A Novel Multimodal Approach to Promote Motor Recovery and Plasticity after Stroke

/ABSTRACT Among the 800,000 individuals who sustain a stroke annually in the United States, up to 65% continue to expe- rience chronic moderate-to-severe impairments in one upper extremity (UE), limiting their ability to perform daily tasks. These impairments, often characterized by limited arm and hand movements, prevent the use of the paretic UE in functional tasks. Functional electrical stimulation (FES)-assisted task-specific practice is the only viable option to promote use-dependent plasticity and improve UE impairment and function. However, the ben- efits are only modest and transient, indicating that FES-assisted task-specific practice alone is insufficient in improving UE impairment and function in this more impaired population. Non-invasive neuromodulatory tech- niques [e.g., repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS)] have also been applied to cortical motor areas to augment the effects of FES-assisted task-specific practice. However, there is limited evidence supporting the effectiveness of these approaches. Thus, there is a critical need for new evidence-based multimodal interventions for moderate to severely impaired individuals who con- stitute the largest cohort of stroke survivors. Transcranial random noise stimulation (tRNS) is a new type of non- invasive brain stimulation that can boost the weak neural signals via random currents applied to the lesioned hemisphere. tRNS is more effective in modulating brain excitability than other conventional neuromodulatory techniques. When delivered during FES-assisted task-specific practice, tRNS can enhance the excitability of the surviving neural pathways to promote use-dependent plasticity and improve UE impairment and function. Indeed, our preliminary data show a profound increase in brain excitability and significant improvements in UE impair- ment and function after 6-weeks of tRNS and FES-assisted task-specific practice. Building on our preliminary data, the specific objective of this proposal is to conduct a blinded, sham-controlled, randomized clinical trial to determine the efficacy of tRNS and FES-assisted task-specific practice to improve UE impairment and function after moderate-to-severe stroke. We will also comprehensively evaluate the effect of this intervention on cortico- spinal excitability by examining the changes at multiple anatomical levels (i.e., cortical, cervicomedullary, and spinal). Our central hypothesis is that tRNS delivered during FES-assisted task-specific practice will augment the effectiveness of FES-assisted task-specific practice. The specific aims of the study are: 1) Determine the effect of tRNS and FES-assisted task-specific practice on UE impairment, 2) Determine the effect of tRNS and FES-assisted task-specific practice on UE function, and 3) Determine the effect of tRNS and FES-assisted task- specific practice on corticospinal excitability. The expected outcomes of this project include a novel multimodal therapeutic paradigm for the largest cohort of stroke survivors who currently do not have any effective interven- tions, which directly aligns with the research priority of the NIH NCMRR to study multimodal approaches to promote plasticity and sensorimotor function. Project Number: 1R01HD120761-01 | Fiscal Year: 2026 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Amit Sethi | Institution: UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH, SALT LAKE CITY, UT | Award Amount: $667,666 | Activity Code: R01 | Study Section: Musculoskeletal Rehabilitation Sciences Study Section[MRS] View on NIH RePORTER: https://reporter.nih.gov/project-details/11286512