Next generation of deep brain stimulation aims to tackle depression

For patients whose depression resists treatment with drugs and electroconvulsive therapy, surgically implanted wires that stimulate the brain might bring relief. But in recent years, two randomized, controlled trials of this approach, known as deep brain stimulation (DBS), were halted after underwhelming results in interim analyses. “It was like the air was let out of the room,Sameer Sheth, a neurosurgeon at Baylor College of Medicine, says of those results. “It was a big let-down.

Now, researchers are testing more sophisticated, personalized DBS techniques they hope will yield stronger results. The tests to date have involved just one or a few patients, far from proof of effectiveness. But researchers hope they’ll inform larger studies that finally cement the effectiveness of DBS in depression. “With all these irons in the fire we will hopefully build up enough understanding and evidence, says Sheth, an author of a case study published this week.

DBS is already approved in the United States to treat epilepsy, obsessive compulsive disorder, and movement disorders such as Parkinson’s disease. Could it also shift patterns of abnormal activity in neural circuits that may drive depression symptoms? Early studies without control groups yielded promising results, but two randomized, controlled trials, sponsored by the medical device companies Medtronic and St. Jude Medical, Inc. (which was later acquired by Abbott Laboratories) did not show significant benefits after several months of DBS, teams reported in 2015 and 2017.

Long-term follow-up of participants has revived some optimism. For example, many people in the 30-participant Medtronic trial improved over 1 year or more—beyond the timeline of the initial study, says Stanford University psychiatrist Mahendra Bhati, a co-investigator. Last month, he and colleagues published a follow-up study of eight trial patients, most of whom continue to use their implant about 10 years later. About one-half have had at least a 50% improvement over their pretreatment score on a depression scale.

Many researchers say that because depression can manifest differently in different brains, personalizing the treatment could make it more effective. Several teams are now exploring more precise stimulation approaches informed by individual brain anatomy and neural recordings.

Helen Mayberg, a neurologist at the Icahn School of Medicine at Mount Sinai who has pioneered the use of DBS in depression, cautions that to be used widely in the clinic, DBS will also have to be cost effective and simple enough that your average, competent neurosurgeon and depression expert can … implement it.”

Her team has identified an area near the front of the brain called the subcallosal cingulate (SCC) as a hub in a network linked to the negative mood component of depression. One of the halted randomized trials, known as BROADEN, aimed to test stimulation of the SCC as a depression treatment. Mayberg suspects subtle differences in where surgeons placed the electrodes account for much of the variation in patient outcomes in that trial. So her group and others now use an MRI approach called tractography to visualize locations of nerve bundles and target electrodes more precisely.

Mayberg is also tracking how the brain responds to this more precise stimulation, hoping to identify neural responses that predict whether and when a persons symptoms will improve. This month in Translational Psychiatry, she and colleagues describe a change in activity in the SCC during brain stimulation in the operating room that correlates with treatment response in the week after surgery in seven studied patients.

Neuropsychologist Isidoor Bergfeld and colleagues at Amsterdam University Medical Center are testing tractography-guided DBS implants in another part of the brain implicated in depression known as the superolateral branch of the medial forebrain bundle. Bergfeld aims to recruit 24 patients and expects results in 2 to 3 years. He hopes data from his groups trial and from a similar ongoing study in Germany can combine to support regulatory approval in the European Union for depression.

Other teams have more extensive personalization in mind. Psychiatrist Katherine Scangos of the University of California, San Francisco, and colleagues are using an individual’s neural data to decide which target region to stimulate and exactly when to deliver the stimulation. Before inserting DBS electrodes, the team implants a second set of electrodes that can record from and stimulate tissue across diverse regions of the brain. Surgeons already rely on the approach, known as stereotactic electroencephalography (sEEG), to identify the source of seizures before epilepsy surgery. Now, Scangoss team has used it to stimulate mood-related regions and select a target where stimulation reliably relieves symptoms. 

For the first patient, of a planned 12 in an ongoing trial, the ideal stimulation target seemed to be the ventral capsule/ventral striatum (VC/VS), already an established target in DBS depression trials. The team also found that activity in a second site in the patient’s brain, the amygdala, strongly predicted periods of severe symptoms. So the patient’s implant—a device called NeuroPace, which is approved to detect and stop seizures—was programmed to stimulate the VC/VS only in the presence of those amygdala activity patterns. Every time that train sort of veers off the tracks, we push it back on,” Scangos says. That first patient has felt significant relief from her symptoms for more than 1 year since the surgery, Scangos and her colleagues reported last month in Nature Medicine.

Other researchers are waiting for more evidence that this automated, closed-loop” approach to the timing of stimulation is necessary. With severe depression, its not like youre alternating between really depressed and totally normal … over moments or hours,” Sheth says. His team is using sEEG electrodes to find the best settings for continuous DBS in each patient. During a 10-day hospital stay, the researchers use sEEG readouts to identify patterns of brain activity associated with a positive mood and track how those readouts change in response to DBS stimulation from electrodes in both the SCC and VC/VS. A computer algorithm then identifies the ideal frequency, amplitude, and other settings for improving mood.

Data from the first participant in an ongoing trial, published today in Biological Psychiatry, show his symptoms improved in the first few months after surgery—and then steadily worsened during a blinded discontinuation phase, when stimulation at some of the sites was reduced gradually at a time point unknown to the patient. (Researchers then turned the implant back to full power.)

Sheth notes that implanting the set of sEEG electrodes to guide treatment is likely too invasive and labor-intensive to be feasible for every patient, though it might offer a chance to adjust DBS in patients whose symptoms arent responding. He also hopes researchers can develop less invasive methods to inform stimulation settings.

“We’re the first to admit that time will tell whether this approach or variants of it can successfully be applied,” Sheth says. But the variety of ambitious DBS approaches being tested is a good sign, he says. “I’m just happy that groups are still fighting to help all these patients.”

source: sciencemag.org