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When Sarah, 36 years old and severely depressed, sat down in a lab with a head full of surgically implanted sensors last year, the last thing she expected was to spontaneously cackle. She hadn’t laughed like that — a real, unforced laugh — in five years.

But something had happened: A subtle electrical shock deep in her brain had interfered with the dark anxious spirals her depression had sent her on since she was a child.

Sarah laughed, and the whole room was taken aback, researchers recalled.

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She had tried “everything,” from all sorts of medications to electroconvulsive therapy; she had been pushed toward various treatments and self-care errands by well-meaning but unhelpful friends. Nothing had worked, until the deep brain stimulation (DBS) device devised specifically for her sent a targeted jolt to just the right spot in her brain before the wave of depression crashed down.

Sarah, who chose to only reveal her first name publicly, is the first patient in the world to undergo this experimental treatment. The two researchers at the University of California at San Francisco behind the work, Katherine Scangos and Andrew Krystal, called it “the most remarkable” experience of their psychiatric careers.

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“Nobody has ever operated in this mode before, ever, in depression therapy,” said Krystal, a professor of psychiatry at the UCSF Weill Institute for Neurosciences, and one of the authors of a paper published Monday in the journal Nature Medicine.

Now, researchers want to see if they can recreate Sarah’s treatment with other patients, and possibly pave a road toward customizable, effective depression therapy for those who haven’t gotten relief from any other treatment.

Here’s how it works: By mapping out a depressed patient’s brain circuitry, researchers were able to identify biological markers that told them symptoms were coming, and implant a device to deliver targeted electrical stimulation and provide immediate relief in something like a cranial call and response.

The implant the UCSF team used, called a NeuroPace device, was granted an investigational exemption by the Food and Drug Administration, but it hasn’t been cleared for more general use in treating depression. And the team had to engineer a completely new infrastructure to make the device work for its study, neurosurgeon and senior study author Edward Chang said during a news conference.

Chang first identified the possibility of using brain stimulation for depression years ago, as he was treating epileptic patients with electrical stimulation and noticed a difference in their moods, anxiety, and depressive symptoms. What emerged were two clinical trials, Scangos said: one for chronic pain, and the one Sarah took part in.

Unlike DBS treatments that send a constant flow of electricity into the brains of patients with epilepsy and Parkinson’s disease, the treatment used on Sarah involves stimulations lasting only six seconds at a time, once each time a specific depressive biomarker is identified. Researchers discovered that the therapeutic effects of stimulation didn’t stop when the electrical current stopped — they persisted.

Sarah, patient
Sarah has reported fewer intrusive thoughts since her treatment and her suicidal thoughts have disappeared. Courtesy JOHN LOK PHOTOGRAPHY

“The idea of stimulating somebody and just a few seconds later, them saying, ‘My depression is gone’ … it is just stunning,” Krystal said. “They have this experience where they haven’t felt this good in years, they get hope. They feel like there’s a sense of relief that it feels like it’s not their fault because it’s changeable by modulating brain circuitry. It’s not that they didn’t do something right. It’s clearly linked to their body, their biology.”

That instantaneous improvement is groundbreaking in the field of psychiatry, which up until recently operated under the assumption that it takes up to eight weeks to know if a treatment is working, lead author Scangos told STAT.

And instead of focusing on one brain region, the researchers can tap into two areas that play a role in depression — and maybe connect to more in the future as devices become more sophisticated, they said. Such an innovation could help scientists better understand how mental health conditions manifest in interconnected parts of the mind, and how to treat them.

“The growing recognition is that there’s not, like, one depression area or one mood area in the brain,” said Chang, who’s been a close collaborator with psychiatry researchers at UCSF. “And unfortunately, that’s the way that we’ve approached this in the previous trials with traditional deep brain stimulation. And what’s particularly exciting to me is that we’re starting to recognize some of the complexity that’s involved with how mood is regulated — the brain as a network, not just one particular node in the part of the brain that’s responsible for all of them, but interacting areas in the brain that give rise to really complex emotions that underlie things like depression, anxiety.”

In the case of Sarah, who was receiving psychiatric treatment at UCSF before she agreed to be the first trial patient, two dozen researchers studied her brain for 10 days. They triggered her depression (with consent) in between her sessions of reading, watching television, and doing needlepoint. They surveyed her constantly, gauging how she felt, to find a pair of target areas.

What they found was her amygdala, the brain region in charge of emotional processing, was a reliable center of depressive activity, sending up more than 18 biological flares per hour, according to Scangos. And a spot deep in Sarah’s brain — in the ventral striatum — could be stimulated and instantly soothe the amygdala’s overreaction, though the exact mechanism by which it works is unclear.

“It was really quite a big difference and was amazing when we were able to stimulate across different regions … and see her depression sort of dissolve when we delivered stimulation at certain key sites,” Scangos told STAT. “And I think one of the times we did that, she said, ‘Oh my goodness. This is me, this is who I remember being.’ And that’s something she hadn’t even thought that she’d be able to feel — normal again.”

In June 2020, Chang implanted the matchbox-sized device into the curve of Sarah’s skull with its spaghetti-like electrode legs reaching down into the two brain regions. In the year since, Sarah has seen marked, consistent improvement in her depression symptoms.

“As time has gone on, it’s been this virtuous cycle, spiral upwards … everything has gotten easier and easier and easier,” Sarah told reporters.

Researchers don’t know how long Sarah will need to have the device in her skull, or if depression circuitry in the brain changes over time. But they can program the device to respond to various inputs, and at the rate of treatment Sarah receives, the device battery should last for about a decade, they said.

From a data standpoint, Sarah is down to about 300 depressive biomarkers per day, from a high of 450, and she is receiving treatment as they arise. She can’t feel the electrical stimulation, but she can feel the relief.

She experiences a full range of human emotion (“anxiety and sadness are important parts of life, they are tools we use,” Krystal said) with much fewer of the intrusive thoughts that left her unable to hold a job, care for herself, or enjoy life. Her persistent suicidal thoughts have disappeared. She has relearned who she is, what she likes and thinks and wants. She can see beauty around her: how sunlight dances on the water of the bay near her home, the vibrant colors of the marshes at the water’s edge.

In recent months, UCSF researchers have been studying two additional patients, a man and a woman in their 30s, and finding results consistent with what they saw in Sarah, according to Scangos. One patient has had the device implanted and begun longer-term treatment. Scangos said the team plans to recruit nine more patients for the clinical trial.

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