M. Mallar Chakravarty

The “State of the Brain” special issue of Aperture Neuro is now in its third year. Each year, we invite the leaders, award winners, and invited speakers of the Organization for Human Brain Mapping (OHBM) Annual Meeting to reflect on the meeting, the community, their own research, the field of brain imaging as a whole, or another topic they feel is of importance to our community. This open-ended call has been a catalyst for a wide range of valuable, unique, and timely insights and perspectives. The nine papers of “State of the Brain: 2025” included calls to look deeper into the physiological and physical origins of the signals we measure, new framings of functional connectivity, consciousness, and generative modeling; and the expansion of cross-species imaging into rodents. Four of the nine 2025 contributions focused on the health of our community itself. Below is a short summary of each of these thought provoking papers from the 2025 issue, and an introduction to our 2026 iteration. Lastly, we offer our own perspective on the journal and how the field has been evolving in the past year.

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.

Anorexia nervosa (AN) is a severe psychiatric disorder with high relapse rates despite successful weight restoration. Altered reward processing and an imbalance between goal-directed and habitual control within the striatum have been proposed to contribute to the persistence of maladaptive behaviours, but the striatal mechanisms underlying recovery and relapse remain unclear. Here, we combined cross-species structural MRI, including cross-sectional analyses in mice and longitudinal neuroimaging and clinical assessments in patients with AN, to investigate striatal alterations associated with recovery. Male mice with deletion of the vesicular acetylcholine transporter (VAChTcKO; n = 9), a model of maladaptive eating behaviour, showed reduced dorsolateral striatal volume compared with wild-type mice (n=9). At baseline, women with AN (n = 71) showed reduced striatal volumes compared with healthy controls (n = 30). Longitudinally, patients with AN (n = 41) and healthy controls (n = 28) were reassessed, revealing substantial recovery of striatal volumes following weight restoration in AN. Posterior-anterior putamen gradient changes differed according to subsequent remission status, with changes in the right putamen gradient predicting relapse. Striatal gradient changes were also associated with goal-directed and habitual behaviour during the slip-of-action task, response consistency during delay discounting, and circulating ghrelin and desacyl ghrelin concentrations. These findings identify longitudinal putamen reorganization as a candidate marker of vulnerability to relapse and link striatal plasticity, goal-directed and habitual control, reward processing, and metabolic processes in AN.

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.

Introduction: Myelin water imaging provides a non-invasive approach for indirectly investigating myelin content of the brain by magnetic resonance Imaging (MRI). Myelin water fraction (MWF) reflects the fraction of water signal associated with water trapped between myelin layers. Postmortem imaging provides a unique opportunity to validate MWF metrics against gold-standard postmortem neuropathology. However, there is a need for validated sequences that would be applicable in postmortem settings. In this study, we validated and compared the applicability of turbo spin echo (TSE) and gradient-and-spin-echo (GRASE) techniques for myelin water imaging in formaldehyde fixed postmortem human brains. Methods: 40 postmortem human brain hemispheres were scanned with TSE and GRASE sequences. Acquired data were reconstructed using a non-parametric multicomponent T ₂ relaxometry approach using a consistent framework to support comparison between GRASE- and TSE-derived measures. Agreement between derived measures was quantified at both voxel and regional level. Maps derived from the full 32-echo GRASE reconstruction were compared against a truncated 14-echo reconstruction to examine the contribution of the longer echoes to the derived maps. Finally, a random forest regression model was trained based on TSE data to predict the GRASE-derived MWF maps. Results: Both sequences provided robust multicomponent T ₂ characterization across the brain, and the derived measures showed anatomical patterns consistent with expected differences across tissue types. TSE and GRASE derived maps had moderate to strong agreement at voxel (0.41< ρ < 0.82, all p _FDR FDR 0.98, p _FDR < 0.001). The nonlinear random forest regression model trained on TSE maps was able to accurately reproduce the MWF maps derived from GRASE (r = 0.91, RMSE = 8.87). Discussion: TSE and GRASE32 capture strongly related multicomponent T₂ information in fixed postmortem human brain tissue, but with systematic and tissue-dependent quantitative differences across derived measures. These differences suggest that direct interchangeability should not be assumed and that cross-sequence mapping or calibration is required when quantitative equivalence is desired.

Neurodegeneration observed in synucleinopathies, like Parkinson’s disease (PD), are hypothesized to be a consequence of the progressive accumulation and spread of misfolded alpha-synuclein (aSyn) throughout the brain. Here, we study the generalizability of this hypothesis across multiple biologically-relevant factors including genotype, aSyn species, and regional vulnerability (i.e.: does the introduction of aSyn into different brain regions have a similar impact) using a detailed longitudinal brain (using magnetic resonance imaging; [MRI]) and behavioural approaches. We first examined wild-type and M83 A53T hemizygous transgenic (engineered to over-express human aSyn) C57BL/6 x C3H mice receiving striatal inoculation with human or mouse preformed fibrils (PFFs) (n=89 mice at the last time point; n=687 MRI). Longitudinal analyses demonstrated a time-dependent increase in network-like atrophy and motor deficits, generalized across genotype and PFF species. We further derived latent dimensions relating brain-behaviour relationships revealing a pattern of sex- and genotype-relevant atrophy. Overall, atrophy was most prominent in M83 mice with mouse PFFs, while human PFFs or wild-type hosts showed attenuated effects. Changing the inoculation site to the hippocampus, a major connectivity hub, revealed differential regional vulnerability in the form of localized atrophy. Computational models previously validated in clinical PD further indicated regional vulnerability with increased predictive ability for atrophy patterns associated with striatal compared to hippocampal inoculation. Our findings reveal atrophy resulting from aSyn spreading is generalizable across genotype and PFF species, but not disease epicentres, emphasizing the role of regional vulnerability in disease progression.

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.

Humans show reproducible sex differences in regional cortical volume (CV), but it remains unclear how these relate to the two biologically dissociable determinants of CV – surface area (SA) and cortical thickness (CT) – or to potentially causal sex chromosomal and gonadal effects. Here, we analyze neuroimaging data in two independent human cohorts ( N = 1754) to identify and interrelate highly reproducible sex differences in regional CV, SA and CT – as well as their alignment with distinct functional networks and histomolecular signatures. Integrating neuroimaging data from clinical cohorts with sex chromosome aneuploidy and isolated gonadotropin-releasing hormone deficiency (N = 313) establishes that regions of sex-biased cortical anatomy are enriched for congruent effects of X-chromosome dosage (e.g., primary sensory and insular cortices) and gonadal hormones (e.g., dorsal parietal regions and angular gyrus). This work refines maps of sex-biased human cortical organization and helps to narrow hypotheses regarding their potential genetic and endocrine causes.