Orbitofrontal rTMS modulates inferior parietal lobule functional reorganization to alleviate negative symptoms in first-episode, drug-naïve patients with schizophrenia.

BACKGROUND

Recent studies have identified the orbitofrontal cortex (OFC) as a potential target for alleviating negative symptoms in schizophrenia. However, the neurobiological mechanisms underlying repetitive transcranial magnetic stimulation (rTMS) delivered to the OFC remain unclear.

METHODS

In this randomized controlled trial, seventy first-episode, drug-naïve patients with schizophrenia were assigned to receive either 20 sessions of active 1 Hz rTMS over the right lateral OFC (N = 36) or sham stimulation (N = 34). Clinical outcomes were measured using the Positive and Negative Syndrome Scale (PANSS). Resting-state functional MRI data were collected before and after treatment to assess changes in regional brain activity and functional connectivity, using fractional amplitude of low-frequency fluctuations (fALFF), regional homogeneity (ReHo), and seed-based connectivity analyses.

RESULTS

Compared to sham stimulation, active OFC-rTMS led to significantly greater reductions in PANSS scores (total: 22.7 vs. 14.3, p = 0.003, Cohen's d = 0.733; negative: 6.2 vs. 4.0, p = 0.037, Cohen's d = 0.510). Neuroimaging analyses revealed increased spontaneous activity (fALFF and ReHo) in the right OFC and bilateral inferior parietal lobule (IPL), along with enhanced functional connectivity between the OFC and IPL in the active rTMS group. Importantly, IPL-related functional reorganization was significantly associated with symptom improvement, particularly in negative and general domains.

CONCLUSIONS

These findings suggest that rTMS targeting the OFC exerts therapeutic effects in schizophrenia by modulating IPL function and OFC-IPL connectivity. The IPL may serve as a critical downstream node mediating the clinical benefits of OFC-rTMS, offering novel insights into network-based neuromodulation strategies for negative symptoms.