Targeted Stimulation of the Sensory Afferents Improves Motoneuron Function in Humans With Spinal Muscular Atrophy

Abstract Spinal Muscular Atrophy (SMA) is an inherited neurodegenerative disease causing motoneuron dysfunction, muscle weakness and early mortality1,2. Three therapies can slow disease progression enabling people to survive albeit with lingering motoneuron dysfunction and severe motor impairments3,4. Here we introduce a neurotechnological approach that improved spinal motoneuron function, muscle strength and walking in three adults with SMA. Starting from preclinical evidence showing that motoneuron dysfunction in SMA originates from the loss of excitatory inputs from primary afferents5,6, we hypothesized that augmentation of sensory neural activity with targeted electrical stimulation could compensate for this loss thereby improving motoneuron function. To test this hypothesis we implanted three adults with SMA with epidural electrodes over the lumbosacral spinal cord to stimulate the sensory axons of the legs7,8. We stimulated participants for 4 weeks 2 hours per day while they executed walking and strength tasks. Remarkably, our neurostimulation regime led to robust improvements in strength, walking and fatigue paralleled by reduced neuronal hyperexcitability, increased sensory inputs and higher motoneuron firing rates. Our data indicates that targeted neurostimulation can reverse degenerative processes of circuit dysfunction thus promoting disease modifying effects in a human neurodegenerative disease.