Scientists at the University of California San Francisco (UCSF) have developed a new personalized, on-demand approach to treat major depression by optimizing and refining deep brain stimulation strategies. For patients with long-term, treatment-resistant depression, this new therapy could be transformative.

The findings published in an article in the journal Nature Medicine titled, ‘Closed-loop neuromodulation in an individual with treatment-resistant depression’ represent a landmark success in attempts to apply advances in neuroscience to the treatment of psychiatric disorders.

Andrew Krystal
Andrew Krystal, MD, professor of Psychiatry and vice chair of Research

“This study points the way to a new paradigm that is desperately needed in psychiatry,” says Andrew Krystal, PhD, professor of psychiatry, member of the UCSF Weill Institute for Neurosciences and senior author of the study. “We’ve developed a precision-medicine approach that has successfully managed our patient’s treatment-resistant depression by identifying and modulating the circuit in her brain that’s uniquely associated with her symptoms.”

In the two-step method, the researchers first identify a symptom-specific neural biomarker in the patient through intracranial electrophysiology over several days. At the same time, they identify a treatment location where focal electrical stimulation improves the symptoms.

The authors then implant a device in the identified location, capable of sensing and stimulating electrical impulses. The device implements a closed-loop therapy that triggers therapeutic deep brain stimulation when the severity of the symptom increases, generating the specific biomarker that is sensed by the device.

The therapy applied in an individual with major depression “resulted in a rapid and sustained improvement in depression”, the authors note. Krystal says, the personalized treatment alleviated the patient’s symptoms of depression almost immediately and has lasted over the 15 months she has had the implanted device.

“I was at the end of the line,” says the patient. “I was severely depressed. I could not see myself continuing if this was all I’d be able to do, if I could never move beyond this. It was not a life worth living.”

The limited success of earlier attempts at treating depression with deep brain stimulation is largely because earlier approaches delivered constant electrical stimulation to one area of the brain whereas depression may involve different regions of the brain in different patients.

The success of this proof-of-principle study rests on the researchers’ discovery of a specific pattern of brain activity that indicates the onset of symptoms (a neural biomarker) in the patient, and their customizing the deep brain stimulation device to trigger a response selectively when it detects the pattern that constitutes the biomarker.

This closed-loop approach creates an on-demand therapy that is unique to the patient’s brain, the affected region, and the neural circuit causing the symptoms.

Work on the new responsive neurostimulation device grew out of a multicenter effort sponsored under President Obama’s 2014 BRAIN (Brain Research through Advancing Innovative Neurotechnologies) Initiative that led Edward Chang, MD, a neurosurgeon at UCSF and his colleagues to investigate depression and anxiety in patients undergoing surgery for epilepsy. This resulted in the team identifying signature electrical activities in the brain that correlate to different moods, and brain regions that when stimulated relieve depression.

“This new study puts nearly all the critical findings of our previous research together into one complete treatment aimed at alleviating depression,” says Chang, who is co-senior author on the paper and the Joan and Sanford Weill Chair of Neurological Surgery.

Chang placed one of the device’s electrode leads in the brain area where the team had found the biomarker and the other lead in the region of the patient’s depression circuit where stimulation best relieved her mood symptoms. The first lead monitors brain activity continuously. When it detects the biomarker pattern, it signals the other lead to deliver a tiny, one milliampere dose of electricity for six seconds. This causes the patient’s neural activity to change.

First author Katherine Scangos, MD, PhD, a member of the Weill Institute says, “The effectiveness of this therapy showed that not only did we identify the correct brain circuit and biomarker, but we were able to replicate it at an entirely different, later phase in the trial using the implanted device. This success is an incredible advancement in our knowledge of the brain function that underlies mental illness.”

“There’s still a lot of work to do,” adds Scangos. “We need to look at how these circuits vary across patients and repeat this work multiple times. And we need to see whether an individual’s biomarker or brain circuit changes over time as the treatment continues.”

Toward this end, two other patients are enrolled in the trial and researchers hope to add nine more.

Scangos says, “The idea that we can treat symptoms in the moment, as they arise, is a whole new way of addressing the most difficult-to-treat cases of depression.”

Krystal says, understanding brain circuits underlying depression is likely to guide future non-invasive treatments that can modulate such circuits specifically.

Regulatory approval for this treatment is still far down the road, requiring trials to establish whether the results and approach of this n-of-1 study generalize to a broader population, but the findings point toward new ways of treating severe depression.

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