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 (mPFC Glu ) 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 mPFC Glu 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.