Functional gradient reorganization and transcriptomic signatures underlying 1 Hz rTMS treatment in first-episode...

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.

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.

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.

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.