Structural Connectome Harmonization Using Deep Learning: The Strength of Graph Neural Networks

Small sample sizes in neuroimaging in general, and in structural connectome (SC) studies in particular limit the development of reliable biomarkers for neurological and psychiatric disorders - such as Alzheimer's disease and schizophrenia - by reducing statistical power, reliability, and generalizability. Large-scale multi-site studies have exist, but they have acquisition-related biases due to scanner heterogeneity, compromising imaging consistency and downstream analyses. While existing SC harmonization methods - such as linear regression (LR), ComBat, and deep learning techniques - mitigate these biases, they often rely on detailed metadata, traveling subjects (TS), or overlook the graph-topology of SCs. To address these limitations, we propose a site-conditioned deep harmonization framework that harmonizes SCs across diverse acquisition sites without requiring metadata or TS that we test in a simulated scenario based on the Human Connectome Dataset. Within this framework, we benchmark three deep architectures - a fully connected autoencoder (AE), a convolutional AE, and a graph convolutional AE - against a top-performing LR baseline. While non-graph models excel in edge-weight prediction and edge existence detection, the graph AE demonstrates superior preservation of topological structure and subject-level individuality, as reflected by graph metrics and fingerprinting accuracy, respectively. Although the LR baseline achieves the highest numerical performance by explicitly modeling acquisition parameters, it lacks applicability to real-world multi-site use cases as detailed acquisition metadata is often unavailable. Our results highlight the critical role of model architecture in SC harmonization performance and demonstrate that graph-based approaches are particularly well-suited for structure-aware, domain-generalizable SC harmonization in large-scale multi-site SC studies.