From inflammation to depression, electricity is transforming medicine

New advances are letting scientists use electrodes instead of drugs to treat dozens of diseases affecting millions of people.

Sharon Laudisi, who runs a green energy consulting company, was driving to see a client in Brooklyn, New York, in 2019, when she was rear-ended. She wound up in the hospital, but was discharged the next day, sent home to tend her bruised arm. Once she was at home, she made her way to the restroom. That’s when she realized she couldn’t button her pants. Her left thumb wouldn’t move, and she’d lost the ability to feel anything with it.

“I went to 15 doctors, all telling me, ‘Forget your thumb. It's not gonna work. It's not gonna bend. Just adapt,’” Laudisi says. But life without the use of her thumb meant she struggled to get dressed, hold her keys, open a bottle, or use a flat iron or blow dryer to style her hair. Before long, she resorted to wearing wigs.

More than a year after her accident, an orthopedic specialist told her about a clinical trial at the Feinstein Institutes of Medical Research in Manhasset, New York, that might help her. In November 2020, Laudisi met with researchers who explained that rather than using drugs or physical therapy, they might be able to heal her thumb with electricity. “They didn’t promise anything,” she says, but at least they gave her hope.

Recent advances in engineering and biology suggest that electricity could treat such conditions as paralysis, depression, and autoimmune conditions. Physicians have demonstrated for decades that it is possible to treat some patients with epilepsy or Parkinson’s disease using deep brain stimulation (DBS)—in which an electrode is surgically implanted deep in the brain to electrically stimulate specific neurons. What’s different now is that there is a growing repertoire of diseases that scientists believe may also respond to electrical stimulation, delivered from both the inside and outside of the body.

The idea of using electricity to modulate brain activity in diseases like severe depression gained new momentum in the 2010s. “It got to a tipping point about ten years ago,” says Kevin Tracey, a neurosurgeon and the CEO at the Feinstein Institutes for Medical Research. But after several small studies had shown promising results, two large clinical trials of DBS for severe depression failed to demonstrate efficacy.

Those trials “let all the air out of the room,” says Sameer Sheth, a neurosurgeon at the Baylor College of Medicine. “It was a big bummer.”

The larger of the two trials stopped enrolling patients after six months. No announcement was published at the time, but several bloggers publicized a scoop that St. Jude, the study sponsor, had halted enrollment. Nonetheless, St. Jude Medical and Abbott, which had purchased St. Jude, agreed to continue following the patients, who already had had the electrodes surgically implanted, for any adverse effects or changes in mood.

Though it took up to two years, half of the patients with implants eventually experienced dramatic improvements in their depressive symptoms, but by then it was too late; the trial had already ended.

In 2020, the researchers at the Feinstein Institutes hoped that they might be able to reactivate Laudisi’s thumb, without surgery, by delivering electrical stimulation from the outside of her body. They fashioned a credit card-sized patch with about 100 electrodes and attached it to the surface of Laudisi’s skin at the back of her neck. There it stimulated nerves traveling down her spinal cord and radiating to her thumb. She felt the sensation in her head at first. “It feels like vibrations or little, teeny pins,” she says. Satisfied with the positioning and the effect, the physicians scheduled her for regular appointments.

Once a week for eight weeks she visited the lab for an hour for bioelectric therapy during which the scientists stuck the electrode patch to her neck and sent electrical signals down her spine.

The treatment began working within the first few weeks, allowing Laudisi to wiggle her thumb. Nine months later, she remembers she was at her regular appointment at the nail salon when suddenly she could feel the technician filing her left thumb nail. Her thumb isn’t as strong as it was before the accident, but today she can use it to open bottles of soda. She can feel sensations again.

“I’m not 100 percent, but I can pick things up,” she says while demonstrating over Zoom how she unscrews and tightens the cap on a soda bottle. She considers the electrical treatment “a modern-day miracle.”

Listening first

How electricity modifies neurons and helps them work again seems to vary for different diseases.

Parkinson’s disease attacks a specific population of neurons that produce the neurotransmitter dopamine in a small part of the brain called the substantia nigra. As these neurons die, the decline in dopamine causes Parkinson’s symptoms such as tremors. Inserting an electrode into this area to deliver periodic bursts of electricity, like a pacemaker, can stimulate the remaining neurons to release more dopamine than they typically would to offset the loss and help ease symptoms.

For epilepsy, the electrodes can help quiet the overactive neurons that initiate seizures.

But when it comes to treating other diseases, the methods aren’t as straightforward. “There’s a number of mechanisms evolving,” says Sheth the Baylor College neurosurgeon. “And we don’t understand them fully.”

Sheth and his colleagues weren’t ready to give up on the idea of deep brain stimulation for depression after hearing about the aborted trials in 2013. Like many scientists, they still believed the treatment had potential. Maybe one of the reasons those trials were not a universal success was because “it was a very one size fits all therapy that was applied to those patients. And, you know, depression is not one size fits all,” he says.

Although patients with Parkinson’s all have damaged neurons in the same area of the brain, epilepsy patients are far more diverse. Before using the treatment to reduce seizures, scientists must use electrodes to map and record each patient’s brain activity over the course of several days to determine where their seizures are originating. Only then will they know where to modulate electrical activity.

Precision medicine for the brain

Sheth and his team wondered if they could use a similar technique identify dysregulated brain circuits in patients with severe depression and launched a clinical trial to find out.

As the COVID-19 pandemic broke out in the United States in March 2020, Sheth and his team were in the hospital working with their first trial patient, a 37-year-old man whose severe depression had persisted for years and had resisted a variety of treatments. To identify which areas of the man’s brain were triggering depression they implanted 10 electrodes in several regions previously implicated in the disease. Then they monitored and recorded the electrical impulses between neurons for 10 days while they kept him in the hospital.

“Those recordings really individualized our understanding of that single patient’s depression networks—networks regulating mood and affective cognitive processes to really drill down on what’s wrong,” says Sheth. Next, they started delivering periodic pulses of electricity to two specific brain regions thought to be involved in regulating positive and negative feelings: the subcallosal singulate and the ventral striatum.

Within the first few days of treatment the man reported more than a 50 percent reduction in depression symptoms. After 22 weeks, doctors said his depression was in remission. After 37 weeks, the scientists reduced the stimulation by 25 percent per week, all the way to zero, to see if his symptoms changed. He reported a steady increase in anxiety and worsening mood. When the researchers reactivated the electrodes, his symptoms dissipated once again, suggesting that the ongoing stimulation was responsible for his improved mood, and that if it continued, he was likely to remain in remission.

“He's doing great,” says Sheth. “He's living a much fuller life. He's working. His social relationships are just going really well.” Last year he visited Sheth’s doctoral students to help deliver a lecture on depression.

Since that first report, Sheth’s team has taken recordings and implanted therapeutic electrodes in two more patients with severe depression. “We're starting to see that our first two patients have, overall, slightly different patterns that predict better versus worse mood,” he says, adding that he’s still analyzing data from the third patient. “This precision medicine, this individualization approach, I think it's going to be critical.”

Amplifying the signal

In the 2010s, Chad Bouton, an engineer and medical researcher at the Feinstein Institutes for Medical Research, was experimenting with electrodes implanted in the brain to help paralyzed patients regain movement. But in 2019, he wondered if he could use electricity to help patients without opening the skull at all.

In most cases of pain or numbness in the extremities after accidents, the nerve or spinal cord is only partially severed. That seemed to be the case with Sharon Laudisi’s thumb injury, meaning a small amount of electrical signaling from the brain can move between the brain and the extremity; it just isn’t enough to ignite sensation or initiate movement.

Bouton and his team suspected that if they could strengthen the signal, they might be able to help Laudisi’s brain communicate with her thumb again. But to do so, they needed to map the neuronal connections she had left.

To determine the ideal placement of the electrode patch on Sharon’s neck, the team stimulated, moved the patch, stimulated, and moved the patch, until they found the location that allowed the patch to communicate with just her hand, and not send errant signals throughout her body.

Stimulating the patch on Laudisi’s neck is like raising the volume on a speaker that’s partially blocked by a piece of furniture. Once they found the placement that maximized the signals to her thumb, Sharon wore the electrode patch once a week for an hour at a time for a total of eight weeks.

By the end of that time, Laudisi was able to generate 715 percent more force with her thumb. Today, her thumb isn’t as strong or flexible as it used to be, but she can click a pen, use her keys, and button a shirt. “I don’t think there are words to describe how impressive it is,” she said.

Bouton says he can’t yet estimate what the cost of such a treatment might be if approved by the FDA but that he believes “it would be affordable and accessible to the many who could benefit from it.”

Short-circuiting inflammation

When he was training to be a surgeon, Tracey, the Feinstein Institute’s CEO, was taking care of a child in the burn unit of a New York Hospital. She died in his arms. “We didn’t know what she died of,” he says. “It was haunting.” But later, upon learning she died of sepsis, he decided to devote his future research to the condition.

He and his team discovered a protein, tumor necrosis factor (TNF), that they believed was responsible for the girl’s death. The researchers went on to describe TNF’s role in promoting inflammation to neutralize invading pathogens like bacteria and viruses, and its more sinister ability to attack the body’s own tissues. Excessive inflammation can cause sepsis, shock, and even cytokine storms—the result of hyperactive immune cells that can worsen diseases like COVID-19 by damaging the very tissues the immune system is trying to protect and heal. If you can block TNF in a patient with dangerously high cytokine levels, “you can cut off the fuel to the disease,” says Tracey.

Tracey’s findings in the 1980s led to the development of drugs to inhibit the TNF protein and reduce inflammation. Several such drugs, like Enbrel and Remicade, are now used to treat autoimmune diseases in which a person’s immune system destroys their own healthy tissue.

But those drugs don’t work for every patient, so Tracey thought there might be a better way to target inflammation. He suspected that since the autonomic nervous system reflexively controls blood pressure, digestion, and other processes, there must be a reflex that controls inflammation. He zeroed in on the vagus nerve, a dense package of about 100,000 nerve fibers that travels from the brain, along each side of your neck passing through the heart, lungs, chest, and all the way to the large intestine.

“We discovered that electrical signaling in the vagus nerve is like the brake line in your car. It stops the TNF system, the inflammatory system, from spinning out of control,” Tracey says. Animal studies showed that if the vagus nerve is cut, damaging inflammation can escalate, exacerbating autoimmune diseases.

He and his team developed an implantable device, less than an inch long, that sits inside the neck, cuffing the vagus nerve to stimulate it, thus decreasing harmful TNF production. Early devices were attached to batteries that would be implanted under a patient’s clavicle, but newer versions are about the size of your pinky nail and can be charged by wearing a metal charging collar once every week or so.

Neurons that makeup the vagus nerve are involved in myriad processes, Tracey explains, but the device targets only those that regulate TNF because they are hypersensitive compared with surrounding nerve cells.

There are hundreds of clinical trials listed on testing forms of vagus nerve stimulation to treat conditions from COVID-19 to chronic pain. Some applications have more scientific backing than others, Tracey says, citing stroke recovery—for which a vagus nerve device has already been approved by the FDA—and controlling inflammation.

For other indications, he emphasizes that scientists may not really understand the mechanisms yet. He’s also dubious of those who claim to stimulate the nerve from outside the skin rather than by implanting an electrode. “How do you know what you’re doing?” he asks, emphasizing that researchers should start by identifying specific targets like TNF before testing therapies.

Electricity everywhere

Although scientists often think of electrical communication taking place between neurons, Michael Levin a biologist and computer scientist at the Wyss Institute in Boston, highlights that every cell in the body communicates via electricity. Cells have channels in their membranes that open and close, allowing charged ions to flow in and out of neighboring cells, influencing how cells grow and work together. Along with molecular signals, electrical gradients between cells help tell a developing fetus it should make two eyes, for example, and how far apart they should be.

“That's really the future of this, manipulating that natural information flow. We want to be able to program the thing with the exact currency that it uses,” Levin says.

Rather than stimulating individual cells, Levin is working to alter the spatial distribution of electronic signals in different areas of the body to encourage groups of cells to work together to heal or regenerate. He likens his strategy to programming software for the body’s genetic hardware.

That means that bioelectric treatments could go far beyond stimulating individual cells with electrodes.

In frogs, for example, he and his team have used computational analysis to determine the ideal electrical environment to stimulate limb regeneration. When they’re tadpoles, these animals can regrow lost tissue, but as they mature, they lose most of that ability. The analysis allowed him to choose five drugs that would open and close the channels on the cells to reach the desired electrical state. After amputating the animal’s hind leg, they fashioned a wearable bioreactor filled with those five drugs. After just 24 hours of wearing the reactor, the animal’s limb continued to regrow for 18 months. The new limb was not fully regrown, but did have skin, bone, blood vessels, and nerves.

It's going to take some time, Levin explained, for scientists to tease apart the different electrical states that guide the activity and development of human cells. But after that, he believes there is little standing in the way of progress. Many drugs that could be used in these therapies, like those in the frog’s bioreactor, already exist. Scientists just need to know how and when to combine them to build the electrical environments the body might need.

Deep brain stimulation and vagus nerve stimulation are “good applications,” of bioelectric medicine, says Levin. “I just want people to understand this is the tip of the iceberg.”

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