Network-Guided Theta Burst Stimulation for Breast Cancer With Chemotherapy-Induced Peripheral Neuropathy: Clinical and fMRI Biomarker Evidence

Network-Guided Theta Burst Stimulation for Breast Cancer With Chemotherapy-Induced Peripheral Neuropathy: Clinical and fMRI Biomarker Evidence

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating complication among breast cancer survivors, frequently associated with chronic neuropathic pain that remains inadequately controlled by pharmacological treatments. Emerging evidence suggests that CIPN pain is related to maladaptive reorganization of pain-related brain networks, highlighting the potential of non-pharmacological, brain-based neuromodulation strategies.

Among the variants of theta burst stimulation (TBS), both prolonged constant theta burst stimulation (pcTBS) and intermittent theta burst stimulation (iTBS) have facilitating effects of cortical excitability. The treatment time for pcTBS (1 min and 44 s, 1200 pulses) is much shorter than that of iTBS and traditional repetitive transcranial magnetic stimulation (rTMS); therefore, pcTBS seems to be a promising neuromodulation method for chronic pain and head-to-head comparison between pcTBS and iTBS has never been done before.

The aim of this two-year randomized, cross-over trial project is 1) to compare the effects of pcTBS and iTBS and determine the optimal TBS paradigm for alleviating CIPN pain a sequential focus on distinct cortical targets; 2) to implement a prospectively defined, network-guided framework using fMRI to characterize sensorimotor and pain-related brain connectivity and to examine whether baseline network features and stimulation-induced connectivity changes moderate clinical outcomes.

In Year 1, 20 breast cancer patients with CIPN will be recruited and randomly assigned to two groups: Group I will initially receive pcTBS over M1 for 5 consecutive days and then iTBS over M1 after a 8-week "wash-out" period. Group II will initially receive iTBS over M1 for 5 consecutive days and then pcTBS over M1 after a 8-week "wash-out" period. In year 2, the stimulation target will be changed to dorsolateral prefrontal cortex (DLPFC) to evaluate analgesic effects, and associated brain network changes related to cognitive-affective pain modulation.

MRI-based neuronavigation will be used to ensure precise and reproducible stimulation targeting. Both resting-state and task-based functional MRI will be acquired before stimulation and used prospectively to identify individualized pain-relevant cortical hotspots within predefined anatomical regions (M1 or DLPFC). Resting-state fMRI will be repeated within 24 hours after the final stimulation session to evaluate treatment-related changes in brain networks. Pain intensity measured by the visual analog scale will serve as the primary outcome, with secondary outcomes including Neuropathic Pain Symptom Inventory, Depression Anxiety Stress Scale 21 and pressure pain threshold testing. Primary and secondary outcomes will be evaluated immediately after the last stimulation session and again at 4-week follow-up.

By integrating a clinically efficient trial design with network-informed neuroimaging, this project is expected to provide target-specific evidence for TBS in CIPN pain and to establish a foundation for future precision-guided neuromodulation studies.

Inclusion Criteria:

• a. breast cancer patients aged between ２０- and 80-years-old with CIPN b. history of receiving chemotherapy including taxane-based neurotoxic agents c. with neuropathic pain, score≥3 in a 0-10 VAS pain scale. d. with fair cognition and can cooperate to evaluate pain severity. e. neither at end-stage cancer nor at the estimated survival time less than 6 months.

Exclusion Criteria:

• a. brain tumor or history of epilepsy b. intracranial metallic devices, artificial cochleae, pacemakers, or any other metal device c. recent myocardial ischemia or unstable angina d. severe cognitive dysfunction or pregnancy e. injuries or fractures in the part of neuropathic pain