Cuneiform Nucleus Stimulation Can Assist Gait Training to Promote Locomotor Recovery in Individuals With Incomplete Tetraplegia

Objective Impaired ability to induce stepping after incomplete spinal cord injury (SCI) can limit the efficacy of locomotor training, often leaving patients wheelchair‐bound. The cuneiform nucleus (CNF), a key mesencephalic locomotor control center, modulates the activity of spinal locomotor centers via the reticulospinal tract. Even with severe corticospinal damage, the widely distributed reticulospinal fibers frequently cross the lesion, and lumbosacral spinal locomotor centers remain responsive. Unilateral deep brain stimulation (DBS) of the CNF (CNF‐DBS) can increase modulatory input to sublesional locomotor centers and was shown to induce stepping and promote locomotor recovery in rodent models of severe incomplete SCI. Given the evolutionarily conserved CNF‐reticulospinal system, we hypothesize that CNF‐DBS can augment training and improve gait in humans with incomplete SCI above the lumbosacral levels. Methods Aiming at bench‐to‐bedside translation, we investigate CNF‐DBS in non‐ambulatory patients ( clinicaltrials.gov , NCT03053791). Here, we present the first 2 individuals with chronic tetraplegia who underwent 6 months of locomotor training supported by unilateral CNF‐DBS, with regular follow‐up assessments of adverse and therapeutic effects performed without and with stimulation. Results The walking distance covered during the 6‐Minute Walking Test (6MWT) after 6 months compared to baseline served as the primary study end point, which was reached by patient 1 in the off‐condition and by patient 2 in the off‐ and the on‐condition. No serious adverse events occurred. Interpretation We show that the CNF‐DBS was well tolerated and had therapeutic potential in the first 2 patients, and discuss the lessons learnt with resulting implementations for the next patients. ANN NEUROL 2025