Spinal Cord Stimulation Improves Leg Strength and Walking in Adults with Spinal Muscular Atrophy

University of Pittsburgh School of Medicine researchers carrying out a small pilot clinical trial demonstrating that a drug-free, minimally invasive intervention targets the root cause of progressive loss of neural function in patients with spinal muscular atrophy (SMA), an inherited neuromuscular disease. The pilot trial in three adults with SMA showed that epidural spinal cord stimulation (SCS), which involves electrical stimulation of the sensory spinal nerves, can gradually reawaken functionally silent motor neurons in the spinal cord and improve leg muscle strength and walking.

Early results from the trial found that one month of regular neurostimulation sessions improved motoneuron function, reduced fatigue, and improved strength and walking in all participants, regardless of the severity of their symptoms. The study is the first to show that a neurotechnology can be engineered to reverse the degeneration of neural circuits and rescue cell function in a human neurodegenerative disease. The researchers also suggest that the same neurostimulation approach could be used to treat other neurodegenerative diseases such as amyotrophic lateral sclerosis, or Huntington’s disease, if appropriate cellular targets can be identified.

“To counteract neurodegeneration, we need two things—stop neuron death and restore function of surviving neurons,” said Marco Capogrosso, PhD, assistant professor of neurosurgery at Pitt. “In this study we proposed an approach to treat the root cause of neural dysfunction, complementing existing neuroprotective treatments with a new approach that reverses nerve cell dysfunction.”

Capogrosso is co-corresponding author of the team’s published study report in Nature Medicine, titled “First-in-human study of epidural spinal cord stimulation in individuals with spinal muscular atrophy.” In their paper, the team noted, “In summary, our results provide insights into the disease mechanisms of SMA that lead to circuit and motoneuron dysfunction in humans. Notably, we leveraged the identification of these mechanisms to design a clinically relevant intervention that manipulated the maladaptive processes induced by SMA, improving function at a cellular, circuit, and behavioral level.”

SMA is a genetic neurodegenerative disease that leads to progressive functional decline and death of motor neurons, the nerve cells that control movement by transmitting signals from the brain and the spinal cord to the muscles. “SMA is an inherited spinal motor circuit disorder caused by the homozygous loss of the SMN1 gene, which results in ubiquitous deficits of SMN protein expression,” the authors further explained. Over time, the loss of motor neurons causes gradual muscle weakness and leads to a variety of motor deficits, which may include difficulty in walking, climbing stairs, and standing up from chairs. “Lack of SMN leads to selective death of spinal motoneurons and progressive muscle atrophy,” the team continued.

While there is no cure for SMA, several promising neuroprotective treatments have become available in the last decade. These include gene replacement therapies and medications, both of which stimulate the production of motoneuron-supporting proteins that prevent neuronal death and that slow down—though do not reverse—disease progression.

Studies show that movement deficits in SMA emerge before widespread motoneuron death, suggesting that underlying dysfunction in spinal nerve circuitry may contribute to disease onset and symptom development. “Animal models of SMA show that motor deficits appear before widespread motoneuron death, suggesting that spinal circuit dysfunction may play a role in disease onset and progression,” the investigators pointed out.

Earlier research in animal SMA models by study co-author George Mentis, PhD, at Columbia University indicated that surviving motor neurons receive fewer stimulation inputs from sensory nerves—fibers that return the information from skin and muscles back to the central nervous system. “Importantly, excitatory synaptic input to spinal motoneurons coming from proprioceptive afferents is lower in SMA,” the authors stated. Compensating for this deficit in neural feedback might improve communication between the nervous system and the muscles, aid muscle movement, and combat muscle wasting. “Upregulating the activity of primary sensory afferents could compensate for the loss of excitatory input to motoneurons, potentially triggering circuit dysfunction reversal,” they suggested.

The Pitt researchers hypothesized that a targeted epidural electrical stimulation therapy could be used to rescue lost nerve cell function by amplifying sensory inputs to the motor neurons and engaging the degenerated neural circuits. These cellular changes could, in turn, translate into functional improvements in movement capacity.

Their reported study was conducted as a pilot clinical trial that enrolled three adults with milder forms of SMA (Type 3 or 4 SMA). During a study period of 29 days, participants were implanted with two SCS electrodes that were placed in the lower back region on each side of the spinal cord, directing the stimulation exclusively to sensory nerve roots. Testing sessions lasted four hours each and were conducted five times a week for a total of 19 sessions, until the stimulation device was explanted.

After confirming that the stimulation worked as intended and engaged spinal motor neurons, the researchers performed a battery of tests to measure muscle strength and fatigue, changes in gait, range of motion, and walking distance, as well as motoneuron function. The results showed that all participants increased their 6-minute walk test score—a measure of muscle endurance and fatigue—by at least 20 meters, compared to a mean improvement of 1.4 meters over three months of comparable exercise regimen unaided by SCS, and a median increase of 20 meters after 15 months of SMA-specific neuroprotective pharmacologic therapy.

These functional gains were mirrored by improved neural function, including a boost in motoneurons’ capacity to generate electrical impulses and transmit them to the muscles. “Our intervention led to improvements in strength (up to +180%), gait quality (mean step length: +40%), and endurance (mean change in 6-minute walk test: +26 m), paralleled by increased motoneuron firing rates,” the team further reported.

Commenting on the findings, co-corresponding author Elvira Pirondini, PhD, assistant professor of physical medicine and rehabilitation at Pitt, said, “Because SMA is a progressive disease, patients do not expect to get better as time goes on. But that is not what we saw in our study. Over the four weeks of treatment, our study participants improved in several clinical outcomes with improvements in activities of daily living. For instance, toward the end of the study, one patient reported being able to walk from their home to the lab without becoming tired.”

In their report, the team stated, “In this study, we demonstrated that electrical stimulation of the sensory afferents alleviated motor deficits in three humans with SMA through a combination of immediate assistive effects and therapeutic effects that appeared over time with SCS OFF. Importantly, we found evidence of improved spinal motoneuron function in an otherwise progressive neurodegenerative disease.”

Added co-corresponding author Robert Friedlander, MD, chair of neurosurgery at Pitt and co-director of the UPMC Neurological Institute, “Our results suggest that this neurostimulation approach could be broadly applied to treat other neurodegenerative diseases beyond SMA, such as ALS or Huntington’s disease, as long as appropriate cell targets are identified in the course of future research. We are hoping to continue working with SMA patients and launch another clinical trial to test the long-term efficacy and safety of electrical spinal cord stimulation.”

The authors further noted that while SCS is being studied as an assistive neuroprosthetic tool to improve movement after spinal cord injury, stroke, and other neurodegenerative diseases, “… this is the first time, to our knowledge, that a neurostimulation therapy was not engineered to assist movement but, rather, to reverse degenerative circuit processes and effectively rescue motoneuron function in a human motoneuron disease.”