Spatial location and molecular interactions have long been linked to the connectivity patterns of neural circuits. Yet, at the macroscale of human brain networks, the interplay between spatial position, gene expression, and connectivity remains incompletely understood. Recent efforts to map the human transcriptome and connectome have yielded spatially resolved brain atlases, however modeling the relationship between high-dimensional transcriptomic data and connectivity while accounting for inherent spatial confounds presents a significant challenge. In this paper, we present the first deep learning approaches for predicting whole-brain functional connectivity from gene expression and regional spatial coordinates, including our proposed Spatiomolecular Transformer (SMT). SMT explicitly models biological context by tokenizing genes based on their transcription start site (TSS) order to capture multi-scale genomic organization, and incorporating regional 3D spatial location via a dedicated context [CLS] token within its multi-head self-attention mechanism. We rigorously benchmark context-aware neural networks, including SMT and a single-gene resolution Multilayer-Perceptron (MLP), to established rules-based and bilinear methods. Crucially, to ensure that learned relationships in any model are not mere artifacts of spatial proximity, we introduce novel spatiomolecular null maps preserving key transcriptomic autocorrelation structure. Context-aware neural networks outperform linear methods, significantly exceed our stringent null map estimates, and generalize across diverse connectomic datasets and parcellation resolutions. Together, these findings demonstrate a strong, predictable link between the spatial distributions of gene expression and functional brain network architecture, and establish a rigorously validated deep learning framework for decoding this relationship.

A fundamental challenge in cognitive neuroscience is understanding how cognition emerges from the interplay between structural connectivity (SC) and functional connectivity (FC). Current machine learning approaches typically seek to establish direct mappings from SC to FC associated with specific cognitive states. However, these methods often treat SC and FC as distinct endpoints, failing to capture the coupling relationship throughout the progressive transformation between them. To address this limitation, we propose BrainFlow, a reversible generative model designed to parametrize flows between the distribution of SC and the mixed distribution of FCs from different cognitive tasks.

Brain disorders have been consistently associated with abnormalities in specific brain regions or neural circuits. Identifying key brain regional activities and functional connectivity patterns is essential for discovering more precise neurobiological biomarkers. However, previous studies have primarily emphasized alterations in functional connectivity while overlooking abnormal neuronal population activity within brain regions. To bridge this gap, we propose a novel Local-Global Coupling Spiking Graph Transformer (LGC-SGT) that jointly models both inter-regional connectivity differences and deviations in neuronal population firing rates within brain regions, enabling a dual-perspective neuropathological analysis. The global pathway leverages spike-based computation in LGC-SGT to model biologically plausible aberrant neural firing dynamics, while the local pathway adaptively captures abnormal graph-based representations of brain connectivity learned by local plasticity in the liquid state machine module. Furthermore, we design a shortcut-enhanced output strategy in LGC-SGT with the hybrid loss function to suppress outlier interference caused by inter-individual and inter-center variability, enabling a more robust decision boundary. Extensive experiments on three brain disorder datasets demonstrate that our model consistently outperforms state-of-the-art graph methods in brain disorder diagnosis.

A fundamental challenge in cognitive neuroscience is understanding how cognition emerges from the interplay between structural connectivity (SC) and dynamic functional connectivity (FC) in the brain. Network neuroscience has emerged as a powerful framework to understand brain function through a holistic perspective on structure-function relationships. In this context, current machine learning approaches typically seek to establish direct mappings between structural connectivity (SC) and functional connectivity (FC) associated with specific cognitive states. However, these state-independent methods often yield inconsistent results due to overlapping brain networks across cognitive states. To address this limitation, we conceptualize to uncover the dendritic coupling mechanism between one static SC and multiple FCs by solving a flow problem that bridges the distribution of SC to a mixed distribution of FCs, conditioned on various cognitive states, along a Riemannian manifold of symmetric positive-definite (SPD) manifold. We further prove the equivalence between flow matching on the SPD manifold and on the computationally efficient Cholesky manifold. Since a spare of functional connections is shared across cognitive states, we introduce the notion of consensus control to promote the shared kinetic structures between multiple FC-to-SC pathways via synchronized coordination, yielding a biologically meaningful underpinning on SC-FC coupling mechanism. Together, we present BrainFlow, a reversible generative model that achieves state-of-the-art performance on not only synthetic data but also large-scale neuroimaging datasets from UK Biobank and Human Connectome Project.

Neural Information Processing Systems http://nips.cc/

Note, the direct FC link and SC detour form a cyclic loop inherited from both SC and FC topology.

Major Depressive Disorder (MDD), affecting millions worldwide, exhibits complex pathophysiology manifested through disrupted brain network dynamics. Although graph neural networks that leverage neuroimaging data have shown promise in depression diagnosis, existing approaches are predominantly data-driven and operate largely as black-box models, lacking neurobiological interpretability. Here, we present NH-GCAT (Neurocircuitry-Inspired Hierarchical Graph Causal Attention Networks), a novel framework that bridges neuroscience domain knowledge with deep learning by explicitly and hierarchically modeling depression-specific mechanisms at different spatial scales. Our approach introduces three key technical contributions: (1) at the local brain regional level, we design a residual gated fusion module that integrates temporal blood oxygenation level dependent (BOLD) dynamics with functional connectivity patterns, specifically engineered to capture local depression-relevant low-frequency neural oscillations; (2) at the multi-regional circuit level, we propose a hierarchical circuit encoding scheme that aggregates regional node representations following established depression neurocircuitry organization, and (3) at the multi-circuit network level, we develop a variational latent causal attention mechanism that leverages a continuous probabilistic latent space to infer directed information flow among critical circuits, characterizing disease-altered whole-brain inter-circuit interactions. Rigorous leave-one-site-out cross-validation on the REST-meta-MDD dataset demonstrates NH-GCAT's state-of-the-art performance in depression classification, achieving a sample-size weighted-average accuracy of 73.3\% and an AUROC of 76.4\%, while simultaneously providing neurobiologically meaningful explanations.

Brain processes occur at various timescales, ranging from milliseconds (neurons) to minutes and hours (behavior). Characterizing functional coupling among brain regions at these diverse timescales is key to understanding how the brain produces behavior. Here, we apply instantaneous and lag-based measures of conditional linear dependence, based on Granger-Geweke causality (GC), to infer network connections at distinct timescales from functional magnetic resonance imaging (fMRI) data. Due to the slow sampling rate of fMRI, it is widely held that GC produces spurious and unreliable estimates of functional connectivity when applied to fMRI data. We challenge this claim with simulations and a novel machine learning approach. First, we show, with simulated fMRI data, that instantaneous and lag-based GC identify distinct timescales and complementary patterns of functional connectivity. Next, we analyze fMRI scans from 500 subjects and show that a linear classifier trained on either instantaneous or lag-based GC connectivity reliably distinguishes task versus rest brain states, with ~80-85% cross-validation accuracy. Importantly, instantaneous and lag-based GC exploit markedly different spatial and temporal patterns of connectivity to achieve robust classification. Our approach enables identifying functionally connected networks that operate at distinct timescales in the brain.

Functional brain networks are well described and estimated from data with Gaussian Graphical Models (GGMs), e.g.\ using sparse inverse covariance estimators. Comparing functional connectivity of subjects in two populations calls for comparing these estimated GGMs. Our goal is to identify differences in GGMs known to have similar structure. We characterize the uncertainty of differences with confidence intervals obtained using a parametric distribution on parameters of a sparse estimator. Sparse penalties enable statistical guarantees and interpretable models even in high-dimensional and low-sample settings. Characterizing the distributions of sparse models is inherently challenging as the penalties produce a biased estimator.