“It may be that stimulation of the nucleus accumbens altered the reward circuitry in the brain in such a way that it lowered the volume of the pleasurable desire that patients with alcohol use disorder feel when they see or are near alcoholic beverages,” says Nir Lipsman. , the study’s principal investigator and a neurosurgeon at Sunnybrook Health Sciences Center.
Lipsman hopes to conduct a larger trial to confirm the findings. Her group is also interested in finding brain signatures associated with alcohol cravings so that stimulation is only needed at certain times.
Scientists working in the DBS space believe that many psychiatric illnesses may ultimately be amenable to therapy. For example, Sheth’s September review in the Journal of Neurology, Neurosurgery and Psychiatryry analyzed 34 studies of DBS to treat obsessive-compulsive disorder. In 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 difficult 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, regulators want to make sure the technique is safe in each region before greenlighting larger human trials. “It’s important to appreciate that this started with very well-controlled and planned mouse studies,” says Halpern. “We didn’t go directly to do surgery on the human brain.”
Trials are also expensive, costing researchers around $100,000 per patient, and requiring complicated surgeries that carry risks for participants. Infections can arise after surgery or develop later at the site of the implanted electrode. A poorly placed electrode or high-frequency stimulation can cause mood swings. (One of the patients in the Toronto trial became more irritable after receiving the brain implants. Once the researchers lowered the voltage, the patient’s mood stabilized.) These challenges mean that studies are often small and lack a placebo group, making it difficult to draw broader conclusions about effectiveness.
They also need to be carried out for long periods for researchers to accurately capture the effects of stimulation, but it can be hard to justify a long trial if patients don’t seem to improve. In the 2010s, two high-profile trials of DBS for depression showed no improvement. In the smaller of the two studies, researchers measured patients’ response rates after just 16 weeks. The largest trial was stopped early by its sponsor, St. Jude Medical, when an interim analysis suggested no benefit compared to a control group given a sham device.
Helen Mayberg, a neurologist at Mount Sinai Health System in New York, a pioneer in the use of DBS in depression and a consultant on the St. Jude study, believes the decision to stop the trial early was a mistake. Her research over the past decade had shown that stimulating the cingulate subcallosum, also called area 25, could alleviate severe depression. The region plays a role in appetite, self-esteem, sleep, and sadness processing and has been found to be overactive in some severely depressed patients. But further research by Mayberg and her colleagues found that many of the trial patients who initially did not respond to 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 did not improve after six months of stimulation. Upon examination, the electrode was not inserted deep enough. When it was moved to the right place, the person’s symptoms began to improve. “We think that proves that location explains most of the variation in the results,” says Mayberg.
Device maker Abbott, which acquired St. Jude Medical in 2017, is preparing for a new trial. Abbott’s system received Breakthrough Device Designation from the FDA in July as a treatment for depression.
However, questions remain about which patients will benefit from DBS. Like Halpern, Mayberg and her team have collected brain recordings from severely depressed patients and believe they have isolated a particular signature that indicates who will respond to therapy. But researchers are still trying to capture potential signs of other psychiatric disorders. “At the same time, there is this incredible promise, but so far unrealized potential,” says George.
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