"I Feel Like I Can Walk a Mile"

A few years ago, when University of Pittsburgh researchers fired up the electrodes they had implanted in Doug McCullough’s spinal cord, they hoped to rejuvenate his legs, which had been severely weakened by spinal muscular atrophy (SMA), a progressive neurodegenerative disease. At first, there was no response. But as they adjusted the signals’ intensity and frequency, McCullough felt a faint pulse. After more treatments, his legs started getting stronger. Soon he was able to walk further and faster than before.

“My legs just felt supercharged,” he told an NPR reporter. “It's like, man, I feel like I can walk a mile.” McCullough, 57, who had come to rely on two canes or a motorized wheelchair, was understandably ecstatic.

So, too, was a scientist at Columbia University Vagelos College of Physicians and Surgeons named George Mentis, the rare bench scientist who has seen his work change the life of a patient, perhaps the first of thousands.

The basics of SMA

More than a decade earlier, Mentis, a professor of pathology and cell biology (in neurology), had begun investigating how defects in a gene called SMN1 (Survival Motor Neuron 1) lead to muscle atrophy in SMA. In SMA, muscles wither and weaken because the neurons that control the muscles—known as motor neurons—degenerate.

At the time Mentis began his research, most SMA scientists were focused on understanding and preventing damaging changes happening inside the motor neurons. Mentis thought that other neurons that communicate with motor neurons were probably also contributing to the disease.

His intuition was confirmed in studies of mice conducted in his lab in Columbia’s Motor Neuron Center. Mentis found that contacts between sensory and motor neurons, called synapses, malfunction in SMA animals, resulting in impaired motor neuron function and muscle weakness.

He later demonstrated that increasing the activity of the synapses with a compound called kainate can improve motor neuron and muscle function in mice with SMA. Unfortunately, the compound is a poor candidate for patients because it can trigger seizures and is toxic after long term use.

“But we provided proof of principle that, as long as there are some functional spinal motor neurons, we could reverse the effects of SMA, at least in mice,” says Mentis.

Stimulating patients

Mentis’ findings caught the eye of Marco Capogrosso, a University of Pittsburgh neuroscientist, who had been using epidural spinal stimulation to boost arm strength in stroke patients. The therapy seemed to work by strengthening the synapses among the nerve cells that control specific arm muscles. Capogrosso suspected that spinal stimulation could also strengthen the synapses Mentis identified in SMA and reached out to Mentis to discuss the idea of a clinical trial.

In 2023, the researchers recruited three volunteers with SMA, including McCullough, to participate in the month-long trial, the first time neurostimulation had been tried with SMA patients. The volunteers were temporarily fitted with a pair of electrodes (implanted by a neurosurgeon on top of the spinal cord), along with a tiny receiver and rechargeable battery, all implanted under the skin in a one-hour procedure. From Mentis’ mouse work, Capogrosso knew exactly where to attach the electrodes on the lumbar region of the spinal cord.

Immediately after the implantation, the volunteers received spinal cord stimulation for two hours a day. McCullough, who was diagnosed with SMA when he was 11, wasn’t expecting much. With SMA, he told NPR, “You never get any better, you’re either maintaining, or you're getting worse.”

However, by the end of the month, the treatment boosted the test subjects’ leg strength by an average of 180%, step length by 40%, and 6-minute walking endurance by 85 feet, Capogrosso and colleagues reported in Nature Medicine this past February. The improvements persisted even when the stimulation was turned off, and no adverse events were reported.

“It worked so well, above and beyond all our expectations,” says Mentis. “And the improvements kept coming during the four weeks, suggesting that further gains are possible.”

Next steps

The benefits faded several months after the trial ended, suggesting the therapy would have to be permanently applied. Even so, it would be a considerable supplement to existing therapies, which can slow or stop the death of motor neurons, but do not improve walking ability, strength, and other movement deficits.

As planned, the devices were removed after the trial, to the volunteers’ disappointment. “One of the patients was begging us, ‘Can’t you lie and just say you removed the electrodes?’” recalls Mentis.

Now Capogrosso’s team, together with Mentis and other colleagues, is trying the same treatment in SMA patients with a more severe form of the disease who are younger and wheelchair bound. But instead of stimulating the segments of the spinal cord responsible for leg function, they are stimulating the region that controls the hands, which are severely affected in these patients.

Importantly, Capogrosso is now planning a larger trial of electrical stimulation therapy for SMA patients that can be stimulated for longer periods of time and test the efficacy of such treatment long-term. Meanwhile, Mentis is continuing his search for a better understanding of the neuronal mechanisms.

Doug McCullough and the 25,000 other SMA patients in the U.S. are no doubt eagerly awaiting their findings.