Predicting Functional Brain Connectivity with Context-Aware Deep Neural Networks

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 both spatial and transcriptomic autocorrelation. Context-aware neural networks outperform linear methods, significantly exceed our stringent null shuffle models, 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. Code to reproduce our results is available at: github.com/neuroinfolab/GeneEx2Conn.