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.
Keywords: BRAIN/GUT INTERACTION; IRRITABLE BOWEL SYNDROME; NEUROBIOLOGY; VISCERAL HYPERSENSITIVITY.
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