A Corticospinal Signature for Interindividual Pain Sensitivity

Pain sensitivity variations represent a critical frontier in pain neuroscience, where advanced neuroimaging has mapped cerebral correlates of nociception for decades, yet conventional brain-centric models persistently overlook the spinal cord’s hub role in pain gating and amplification. Here we show that a corticospinal pain sensitivity signature, a pattern of functional connectivity from simultaneous corticospinal magnetic resonance imaging, predicts individual pain sensitivity and clinical pain. Trained on resting-state data and validated across independent healthy (n = 723) and patient cohorts (n = 46), the model generalized to new datasets, distinguished pain from non-pain, and outperformed brain-centric models. Crucially, transcranial magnetic stimulation perturbation revealed a causal axis where enhanced motor cortex-spinal connectivity directly changes pain perception (r = 0.55). These results indicate a previously unknown corticospinal biomarker that bridges laboratory pain measures and patient symptoms, providing insights into translating pain mechanisms from healthy individuals to clinical populations and informing neuromodulation approaches. In this study, the authors present an fMRI‑based signature of corticospinal connections, which predicts individual pain sensitivity, generalizes to patient cohorts, and tracks changes after brain stimulation, suggesting a biomarker to guide personalized pain care.