Targeted stimulation of the sensory afferents improves motoneuron function in humans with a degenerative motoneuron disease

Spinal Muscular Atrophy (SMA) is an inherited neurodegenerative disease causing motoneuron dysfunction, muscle weakness and early mortality. Three therapies can slow disease progression enabling people to survive albeit with lingering motoneuron dysfunction and severe motor impairments. 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 afferents 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 legs. We stimulated participants for 4 weeks 2 hours per day while they executed tested 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 indicate that targeted neurostimulation can reverse degenerative processes of circuit dysfunction thus promoting disease modifying effects in a human neurodegenerative disease. ### Competing Interest Statement MC, GPO and ME hold patent applications that relate to this work. ### Clinical Trial [NCT05430113][1] ### Clinical Protocols ### Funding Statement This study was supported by an exploratory research grant from F. Hoffmann La Roche to MC and RMF. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: IRB STUDY21080158 of University of Pittsburgh gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT05430113&atom=%2Fmedrxiv%2Fearly%2F2024%2F02%2F17%2F2024.02.14.24302709.atom