Depression treated successfully with on-demand brain stimulation

The team said the breakthrough is ‘a landmark success’ in applying advances in neuroscience to the treatment of psychiatric disorders. Their research is published in Nature Medicine.

“This study points the way to a new paradigm that is desperately needed in psychiatry,” said Andrew Krystal, PhD, professor of psychiatry and member of the University of California San Francisco (UCSF) Weill Institute for Neurosciences. “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.”

Previous clinical trials have shown limited success for treating depression with traditional deep brain stimulation (DBS), in part because most devices can only deliver constant electrical stimulation and usually only in one area of the brain. A major challenge for the field is that depression may involve different brain areas in different people.

The proof-of-principle trial was successful due to the discovery of a neural biomarker – a specific pattern of brain activity that indicates the onset of symptoms – and the team’s ability to customise a new DBS device to respond only when it recognises that pattern. The device then stimulates a different area of the brain circuit, creating on-demand, immediate therapy that is unique to the patient’s brain and the neural circuit causing illness.

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This customised approach alleviated the patient’s depression symptoms almost immediately, Krystal said, in contrast to the four- to eight-week delay of standard treatment models and has lasted over the 15 months she has had the implanted device.

“I was at the end of the line,” said 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 path to this project at UCSF began with research sponsored under the BRAIN (Brain Research through Advancing Innovative Neurotechnologies) Initiative. UCSF neurosurgeon Edward Chang, MD, and colleagues – conducting studies to understand depression and anxiety in patients undergoing surgical treatment for epilepsy - discovered patterns of electrical brain activity that correlated with mood states and identified new brain regions that could be stimulated to relieve depressed mood.

Chang, Krystal, and Katherine Scangos, MD, PhD then developed a strategy relying on mapping the patient’s depression circuit and characterising her neural biomarker.

“This new study puts nearly all the critical findings of our previous research together into one complete treatment aimed at alleviating depression,” said Chang.

The team evaluated the new approach in June 2020 under an FDA investigational device exemption, when Chang implanted a responsive neurostimulation device that he has successfully used in treating epilepsy.

To personalise the therapy, Chang put 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 mood symptoms. The first lead constantly monitored activity; when it detected the biomarker, the device signalled the other lead to deliver a 1mA dose of electricity for six seconds, which caused the neural activity to change.

“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,” said Scangos. “This success in itself is an incredible advancement in our knowledge of the brain function that underlies mental illness.”

While the approach appears promising, the team advises that this is the first patient in the first trial.

“There’s still a lot of work to do,” said 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.”