Customized Brain Stimulation: New Hope for Severe Depression

Megan Brooks

October 05, 2021

Personalized deep brain stimulation (DBS) appears to rapidly and effectively improve symptoms of treatment-resistant depression, new research suggests.

In a proof-of-concept study, investigators identified specific brain activity patterns responsible for a single patient's severe depression and customized a DBS protocol to modulate the patterns. Results showed rapid and sustained improvement in depression scores.

"This study points the way to a new paradigm that is desperately needed in psychiatry," study investigator Andrew Krystal, PhD, Weill Institute for Neurosciences, University of California San Francisco, said in a news release.

"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," Krystal added.

The findings were published online October 4 in Nature Medicine.  

Closed-Loop, On-Demand Stimulation

The patient was a 36-year-old woman with long-standing, severe, and treatment-resistant major depressive disorder. She was unresponsive to multiple antidepressant combinations and electroconvulsive therapy.

Researchers used intracranial electrophysiology and focal electrical stimulation to identify the specific pattern of electrical brain activity that correlated with her depressed mood.

They identified the right ventral striatum — which is involved in emotion, motivation, and reward — as the stimulation site that led to consistent, sustained, and dose-dependent improvement of symptoms and served as the neural biomarker.

In addition, the investigators identified a neural activity pattern in the amygdala that predicted both the mood symptoms, symptoms severity, and stimulation efficacy. 

The patient was implanted with the FDA-approved NeuroPace RNS System. The device was placed in the right hemisphere. A single sensing lead was positioned in the amygdala and the second stimulation lead was placed in the ventral striatum.

When the sensing lead detected the activity pattern associated with depression, the other lead delivered a tiny dose (1 milliampere/1 mA) of electricity for 6 seconds, which altered the neural activity and relieved mood symptoms.

Remission Achieved

Once this personalized, closed-loop therapy was fully operational, the patient's depression score on the Montgomery-Åsberg Depression Rating Scale (MADRS) dropped from 33 before turning treatment ON to 14 at the first ON-treatment assessment carried out after 12 days of stimulation. The score dropped below 10, representing remission, several months later.

The treatment also rapidly improved symptom severity, as measured daily with Hamilton Depression Rating Scale (HAMD-6) and visual analog scales.

"Success was predicated on a clinical mapping stage before chronic device placement, a strategy that has been utilized in epilepsy to map seizure foci in a personalized manner but has not previously been performed in other neuropsychiatric conditions," the investigators write.

This patient represents "one of the first examples of precision psychiatry — a treatment tailored to an individual," the study's lead author Katherine Scangos, also with UCSF Weill Institute, told Medscape Medical News.

She added that the treatment "was personally tailored both spatially," meaning at the brain location, and temporally — the time it was delivered.

"This is the first time a neural biomarker has been used to automatically trigger therapeutic stimulation in depression as a successful long-term treatment," said Scangos.

However, "we have a lot of work left to do," she added.

"This study provides proof-of-principle that we can utilize a multimodal brain mapping approach to identify a personalized depression circuit and target that circuit with successful treatment. We will need to test the approach in more patients before we can determine its efficacy," Scangos said.

First Reliable Biomarker in Psychiatry

In a statement from the UK nonprofit Science Media Centre, Vladimir Litvak, PhD, with the Wellcome Centre for Human Neuroimaging, University College London, said that the study is interesting, noting that it is from "one of the leading groups in the field."

The fact that depression symptoms can be treated in some patients by electrical stimulation of the ventral striatum is not new, Litvak said. However, what is "exciting" is that the authors identified a particular neural activity pattern in the amygdala as a reliable predictor of both symptom severity and stimulation effectiveness, he noted.

"Patterns of brain activity correlated with disease symptoms when testing over a large group of patients are commonly discovered. But there are just a handful of examples of patterns that are reliable enough to be predictive on a short time scale in a single patient," said Litvak, who was not associated with the research.

"Furthermore, to my knowledge, this is the first example of such a reliable biomarker for psychiatric symptoms. The other examples were all for neurological disorders such as Parkinson's disease, dystonia, and epilepsy," he added.

He cautioned that this is a single case, but "if reproduced in additional patients, it will bring at least some psychiatric conditions into the domain of brain diseases that can be characterized and diagnosed objectively rather than based on symptoms alone."

Litvak pointed out two other critical aspects of the study: the use of exploratory recordings and stimulation to determine the most effective treatment strategy; and the use of a closed-loop device that only stimulates when detecting the amygdala biomarker.

"It is hard to say based on this single case how important these will be in the future. There is no comparison to constant stimulation that might have worked as well because the implanted device used in the study is not suitable for that," Litvak said.

It should also be noted that implanting multiple depth electrodes at different brain sites is a "traumatic invasive procedure only reserved to date for severe cases of drug-resistant epilepsy," he said. "Furthermore, it only allows [researchers] to test a small number of candidate sites, so it relies heavily on prior knowledge."

"Once clinicians know better what to look for, it might be possible to avoid this procedure altogether by using noninvasive methods," such as functional MRI or EEG, to match the right treatment option to a patient, Litvak concluded.

The research was funded by the National Institutes of Health, the Brain & Behavior Research Foundation, and the Ray and Dagmar Dolby Family Fund through the Department of Psychiatry at UCSF. Scangos has reported no relevant financial relationships. A complete list of author disclosures is available in the original article. Litvak is currently participating in a research funding application to search for electrophysiological biomarkers of depression symptoms using invasive recordings.

Nature Med. Published online October 4, 2021. Abstract

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