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Humans display reproducible sex differences in cognition and behavior, which may partly reflect intrinsic sex differences in regional brain organization. However, the consistency, causes and consequences of sex differences in the human brain are poorly characterized and hotly debated. In contrast, recent studies in mice—a major model organism for studying neurobiological sex differences—have established: 1) highly consistent sex biases in regional gray matter volume (GMV) involving the cortex and classical subcortical foci, 2) a preponderance of regional GMV sex differences in brain circuits for social and reproductive behavior, and 3) a spatial coupling between regional GMV sex biases and brain expression of sex chromosome genes in adulthood. Here, we directly test translatability of rodent findings to humans. First, using two independent structural-neuroimaging datasets (n > 2,000), we find that the spatial map of sex-biased GMV in humans is highly reproducible (r > 0.8 within and across cohorts). Relative GMV is female biased in prefrontal and superior parietal cortices, and male biased in ventral occipitotemporal, and distributed subcortical regions. Second, through systematic comparison with functional neuroimaging meta-analyses, we establish a statistically significant concentration of human GMV sex differences within brain regions that subserve face processing. Finally, by imagingtranscriptomic analyses, we show that GMV sex differences in human adulthood are specifically and significantly coupled to regional expression of sex-chromosome (vs. autosomal) genes and enriched for distinct cell-type signatures. These findings establish conserved aspects of sex-biased brain development in humans and mice, and shed light on the consistency, candidate causes, and potential functional corollaries of sex-biased brain anatomy in humans.

•Competitive null models may yield false positives from co-expression.•Self-contained null models may yield false positives from bimodal correlations.•Test statistics interact differently with two types of null models.•Supplementary analyses with various configurations support the findings. Correlating transcriptional profiles with imaging-derived phenotypes has the potential to reveal possible molecular architectures associated with cognitive functions, brain development and disorders. Competitive null models built by resampling genes and self-contained null models built by spinning brain regions, along with varying test statistics, have been used to determine the significance of transcriptional associations. However, there has been no systematic evaluation of their performance in imaging transcriptomics analyses. Here, we evaluated the performance of eight different test statistics (mean, mean absolute value, mean squared value, max mean, median, Kolmogorov-Smirnov (KS), Weighted KS and the number of significant correlations) in both competitive null models and self-contained null models. Simulated brain maps (n = 1,000) and gene sets (n = 500) were used to calculate the probability of significance (Psig) for each statistical test. Our results suggested that competitive null models may result in false positive results driven by co-expression within gene sets. Furthermore, we demonstrated that the self-contained null models may fail to account for distribution characteristics (e.g., bimodality) of correlations between all available genes and brain phenotypes, leading to false positives. These two confounding factors interacted differently with test statistics, resulting in varying outcomes. Specifically, the sign-sensitive test statistics (i.e., mean, median, KS, Weighted KS) were influenced by co-expression bias in the competitive null models, while median and sign-insensitive test statistics were sensitive to the bimodality bias in the self-contained null models. Additionally, KS-based statistics produced conservative results in the self-contained null models, which increased the risk of false negatives. Comprehensive supplementary analyses with various configurations, including realistic scenarios, supported the results. These findings suggest utilizing sign-insensitive test statistics such as mean absolute value, max mean in the competitive null models and the mean as the test statistic for the self-contained null models. Additionally, adopting the confounder-matched (e.g., coexpression-matched) null models as an alternative to standard null models can be a viable strategy. Overall, the present study offers insights into the selection of statistical tests for imaging transcriptomics studies, highlighting areas for further investigation and refinement in the evaluation of novel and commonly used tests.

Deep brain stimulation targeting the posterior hypothalamus (pHyp-DBS) is being investigated as a treatment for refractory aggressive behavior, but its mechanisms of action remain elusive. We conducted an integrated imaging analysis of a large multi-centre dataset, incorporating volume of activated tissue modeling, probabilistic mapping, normative connectomics, and atlas-derived transcriptomics. Ninety-one percent of the patients responded positively to treatment, with a more striking improvement recorded in the pediatric population. Probabilistic mapping revealed an optimized surgical target within the posterior-inferior-lateral region of the posterior hypothalamic area. Normative connectomic analyses identified fiber tracts and functionally connected with brain areas associated with sensorimotor function, emotional regulation, and monoamine production. Functional connectivity between the target, periaqueductal gray and key limbic areas – together with patient age – were highly predictive of treatment outcome. Transcriptomic analysis showed that genes involved in mechanisms of aggressive behavior, neuronal communication, plasticity and neuroinflammation might underlie this functional network.

Background Neuroimaging evidence indicates brain alterations in rhegmatogenous retinal detachment (RRD), but the molecular and neurochemical correlates of these macroscale patterns remain unclear. Methods We examined gray matter volume (GMV), intrinsic neural timescale (INT) and structural covariance network (SCN) gradients in 51 patients with RRD and 45 healthy controls (HCs). Two‐sample Mendelian randomization (MR) evaluated whether RRD‐related genetic liability was consistent with a putative causal effect on GMV. SCN‐gradient alterations were further evaluated using exploratory spatial association analyses based on the Allen Human Brain Atlas (AHBA) and complementary neurotransmitter maps. SHAP‐explainable machine‐learning classification models compared the discriminative utility of structural versus functional features. Results Patients with RRD showed reduced GMV in the visual network (VN) and shortened INT in the default mode network (DMN). MR results were consistent with a putative causal effect of RRD genetic liability on VN atrophy. SCN gradients revealed a hierarchical “visual‐downward and limbic‐upward” shift. Exploratory imaging‐transcriptomic spatial association analyses suggested that gradient alterations were spatially aligned with gene expression patterns enriched for neurodevelopmental and synaptic pathways, including excitatory/inhibitory neuronal and microglial signatures; complementary neurotransmitter mapping analyses further suggested spatial correspondence with normative monoaminergic/cholinergic and μ‐opioid maps, together with an inverse spatial association with GABAa receptor density maps. INT‐based ML models outperformed GMV‐based models (best AUC = 0.753), with SHAP identifying INT as the predominant contributor. Conclusion RRD is associated with coordinated structural and functional alterations across cortical hierarchies. Exploratory transcriptomic and neurotransmitter spatial association patterns may provide biological context for these imaging abnormalities and inform future studies of prognosis and underlying mechanisms. RRD triggers multiscale cortical reorganization, including visual‐network atrophy, shortened intrinsic neural timescale, and altered structural covariance gradients. Integrating Mendelian randomization with AHBA and PET/SPECT biological anchoring and SHAP‐based classification highlights INT as a sensitive imaging biomarker for RRD‐related brain remodeling.

The link between metabolic syndrome (MetS) and neurodegenerative as well as cerebrovascular conditions holds substantial implications for brain health in at-risk populations. This study elucidates the complex relationship between MetS and brain health by conducting a comprehensive examination of cardiometabolic risk factors, brain morphology, and cognitive function in 40,087 individuals. Multivariate, data-driven statistics identified a latent dimension linking more severe MetS to widespread brain morphological abnormalities, accounting for up to 71% of shared variance in the data. This dimension was replicable across sub-samples. In a mediation analysis, we could demonstrate that MetS-related brain morphological abnormalities mediated the link between MetS severity and cognitive performance in multiple domains. Employing imaging transcriptomics and connectomics, our results also suggest that MetS-related morphological abnormalities are linked to the regional cellular composition and macroscopic brain network organization. By leveraging extensive, multi-domain data combined with a dimensional stratification approach, our analysis provides profound insights into the association of MetS and brain health. These findings can inform effective therapeutic and risk mitigation strategies aimed at maintaining brain integrity.

•Original virtual histology identifies cell types associated with MRI phenotypes.•Case-control virtual histology uses case-control gene expression maps.•Inferred loss of excitatory and inhibitory neurons in regions most thinned in Alzheimer's disease.•Different cell types are associated with Alzheimer's disease using case-control and original virtual histology. Many neuropsychiatric disorders are characterised by altered cortical thickness, but the cell types underlying these changes remain largely unknown. Virtual histology (VH) approaches map regional patterns of gene expression with regional patterns of MRI-derived phenotypes, such as cortical thickness, to identify cell types associated with case-control differences in those MRI measures. However, this method does not incorporate valuable information of case-control differences in cell type abundance. We developed a novel method, termed case-control virtual histology (CCVH), and applied it to Alzheimer's disease (AD) and dementia cohorts. Leveraging a multi-region gene expression dataset of AD cases (n = 40) and controls (n = 20), we quantified AD case-control differential expression of cell type-specific markers across 13 brain regions. We then correlated these expression effects with MRI-derived AD case-control cortical thickness differences across the same regions. Cell types with spatially concordant AD-related effects were identified through resampling marker correlation coefficients. Among regions thinner in AD, gene expression patterns identified by CCVH suggested fewer excitatory and inhibitory neurons, and greater proportions of astrocytes, microglia, oligodendrocytes, oligodendrocyte precursor cells, and endothelial cells in AD cases vs. controls. In contrast, original VH identified expression patterns suggesting that excitatory but not inhibitory neuron abundance was associated with thinner cortex in AD, despite the fact that both types of neurons are known to be lost in the disorder. Compared to original VH, cell types identified through CCVH are more likely to directly underlie cortical thickness differences in AD. Sensitivity analyses suggest our results are largely robust to specific analysis choices, like numbers of cell type-specific marker genes used and background gene sets used to construct null models. As more multi-region brain expression datasets become available, CCVH will be useful for identifying the cellular correlates of cortical thickness across neuropsychiatric illnesses.

A hexanucleotide repeat expansion (HRE) intronic to chromosome 9 open reading frame 72 ( ) is recognized as the most common genetic cause of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and ALS-FTD. Identifying genes that show similar regional co-expression patterns to may help identify novel gene targets and biological mechanisms that mediate selective vulnerability to ALS and FTD pathogenesis. We leveraged mRNA expression data in healthy brain from the Allen Human Brain Atlas to evaluate co-expression patterns. To do this, we correlated average expression values in 51 regions across different anatomical divisions (cortex, subcortex, and cerebellum) with average gene expression values for 15,633 protein-coding genes, including 54 genes known to be associated with ALS, FTD, or ALS-FTD. We then performed imaging transcriptomic analyses to evaluate whether the identified co-expressed genes correlated with patterns of cortical thickness in symptomatic pathogenic HRE carriers ( = 19) compared to controls ( = 23). Lastly, we explored whether genes with significant imaging transcriptomic correlations (i.e., \" imaging transcriptomic network\") were enriched in specific cell populations in the brain and enriched for specific biological and molecular pathways. A total of 2,120 genes showed an anatomical distribution of gene expression in the brain similar to and significantly correlated with patterns of cortical thickness in HRE carriers. This imaging transcriptomic network was differentially expressed in cell populations previously implicated in ALS and FTD, including layer 5b cells, cholinergic neurons in the spinal cord and brainstem and medium spiny neurons of the striatum, and was enriched for biological and molecular pathways associated with protein ubiquitination, autophagy, cellular response to DNA damage, endoplasmic reticulum to Golgi vesicle-mediated transport, among others. Considered together, we identified a network of associated genes that may influence selective regional and cell-type-specific vulnerabilities in ALS/FTD.

Neuro-oncology research is broad and includes several branches, one of which is neuroimaging. Magnetic resonance imaging (MRI) is instrumental for the diagnosis and treatment monitoring of patients with brain tumors. Most commonly, structural and perfusion MRI sequences are acquired to characterize tumors and understand their behaviors. Thanks to technological advances, structural brain MRI can now be transformed into a so-called average brain accounting for individual morphological differences, which enables retrospective group analysis. These normative analyses are uncommonly used in neuro-oncology research. Once the data have been normalized, voxel-wise analyses and spatial mapping can be performed. Additionally, investigations of underlying connectomics can be performed using functional and structural templates. Additionally, a recently available template of spatial transcriptomics has enabled the assessment of associated gene expression. The few published normative analyses have shown relationships between tumor characteristics and spatial localization, as well as insights into the circuitry associated with epileptogenic tumors and depression after cingulate tumor resection. The wide breadth of possibilities with normative analyses remain largely unexplored, specifically in terms of connectomics and imaging transcriptomics. We provide a framework for performing normative analyses in oncology while also highlighting their limitations. Normative analyses are an opportunity to address neuro-oncology questions from a different perspective.

For over a century, brain research narrative has mainly centered on neuron cells. Accordingly, most neurodegenerative studies focus on neuronal dysfunction and their selective vulnerability, while we lack comprehensive analyses of other major cell types’ contribution. By unifying spatial gene expression, structural MRI, and cell deconvolution, here we describe how the human brain distribution of canonical cell types extensively predicts tissue damage in 13 neurodegenerative conditions, including early- and late-onset Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, amyotrophic lateral sclerosis, mutations in presenilin-1, and 3 clinical variants of frontotemporal lobar degeneration (behavioral variant, semantic and non-fluent primary progressive aphasia) along with associated three-repeat and four-repeat tauopathies and TDP43 proteinopathies types A and C. We reconstructed comprehensive whole-brain reference maps of cellular abundance for six major cell types and identified characteristic axes of spatial overlapping with atrophy. Our results support the strong mediating role of non-neuronal cells, primarily microglia and astrocytes, in spatial vulnerability to tissue loss in neurodegeneration, with distinct and shared across-disorder pathomechanisms. These observations provide critical insights into the multicellular pathophysiology underlying spatiotemporal advance in neurodegeneration. Notably, they also emphasize the need to exceed the current neuro-centric view of brain diseases, supporting the imperative for cell-specific therapeutic targets in neurodegeneration.

Abstract Mental disorders refer to abnormal states that affect an individual’s thinking, emotion, behavior, and perception, and are generally associated with dysregulation of brain function. They exhibit genetic heterogeneity as well as multi-level structural and functional abnormalities of the brain. Magnetic resonance imaging has been widely applied to detect macroscopic neurophenotypic alterations in patients with psychiatric disorders; however, it remains limited in directly revealing the underlying molecular and cellular mechanisms. Imaging transcriptomics, by integrating whole-brain gene expression atlases with neuroimaging features, offers a novel paradigm for exploring the associations between microscopic genetic expression and macroscopic neuroimaging phenotypes. This review systematically summarizes the methodological framework of imaging transcriptomic association studies and highlights recent advances in their application to psychiatric disorders such as depression. A growing body of evidence has revealed spatial coupling between structural and functional abnormalities in disease-related brain regions and gene expression in synaptic transmission, ion channels, neurodevelopment, and immune signaling. Imaging transcriptomics not only facilitates a multiscale understanding of the pathophysiological mechanisms of psychiatric disorders but also provides potential pathways for disease classification, targeted intervention, and precision diagnosis and treatment. Future research should further promote the integration of longitudinal imaging omics and spatial transcriptomic data to construct translatable multimodal models, thereby accelerating the translation of psychiatric neuroimaging from mechanistic research to clinical application.