Combinatorial approaches increasing neuronal activity accelerate recovery after spinal cord injury

Combinatorial approaches targeting multiple aspects of spinal cord injury (SCI) pathophysiology are needed to maximize functional recovery. We hypothesized that enhancing neuronal activity-by strengthening corticospinal synapses through Hebbian stimulation and increasing neuronal transmission with 4-aminopyridine (4-AP), a potassium blocker-could accelerate locomotor recovery in individuals with chronic SCI. Participants were randomly assigned to receive 10 mg of 4-AP or placebo, where both groups followed with 60 min of Hebbian stimulation targeting corticospinal-motor neuronal synapses supplying leg muscles involved in locomotion and 60 min of standard exercise rehabilitation for 40 sessions over 8-14 weeks. During Hebbian stimulation, 720 paired pulses were delivered to elicit corticospinal action potentials via electrical stimulation of the thoracic spine, ensuring volleys reached the spinal cord 1-2 ms before motor neurons were retrogradely activated through bilateral electrical stimulation of the femoral, common peroneal, and posterior tibial nerves (targeting the quadriceps femoris, tibialis anterior and soleus muscles, respectively). Results showed that participants who received 4-AP exhibited significantly greater improvements in walking speed and endurance, corticospinal excitability, and light touch sensation compared to those who received the placebo. The minimal clinically important difference in walking speed and endurance was achieved after 20 sessions in the 4-AP group, but was not consistently reached in the placebo group. Although walking continued to improve in both groups over the course of 40 sessions, the 4-AP group demonstrated significantly greater progress. Improvement in the 4-AP group was still present approximately 12 months later. These findings suggest that 4-AP represents a strategy to potentiate and accelerate Hebbian stimulation effects on motor recovery in individuals with chronic SCI.