529: Targeting The Ventral Lateral Septum With Electroacupuncture and rTMS Relieves Visceral Pain

Topic: Clinical Science
Subtopic: Pain category (ICD-11), Chronic primary visceral / pelvic pain, Assessment and Measurement of Pain/Nociception, Neuromodulation (e.g. TMS, TDCS, FUS, SCS, MCS, DBS, vagus nerve stimulation), Treatment/management

Background and Aims: Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by chronic visceral pain and limited therapeutic options. Converging evidence suggests that central neuromodulation may offer effective analgesia, yet the underlying circuit mechanisms and translational relevance remain incompletely understood. This study aimed to integrate preclinical and clinical evidence to evaluate the therapeutic efficacy of repetitive transcranial magnetic stimulation (rTMS) and electroacupuncture (EA), with a specific focus on the ventral lateral septal nucleus (LSV) as a key neural substrate mediating visceral pain.

Methods: In a neonatal acetate-induced mouse model of chronic visceral pain, colorectal distension (CRD) combined with abdominal electromyography was used to assess pain responses. Immunofluorescence was performed to detect c-Fos expression and its co-localization with glutamatergic neurons in the LSV. Optogenetic approaches were applied to bidirectionally modulate LSV glutamatergic neuronal activity, while fiber photometry was employed to monitor real-time glutamate and cannabinoid dynamics during CRD stimulation. EA and rTMS, alone or in combination, were administered to evaluate their analgesic effects. In parallel, a prospective, randomized, double-blind, sham-controlled clinical trial was conducted in 46 IBS-D patients. Participants were assigned to active or sham rTMS targeting the LSV for a 2-week intervention. The primary endpoint was the composite response rate, defined as ≥30% reduction in abdominal pain and ≥50% reduction in diarrhea days. Secondary outcomes included IBS-SSS, IBS-QOL, BSFS, stool frequency, and abdominal pain visual analog scale (VAS).

Results: Preclinical data demonstrated that CRD predominantly activated glutamatergic neurons in the LSV. Optogenetic manipulation confirmed that LSV glutamatergic neurons bidirectionally regulate visceral pain behaviors. Both EA and rTMS significantly suppressed LSV neuronal activation and alleviated visceral hypersensitivity, whereas combined EA and rTMS produced a more robust analgesic effect. Mechanistically, these interventions reduced glutamate release while enhancing cannabinoid signaling within the LSV. Clinically, rTMS targeting the LSV significantly improved therapeutic outcomes compared with sham stimulation, with a higher response rate (61.2% vs. 15.2%). Treatment markedly reduced IBS-SSS scores, decreased bowel movement frequency, improved stool consistency, and alleviated abdominal pain. Improvements were sustained during follow-up, with a lower relapse rate observed in the rTMS group.

Conclusions: These findings identify LSV glutamatergic neurons as a critical neural substrate underlying chronic visceral pain and establish the LSV as a translationally relevant target for neuromodulation. Both EA and rTMS exert significant analgesic effects, and their combination achieves superior efficacy through coordinated regulation of excitatory and neuromodulatory signaling within the LSV. Importantly, clinical evidence supports the therapeutic potential of LSV-targeted rTMS in IBS-D patients, highlighting a mechanistically grounded, non-pharmacological strategy for visceral pain management.

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Presenting Author: Shufen Hu
Submitting Author: Ruixia Weng

Senior Author: Guang-Yin Xu

IASP 2026 Global Year theme of Neuropathic Pain: Yes

• Rui-Xia Weng: PhD - Department of Gastroenterology, the First Affiliated Hospital of Soochow University
• Yong-Chang Li: PhD - Jiangsu Key Laboratory of Drug Discovery and Translational Research for Brain Diseases and Institute of Neuroscience, Suzhou Medicine College, Soochow University
• Shufen Hu: Master - Jiangsu Key Laboratory of Drug Discovery and Translational Research for Brain Diseases and Institute of Neuroscience, Suzhou Medicine College, Soochow University
• Guang-Yin Xu: PhD - Jiangsu Key Laboratory of Drug Discovery and Translational Research for Brain Diseases and Institute of Neuroscience, Suzhou Medicine College, Soochow University