Cortical Specificity Matters: the Importance of Stimulating Hindlimb Representation for the Recovery of Skilled Locomotion after Severe Spinal Cord Injury

BACKGROUND:The motor cortex exhibits a somatotopic organization that enables skilled control of lower limbs during locomotion. Following spinal cord injury (SCI), descending cortical commands are completely or partially disrupted, resulting in impaired volitional walking. We previously developed a closed-loop paradigm delivering intracortical microstimulation (ICMS) to hindlimb motor representations in synchrony with locomotion, which immediately improves walking deficits and enhances long-term recovery of voluntary locomotor control in rodent models. However, as clinical efforts prioritize less invasive neurostimulation approaches, the necessity of functionally specific cortical targeting remains a critical question. OBJECTIVE:Here, we tested whether stimulation of hindlimb-specific cortical territories provides superior recovery compared to non-specific stimulation or no stimulation in a feline model of severe thoracic spinal contusion (T10) producing chronic bilateral locomotor deficits. METHODS:Following recovery of weight-supported stepping, cats underwent a three-week locomotor training intervention, with or without concurrent ICMS depending on group assignment: no stimulation (n = 5); ICMS targeting the specific contralateral hindlimb representation (n = 2); or non-specific ICMS recruiting multiple body parts (n = 3). Locomotor performance was assessed on a flat treadmill, ladder treadmill, and during obstacle avoidance up to four weeks post-therapy. RESULTS:Our results indicate that while all groups exhibited improvements in basic treadmill locomotion, only hindlimb-specific ICMS restored voluntary locomotor control to near-intact levels, particularly during tasks requiring high-precision paw placement. CONCLUSIONS:These findings provide preclinical evidence that the functional specificity of cortical stimulation is essential for optimizing skilled locomotor recovery, highlighting the importance of precise spatial targeting in neuroprosthetic interventions.