Low-frequency repetitive transcranial magnetic stimulation attenuates visceral pain in IBS with diarrhoea via inhibition of the medial prefrontal cortex

Background: Chronic visceral pain in IBS with diarrhoea (IBS-D) is a profound therapeutic challenge. While aberrant central processing is implicated, the key brain regions driving this visceral pain and their suitability as neuromodulatory targets remain undefined. Objective: To identify a central hub of visceral pain in IBS-D and elucidate the mechanism by which repetitive transcranial magnetic stimulation (rTMS) confers analgesic effects. Design: Combined functional MRI with visceral sensitivity assessments was used to pinpoint hyperactive brain regions of patients with IBS-D. Mechanistic studies were conducted in a well-established IBS mouse model. A clinical trial was performed to validate the therapeutic potential of rTMS in patients with IBS-D. Results: Clinical observations identified hyperexcitability of the medial prefrontal cortex (mPFC) as strongly correlated with visceral pain in patients with IBS-D. In IBS mice, visceral pain was driven by the hyperactivity of mPFC glutamatergic (mPFCGlu) neurons, which received nociceptive inputs from the anterior cingulate cortex via an NR2A-dependent mechanism. Low frequency (lf)-rTMS of the mPFC sustainably alleviated visceral pain in IBS mice by inhibiting mPFCGlu neurons and restoring normal synaptic plasticity. Building on these findings, a clinical trial validated that a 2-week course of mPFC-targeted lf-rTMS in patients with IBS-D effectively alleviated visceral pain and improved bowel habits, effects associated with reduced mPFC activity and sustained for at least 8 weeks. Conclusions: Hyperexcitability of the mPFC drives chronic visceral pain in patients with IBS-D and lf-rTMS provides analgesia by suppressing this hyperactivity, offering a novel, mechanism-based neuromodulation strategy for IBS-D treatment.