Functional gradient reorganization and transcriptomic signatures underlying 1 Hz rTMS treatment in first-episode schizophrenia following right orbitofrontal cortex stimulation

<h4>Background</h4>The orbitofrontal cortex (OFC) represents a promising yet underexplored neuromodulation target for negative symptoms in schizophrenia, and the macroscale and microscale mechanisms underlying its therapeutic effects remain unclear.<h4>Methods</h4>In a randomized, double-blind, sham-controlled trial, 84 patients with drug-naïve first-episode schizophrenia received consecutive 20 days of active 1-Hz repetitive transcranial magnetic stimulation (rTMS) over the right OFC (n = 45) or sham (n = 39). Resting-state fMRI gradient mapping was integrated with imaging transcriptomics to characterize multiscale neural reorganization and predict treatment response.<h4>Results</h4>Active rTMS was associated with greater improvement in negative symptoms and general psychopathology compared with sham stimulation. Gradient analyses indicated a renormalization of macroscale functional hierarchy, with increased principal gradient scores in transmodal nodes (e.g., right middle occipital gyrus and angular gyri) and decreased scores in salience-related regions (e.g., anterior cingulate cortex). These spatial patterns were coupled to transcriptomic signatures enriched for synaptic plasticity and ion transport, with cell-type enrichment implicating cortical interneurons and oligodendrocytes. In addition, baseline gradient topographies in the right middle occipital gyrus and ventral attention network predicted improvements in negative and general symptoms, respectively.<h4>Conclusions</h4>Low-frequency OFC-rTMS was associated with alleviation of negative symptoms in first-episode schizophrenia, alongside a reconfiguration of cortical functional hierarchy. The observed gradient effects were spatially linked to molecular pathways underlying synaptic plasticity and excitation-inhibition regulation, supporting functional gradients as biomarkers for precision neuromodulation in early-stage schizophrenia.