New Optogenetic Approach Shows Promise for Treating Muscle Tremor and Restoring Limb Movement

MIT researchers have demonstrated for the first time that leg nerves activated by light could provide a new way to restore mobility.

The team showed that with the help of cues produced by the movement of the limb itself, nerves designed to express proteins—which can be stimulated by light—create limb movements that can be altered in real time. The method results in movements that are not only smoother but are also less tiring when compared to analogous electrical systems that are at times used for activating nerves in spinal cord injury patients and other similar patients.

Although this technique was tested on animals, more studies and upcoming trials in humans could enable this optogenetic method to be used for restoring movement in paralyzed patients, or for treating unnecessary movements like muscle tremor in patients with Parkinson’s disease, stated Shriya Srinivasan, a PhD student in medical engineering and medical physics at the MIT Media Lab and the Harvard-MIT Division of Health Sciences and Technology.

While the initial applications of the technology would be to power prosthetics or to restore motion to paralyzed limbs, an optogenetic system has the ability to turn off unnecessary pain signals, restore limb sensation, or treat rigid or spastic muscle movements in neurological diseases like amyotrophic lateral sclerosis (ALS), suggested Srinivasan and her colleagues.

According to Srinivasan, the MIT group is one among the few research groups to control nerves beyond the brain region through optogenetics.

“Most people are using optogenetics as sort of a tool to learn about neural circuits, but very few are looking at it as a clinically translatable therapeutic tool as we are.”

“Artificial electrical stimulation of muscle often results in fatigue and poor controllability. In this study, we showed a mitigation of these common problems with optogenetic muscle control,” stated Hugh Herr, who heads the research group and leads the Media Lab’s Biomechatronics group. “This has great promise for the development of solutions for patients suffering from debilitating conditions like muscle paralysis.”

The study was published in the December 13^th, 2018, issue of Nature Communications. The group included MIT researchers Maurizio Diaz, Benjamin E. Maimon, and Hyungeun Song.

Light versus electricity

At the clinical level, electrical stimulation of nerves is used for treating bladder, bowel, breathing, and sexual dysfunction in patients suffering from spinal cord injury, and also for improving muscle conditioning in patients with muscular degenerative diseases. Such an electrical stimulation can even control prosthetics and paralyzed limbs. In all examples, electrical pulses conveyed to nerve fibers known as axons stimulate movement in muscles triggered by the fibers.

Electrical stimulation of this kind can be painful, can rapidly tire out muscles, and is difficult to target accurately. Despite this fact, prominent researchers like Maimon and Srinivasan are seeking alternative techniques to stimulate nerves.

Optogenetic stimulation depends on nerves that have been genetically designed to express light-sensitive algae proteins known as opsins. These types of proteins regulate electrical signals like nerve impulses—in essence, turning them on and off—upon exposure to specific wavelengths of light.

Through rats and mice made to express these opsins in two major leg nerves, the team successfully controlled the up and down motion of the ankle joint of the rodents by switching on an LED that was either implanted inside the leg or fixed over the skin.

According to the researchers, this is the first time where a “closed-loop” optogenetic system has been applied for powering a limb. When compared to “open-loop” systems that do not react to feedback from the body, closed-loop systems are capable of altering their stimulation in response to signals from the nerves they are stimulating.

With regards to the rodents, different cues such as variations in the length of the muscle fibers and the angle of the ankle joint were the feedback used for controlling the movement of the ankle. According to Srinivasan, it is a system “that in real time observes and minimizes the error between what we want to happen and what’s really happening.”

Stroll versus sprint

Furthermore, compared to electrical stimulation, optogenetic stimulation resulted in fatigue at the time of cyclic motion, in a way that truly stunned the researchers. Large-diameter axons in electrical systems are first activated, along with their big and oxygen-hungry muscles, prior to shifting to smaller muscles and axons. Optogenetic stimulation operates in the reverse way, triggering smaller axons prior to moving on to larger fibers.

When you’re walking slowly, you’re only activating those small fibers, but when you run a sprint, you’re activating the big fibers. Electrical stimulation activates the big fibers first, so it’s like you’re walking but you’re using all the energy it requires to do a sprint. It’s quickly fatiguing because you’re using way more horsepower than you need.

Shriya Srinivasan, PhD Student, MIT Media Lab and Harvard-MIT Division of Health Sciences and Technology.

In addition, the researchers observed another strange pattern in the light-activated system that was different from electrical systems. “When we kept doing these experiments, especially for extended periods of time, we saw this really interesting behavior,” stated Srinivasan. “We’re used to seeing systems perform really well, and then fatigue over time. But here we saw it perform really well, and then it fatigued, but if we kept going for longer the system recovered and started performing well again.”

This unanticipated rebound is associated with how opsin activity cycles in the nerves, in a manner that enables the whole system to regenerate, concluded the researchers.

Since the optogenetic system involves less fatigue, it could prove to be an excellent future fit for long-term motor operations like robotic exoskeletons that enable certain paralyzed people to walk, or it could be used as long-term rehabilitation tools for patients suffering from degenerative muscle diseases, suggested Srinivasan.

For the technique to become viable in humans, scientists would need to try out the most optimum methods to send light to nerves deep inside the body, and also explore ways to express opsins in human nerves in a safe and efficient way.

There are already some 300 trials using gene therapy, and a few trials that use opsins today, so it’s likely in the foreseeable future.

Shriya Srinivasan, PhD Student, MIT Media Lab and Harvard-MIT Division of Health Sciences and Technology.

The MIT Media Lab Consortium funded the study.