Simultaneous engagement of networks for alleviating pain - this is a feasibility and pilot trial of a new approach to invasive brain stimulation for chronic pain

The National Institute of Neurological Disorders and Stroke awarded the Regents of the University of Minnesota a cooperative agreement valued at $769,903 on August 1, 2026, to conduct a feasibility and pilot trial of a novel invasive brain stimulation approach for chronic neuropathic pain.

The study combines precision functional mapping and individualized neurostimulation targeting the somato-cognitive action network and cingulo-opercular network—two key circuits in pain processing—to address treatment-resistant central neuropathic pain in patients for whom existing therapies have failed. The approach leverages MR-guided neuromodulation, optimized electrode placement, and Bayesian optimization to move beyond one-size-fits-all motor cortex stimulation models that historically have shown variable efficacy. In the UG3 phase, the recipient will refine its neuroimaging and modeling pipeline for targeting these networks in chronic, centralized pain patients; complete Data and Safety Monitoring Board setup; and enroll two initial participants to validate the pipeline. If go/no-go milestones are met, a subsequent UH3 phase will expand enrollment to eight additional participants to test workflow feasibility.

Work is performed at the University of Minnesota in Minneapolis, Minnesota, with a period of performance through July 31, 2027. The award falls under the Drug Use and Addiction Research Programs (CFDA 93.279), which supports basic, clinical, translational, and implementation research to develop new knowledge and approaches for prevention, diagnosis, and treatment of substance use, misuse, addiction, and drug overdose.

Our study addresses the critical challenge of neuropathic pain, which affects up to 40% of adults in the U.S., contributing to over $300 billion in annual costs and fueling the opioid crisis due to the lack of effective treatments. We specifically target the subpopulation for whom existing treatments have failed and who have central neuropathic pain. Leveraging groundbreaking findings from our recent studies, we propose a novel approach to pain relief through precision functional mapping (PFM) and individualized neurostimulation targeting the somato-cognitive action network (scan) and the cingulo-opercular network (CON), two key circuits implicated in pain processing and action execution. These networks may explain the variable efficacy of motor cortex stimulation (MCS) in neuropathic pain management. Our approach advances the field by combining personalized MR-guided neuromodulation, PFM for precise targeting, optimized electrode placement, and bayesian optimization for individualized stimulation parameters, aiming to maximize pain relief by moving beyond the one-size-fits-all model that has historically limited MCS effectiveness. The study's aims include finalizing a minimally supervised electrode placement pipeline, testing the feasibility and efficacy of PFM-guided joint CON and scan stimulation in a phase i clinical trial, and determining optimal stimulation parameters through bayesian preference learning. In the UG3 phase, we will refine our neuroimaging and modeling pipeline for targeting scan and CON in chronic, centralized pain patients (aim 1), complete the data and safety monitoring board (dsmb) setup, and enroll two initial participants to validate our pipeline. If go/no-go milestones are met, the UH3 phase will expand enrollment to eight additional participants, testing workflow feasibility and acute pain response with sham control and blinding (aim 2). Finally, in aim 3, we will use bayesian preference optimization, previously validated in two patients, to individualize waveform parameter settings for each cortical target. We will compare optimized stimulation parameters to standard clinical settings to determine if individualized optimization can reduce heterogeneity in outcomes due to stimulation programming. This comprehensive approach promises not only to improve understanding of pain mechanisms but also to establish a foundation for more effective, personalized treatments for chronic pain. Success would advance a novel mechanistic framework for pain neuromodulation, provide a translational pathway to larger efficacy trials, and potentially reduce reliance on opioids while improving the quality of life. Our multidisciplinary team integrates technical expertise and patient advocacy to ensure both scientific rigor and real-world applicability.