum and effects of testicular hormones in the amygdala. Together, these findings provide a reference map for the fine-grained spatial patterning of sex differences in adult subcortical shape, demonstrating its replicability, establishment before pubertal progression, and spatial concordance with potentially causal sex chromosomal and gonadal effects.

Sex and gender are distinct but intertwined determinants of health. Both adherence to and deviation from gender norms carry consequences for health, yet gender’s contribution to disease risk beyond binary sex remains largely unexplored. As gender is organized around sex from its developmental origins, masculine and feminine health behaviors can be defined by how males and females behave collectively. Individuals vary in how closely they align with these norms, defining a biopsychosocial gender spectrum. Here, we used machine learning to reconstruct population-specific masculine and feminine behavioral norms, yielding a continuous Index of Gendered Life-domains (IGL) in 301,113 UK Biobank participants. In sex-stratified analyses of body and brain health phenotypes, masculine behavioral profiles were associated with greater physiological load and cardiometabolic disease risk, and feminine profiles with higher trait anxiety and musculoskeletal vulnerability. Sex–IGL incongruence predicted state-like psychiatric symptoms and severe mental health diagnoses. An intersectional approach revealed differences in gendered behaviors and their health associations across ethnic groups, demonstrating that gender measurement must be sensitive to sociocultural context to characterize health risk in diverse populations. These findings establish gender as a socioculturally embedded determinant of health whose health associations go beyond binary sex.

Visualizations are vital for communicating scientific results. Historically, brain images in neuroscience figures have only depicted regions that surpass a given statistical threshold. This practice substantially biases interpretation of the results and subsequent meta-analyses, particularly toward non-reproducibility. We advocate for ‘transparent thresholding’ that not only highlights statistically significant regions but also includes subthreshold locations, retaining key experimental context. This balances the dual needs of distilling modeling results and enabling informed interpretations of neuroimaging results. Transparent thresholding removes ambiguity, decreases hypersensitivity to nonphysiological features, helps catch potential artifacts, improves cross-study comparisons, reduces non-reproducibility biases and clarifies interpretations. We address considerations raised by researchers in the field and highlight the many software packages implementing transparent thresholding, several of which were added or streamlined as part of this work. We hope that by showing how transparent thresholding can meaningfully improve the interpretation (and reproducibility) of neuroimaging findings, we will encourage more researchers to adopt this method.

The cerebellum has long been considered a late-maturing structure subordinate to neocortical development, therefore its potential role as an early driver of cortical organization remains largely unexplored. Using two large longitudinal neuroimaging cohorts of developing children together with lesion experiments in mice, we show that early cerebellar morphology may drive neocortical maturation in a regionally specific manner. These cross-species findings implicate the cerebellum as a possible regulator of neocortical organization.

Neuroimaging data management and processing are tedious and error-prone, prompting reproducibility concerns. Globally, studies with heterogeneous infrastructure and governance policies lead to eclectic data processing and sharing, necessitating standardization of data workflows to ensure reusability and comparability of multi-centric datasets. The Nipoppy neuroinformatics framework facilitates such standardization by combining specification, protocol, and software to manage study-level data workflows. With its adoption, researchers can share standardized, derived datasets enabling efficient, reproducible, and inclusive research.

STUDY QUESTION: Is prenatal maternal stress (PNMS) in humans associated with alterations in the sexually differentiated reproductive axis structures in the offspring? SUMMARY ANSWER: PNMS, experienced by pregnant mothers exposed to a natural disaster in 1998, was associated with structural changes in hypothalamic-pituitary-axis (HPG) structures of 18.5-year-old offspring. WHAT IS KNOWN ALREADY: In a human prospective study, PNMS was associated with higher childhood BMI, which in turn predicted earlier menarche. Epidemiological studies have shown that maternal life event stress is associated with changes in gonadal morphology and function. STUDY DESIGN, SIZE, DURATION: A prospective study of mothers exposed to a severe ice storm in 1998 (N = 224) collected measures of PNMS (objective hardship and subjective distress). Offspring reproductive structures were assessed in early adulthood. PARTICIPANTS/MATERIALS, SETTING, METHODS: PNMS-exposed offspring (ICE; n = 39, 21 F, 18 M) and a control group (n = 31, 14 F, 17 M; born in 1997) were assessed at age 18.5 years. Participants underwent MRI. Using a novel approach, the structural integrity of the entire HPG axis was assessed using gold-standard manual delineation from their MRI scans. Ovarian antral follicles (2–10 mm) were also counted from MRI images. Salivary estradiol and testosterone were measured with ELISA. Data were analyzed with ANOVA and multiple regression. MAIN RESULTS AND THE ROLE OF CHANCE: The expected sex difference in hypothalamic volume (M > F) was detected in controls. Within ICE, the sex difference was observed at low, but not at high, levels of PNMS (objective and subjective). Greater objective hardship was associated with smaller hypothalamic volume in men. Similarly, pituitary volume was smaller in ICE men compared to control men. Within ICE, greater objective hardship was associated with smaller left testicular volume. Finally, compared to controls, the left ovary had more antral follicles and tended to be larger in ICE women. The group differences and associations between PNMS and HPG morphology were generally medium to large. LIMITATIONS, REASONS FOR CAUTION: The relatively small sample size may have limited our ability to detect small differences and to test interactions with gestational timing of prenatal stress exposure. In addition, the majority of women were taking oral contraceptives, and thus results must be interpreted with caution. WIDER IMPLICATIONS OF THE FINDINGS: PNMS from a natural disaster may lead to functional changes in the human reproductive axis in adulthood. STUDY FUNDING/COMPETING INTEREST(S): Funding was provided by a grant from the Canadian Institutes of Health Research (CIHR, FRN 125892; to S.K., D.P.L., and J.C.P., and CIHR MOP 125892 to co-investigators S.K. S.L.J. was funded by a postdoctoral fellowship provided by the Fonds de Québec—Santé (FRQ-S). The funding sources were not involved in the collection, analyses, or interpretation of the data, or writing of the report. The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.