Project Summary – Project 3 More than half of patients treated with commonly used platinum- and taxane-based anti-cancer agents suffer painful chemotherapy-induced peripheral neuropathy (CIPN). Non-Hispanic Black (NHB) patients have a greater risk (risk ratio=1.6-2.4) of experiencing clinically relevant CIPN and consequent chemotherapy dose reductions compared to non-Hispanic Whites (NHWs). Despite the greater risk of painful CIPN in NHB cancer patients, clinical trials in patients suffering with CIPN have historically included homogeneous patient populations of NHWs. Only duloxetine is approved to treat painful CIPN and is not effective for or tolerated by all patients. Transcranial direct current stimulation (tDCS) of the motor cortex is emerging as a promising, safe, and effective intervention for the pain of neuropathy. An additional benefit of tDCS is that it can be administered at home and supervised remotely, minimizing stressful visits to a hospital venue for treatment. A recent randomized experimental study in healthy individuals completed by the PI showed that one 20-minute session of motor cortex tDCS reduced capsaicin-induced hyperalgesia. To understand the mechanism of pain ameliorating effects of motor cortex tDCS, the PI found enhanced neurophysiological responses of the descending pain modulatory network (DPMN), a group of brain structures activated in response to painful stimuli, after active compared to sham stimulation. Previous investigations have observed differences in opioid receptor binding and pain responses in the DPMN (notably the cingulate cortex and ventral striatum) between healthy NHBs and NHWs as well as differences in pain sensitivity. Likely relevant to the mechanism of CIPN, PET scanning of chemotherapy patients reveals neuroinflammation throughout the brain. The facts that 1) NHB individuals experience a greater rate of CIPN, but have not been represented in relevant clinical studies, 2) non-invasive tDCS is emerging as a safe and effective treatment for neuropathic pain and can be implemented in the home 3) the DPMN is implicated in central pain responses and is activity is enhanced after tDCS and 4) neuroinflammation likely plays a role in CIPN have led us to the present research plan. The overarching goal of this proposal to conduct an exploratory double-blind randomized controlled trial (RCT) addressing 3 specific aims: 1) determine the feasibility and efficacy of active tDCS targeting motor cortex as an analgesic and anti- hyperalgesic intervention in patients with painful CIPN, 2) determine structural and functional brain correlates of painful CIPN in the DPMN in NHBs and NHWs, and 3) determine inflammatory mediators in patients with painful CIPN and their relationship to the severity of painful CIPN and DPMN structure and function. We expect NHB subjects will experience greater therapeutic effects of tDCS compared to NHW subjects, since NHBs have a dysregulated DPMN potentially affected by neuroinflammation. The goals of this project align with the mission of RCMI@Morgan to understand and combat urban health disparity issues in the City of Baltimore and elsewhere.

U54MD013376

2024-08-26

2029-02-28