The brain is constantly pulsing with electricity. Rapid electrical bursts, passed from neuron to neuron, drive our thoughts, behaviors, and perceptions of the world. Networks of neurons form circuits that, when activated, carry out specific functions. Sometimes this complex electrical wiring goes awry, which can be a factor in neurological and psychiatric disorders. But what if the rhythm of these circuits could be restored with a kind of factory reset button?
That’s the idea behind deep brain stimulation, a technique that delivers tiny zaps of electricity to brain tissue via implanted electrodes. DBS is akin to a pacemaker, but instead of controlling an abnormal heartbeat, it uses electricity to stabilize irregular brain circuit activity. Over the past three decades, it as been used to treat Parkinson’s disease; in more recent years it has been approved for a handful of other movement disorders, including severe epilepsy. Its success in managing these conditions has spurred interest in applying it to hard-to-treat psychiatric conditions. Within the past few months, three different research groups have published papers showing its potential for treating eating disorders, alcohol addiction, and obsessive-compulsive disorder—but many unknowns remain.
“We just understand a lot more about the motor system than we do more complex systems that have to do with emotion, thoughts, and feelings. Those live in different brain areas,” says Sameer Sheth, a neurosurgeon at Baylor College of Medicine who studies DBS and coauthored a recent review paper on its use for obsessive-compulsive disorder. “The better we can understand these circuits, the better chance we will have using therapies like DBS to restore those circuits.”
Deep brain stimulation requires surgeons to drill nickel-sized holes in each side of the skull to insert a needlelike electrode into each brain hemisphere. The tip of each delivers electrical pulses from a battery-powered stimulator that’s implanted in the chest. (The two devices are connected by a wire beneath the skin.) Where the electrodes are placed in the brain depends on what doctors want to treat. For Parkinson’s, the electrodes are nestled into the movement center of the brain.
In other words, the approach is extreme and isn’t for everyone. “It is invasive; it requires brain surgery. You wouldn't want to do this if you can fix the problem easier, quicker, and better with something else,” says Mark George, who pioneered a noninvasive form of brain stimulation called transcranial magnetic stimulation and is a professor of psychiatry, radiology, and neuroscience at the Medical University of South Carolina. “But it wouldn’t be beyond the pale for the group of people for whom conventional treatments are not working. And that's a big group.”
The therapy is used in Parkinson’s when medication no longer works to control tremors, stiffness, and slowness. For severe psychiatric conditions, the authors behind the recent papers say, it could help people who haven’t responded to talk therapy, medication, or other treatments. In a study published in August in Nature Medicine, researchers at the University of Pennsylvania tested DBS as a treatment for two severely obese people with binge eating disorder. Both had already undergone gastric bypass surgery and tried medication and behavioral therapy but gained back the weight and couldn’t stop binge eating.
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Casey Halpern, an associate professor of neurosurgery at Penn Medicine who led the study, is targeting a part of the brain called the nucleus accumbens, which is involved in processing pleasure and reward. In a previous study in mice, Halpern’s group found a distinctive signal in this area—”a slow wave,” as he calls it—that preceded binge eating episodes but not normal eating, and he wanted to see whether this wave was detectable in people with the disorder.
After their electrodes were implanted, the two study participants came into a research lab for an initial test. They were presented with their favorite high-calorie foods, including candy and fast food, so that researchers could capture their brain signals before they ate. Then, at home, they lived with the implants for the following six months—at this point, the devices simply recorded brain activity but didn’t deliver any stimulation. The participants kept daily logs of when they experienced food cravings. As in the mouse experiment, their electrodes detected that same slow wave signature before they had a bingeing episode.
For DBS users with Parkinson’s disease, the electrodes’ stimulation is constant. While DBS can work in those patients for 15 years or more, it can become less effective as the brain becomes tolerant to its effects. To prevent this, Halpern and others are experimenting with delivering short bursts of electricity only when needed. In the mouse study, Halpern and his team stimulated the nucleus accumbens only when craving-related “slow wave” brain activity occurred, and found that the animals ate significantly less of a tasty, high-fat food compared to when they were allowed to eat freely.
Halpern and his team tried the same approach in the two human participants. After six months of collecting brain signals, researchers turned on the stimulation, setting it to occur only when the electrodes detected the onset of a bingeing episode. For the next six months, the devices stimulated each person for what added up to about 10 minutes a day. By the end of the study, the participants reported fewer binge eating episodes, and each lost around 11 pounds. One of the two improved so much that she no longer met the criteria for having the disorder.
“The improvement in self control is remarkable,” Halpern says. “Presumably over time, this craving signal that we defined has gone down for these patients so that it's not as frequent. It's possible that we are sort of retraining the circuit to behave in a more normal way.”
Of course, an experiment based on two people doesn’t prove that the therapy will be broadly applicable, but Halpern and his team now have the go-ahead from the US Food and Drug Administration to try DBS in more patients with binge eating disorder and are enrolling them for a larger trial. Halpern says the initial two participants have decided to continue using the devices because the effects have been so positive.
Stimulation of the nucleus accumbens is also being studied to treat alcohol addiction. In a small study in Toronto, researchers implanted electrodes in six people who had been consuming six to 18 alcoholic drinks per day for several years or longer. None had been able to stop drinking despite medication, psychotherapy, and stays at rehabilitation facilities. After 12 months of constant stimulation, participants reported fewer cravings, and their daily alcohol consumption dropped from an average of 10 drinks to three, according to findings published in July in the journal Molecular Psychiatry.
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“It may be that stimulation of the nucleus accumbens altered the reward circuitry in the brain such that it turned down the volume on the pleasurable craving that patients with alcohol use disorder feel when they see or are around alcoholic beverages,” says Nir Lipsman, the study’s principal investigator and a neurosurgeon at Sunnybrook Health Sciences Centre.
Lipsman is hoping to conduct a larger trial to confirm the findings. His group is also interested in finding brain signatures associated with alcohol cravings so that stimulation might only be needed at certain times.
Scientists working in the DBS space think many psychiatric diseases may ultimately be amenable to the therapy. For example, Sheth’s September review in the Journal of Neurology, Neurosurgery, and Psychiatry analyzed 34 studies of DBS to treat obsessive-compulsive disorder. Across 352 patients, he concluded, it was effective for 66 percent of them.
But there are challenges to scaling the therapy. Some psychiatric disorders, such as anorexia and bulimia, are hard to replicate in mice. That makes it difficult to move forward with human research. And because doctors would target different parts of the brain depending on the disorder, regulatory authorities want to make sure the technique is safe in each region before green-lighting larger human trials. “It's important to appreciate that this started with very well controlled and planned mouse studies,” Halpern says. “We didn’t just go straight to doing surgery in the human brain.”
The trials are also expensive—costing researchers around $100,000 per patient—and require complicated surgeries that carry risks for participants. Infections can arise after surgery or develop later at the site of the implanted electrode. A misplaced electrode, or a high frequency of stimulation, can cause changes in mood. (One of the Toronto trial patients became more irritable after getting the brain implants. Once researchers reduced the voltage, the patient’s mood stabilized.) These challenges mean studies are often small and lack a placebo group, making it difficult to draw broader conclusions about effectiveness.
They also need to take place over long periods so that researchers can accurately capture the effects of stimulation—but it can be hard to justify a long trial if patients don’t seem to be getting better. In the 2010s, two high-profile DBS trials for depression failed to show improvement. In the smaller of the two studies, researchers measured patients’ response rates after just 16 weeks. The larger trial was stopped early by its sponsor, St. Jude Medical, when an interim analysis suggested there was no benefit compared to a control group that received a sham device.
Helen Mayberg, a neurologist at Mount Sinai Health System in New York who pioneered the use of DBS in depression and was a consultant on the St. Jude study, thinks the decision to stop the trial early was a mistake. Her research over the past decade had shown that stimulating the subcallosal cingulate, also called area 25, could relieve severe depression. The region plays a role in appetite, self-esteem, sleep, and the processing of sadness and has been found to be hyperactive in some patients with severe depression. But subsequent research by Mayberg and her colleagues found that many of the trial’s patients who didn’t initially respond to the therapy eventually showed improvement.
She also thinks the placement of the device affects how well the therapy works. She recalls one of her patients who wasn’t improving after six months of stimulation. Upon examination, the electrode wasn’t inserted deep enough. When it was moved to the correct spot, the person’s symptoms started improving. “We think that proves that location explains most of your variance in outcomes,” Mayberg says.
Device maker Abbott, which acquired St. Jude Medical in 2017, is gearing up for a new trial. Abbott’s system was granted breakthrough device designation by the FDA in July as a treatment for depression.
Yet questions remain about which patients will benefit from DBS. Like Halpern, Mayberg and her team have gathered brain recordings from severely depressed patients and believe they have isolated a particular signature that indicates who will respond to the therapy. But researchers are still trying to capture potential signals for other psychiatric disorders. “There’s simultaneously this amazing promise, but so far an unrealized potential,” says George.