Woman's depression cured by targeted electrical brain stimulation, a first, pioneered by UCSF researchers

Sarah went more than five years without laughing.

Living in the San Francisco Bay Area, she long ago stopped noticing the region's natural beauty. She had so lost touch with her own opinions that she ordered whatever her friends were having when they went out to dinner. All she knew was that she wanted to die.

But some piece of her was still open enough that she volunteered for a clinical trial at the University of California, San Francisco, to treat severe depression.

A year and two brain surgeries later, Sarah, 36, chuckles while telling her story.

Sarah, who asked to be identified by her first name, is the only person to ever be treated with electrodes implanted deep in her brain that send quick energy bursts when they detect activity in a brain circuit involved in her depression.

Those 6-second zaps – as many as 300 a day – have transformed her life and provided new insights into the biological nature of depression.

What she's been through is way too complicated to replicate for the millions of people who suffer from deep, unrelenting despair, but her success may suggest new ways to address one of the most hard-to-reach mental illnesses.

"It's really cool," said Dr. Darin Dougherty, a psychiatrist who uses a similar, but less advanced approach to treating obsessive-compulsive disorder at Massachusetts General Hospital and McLean Hospital. "It's very exciting because it's the next step … for depression, this is exactly what we need to be doing."

Andres Lozano, a professor of neurosurgery at the University of Toronto, said the research should be received enthusiastically but with caution.

"It's only one patient, so we have to be careful," he said. "But if it translates to other patients and if the results are longstanding and enduring then it's very exciting."

Help out of hopelessness

Deep brain stimulation has been used for years to treat Parkinson's disease, epilepsy and obsessive-compulsive disorder, but the UCSF approach went further, by personalizing the treatment, targeting specific brain circuits instead of regions, and providing intermittent currents rather than a continuous stream of electricity.

Katherine Scangos, who helped lead the research, published Monday in Nature Medicine, said such complexity and specificity is required to treat a condition as challenging and individualized as depression.

Two other patients have been enrolled in the trial and Scangos hopes to eventually include nine more. Additional patients will allow the team to look at how brain circuits involved in depression differ and help improve the personalization process.

Better understanding these brain circuits may lead to different ways of modulating them – hopefully ways that won't require brain surgery and will be easier to provide to large numbers of people, Scangos said.

Approximately 250 million people worldwide have depression and 10%-20% of them don't get help from current treatments. Sarah was among them. She tried numerous medications and electroconvulsive therapy during her five years of extreme depression, all without substantial improvement.

Her mood lifted almost immediately when the stimulator was first turned on.

"I felt the most intensely joyous sensation," she said. She remembers the researchers looking at her when she laughed out loud. "It was the first time I had spontaneously laughed, I had smiled – where it wasn't faked – for five years."

Dark thoughts would return when the device was turned off, but more than a year after it became fully operational, her depression remains a distant memory.

"Within a few weeks, the suicidal thoughts just disappeared," she said. "Then it was just a gradual process where it was like my lens on the world changed."

Hobbies she had used to distract herself from suicidal thoughts were pleasurable for the first time. Riding home from one session, she noted the gorgeous color and light of the San Francisco Bay where it met the marshes. The friend who was driving "looked at me like I was insane – it was so shocking to them that I said something like that," she said. "When I was in the depths of depression, all I saw was what was ugly."

She's now in what she describes as a virtuous cycle, where getting pleasure from activities enables her to feel better and she can benefit from therapy that didn't help when she was at her lowest.

Triggering the right circuit

Neurosurgeon Edward Chang, who operated on Sarah and first conceived of the experiment seven years ago, said he expects brain stimulation will not be a "standalone" therapy but used in coordination with other approaches including rehabilitation and medication.

The stimulation is carefully calibrated so Sarah can't feel the zaps, though she said she thinks she knows within a 15- to 20-minute window when the stimulator has gone off because she has a heightened sense of alertness, energy and positivity.

To identify the exact circuit involved in Sarah's depression required repeated hourslong visits to UCSF, turning the stimulator on and off and calibrating the charge.

Scangos said she was concerned too much stimulation might trigger mania, a different psychiatric condition, but Sarah has had no such side effects. In fact, she said, she has fewer side effects than with many of the nonsurgical approaches she tried.

Chang said he expects the process can be simplified as researchers better understand the impact of stimulating different brain circuits and improve their ability to identify the crucial one in each individual.

In Sarah's case, one of her two implanted devices identified the site of abnormal activity, while the stimulator, typically used to treat epilepsy, automatically sends an electrical stimulus when it detects that activity.

The stimulator only goes off when this circuit believed to lie at the root of her depression malfunctions. That means the battery will last longer – about 10 years, Scangos estimates.

The match-box-sized battery is embedded in her cranial bone so she can't feel it. The two minimally-invasive surgeries were less annoying, Sarah said, than the extended MRIs she had to undergo to identify her faulty brain circuit.

Chang said he had to customize existing devices to make them work the way he wanted them to. The basic equipment cost about $30,000, he said.

"We're at the very beginning of figuring out how this works," Chang said. "We have a lot to learn."

The hope, Chang said, is eventually it will be possible to identify and target key circuits in a depressed person's brain without needing surgery.

For now, he said, surgery seems to be "more precise and targeted with more control and fewer side effects." Plus, because the stimulator can be monitored remotely, the patient doesn't have to come back repeatedly for adjustments.

Decreasing depression stigma

One of the unknowns is how long the benefits will last.

Earlier studies using deep brain stimulation to combat depression showed no difference at six months between people who had a stimulator turned on and those who didn't. Follow-up studies at two years, though, did show substantial improvement in half of the people who'd been stimulated, said Lozano, who was involved in the research.

In those cases, the stimulator was turned on 24/7 and its location wasn't personalized.

Lozano said it makes sense that better results would come from doing both. "The brain works by getting the right information at the right time to the right place," he said, and more precise targeting will hopefully yield better and longer-lasting results.

He also thinks the UCSF team's work targeting a circuit instead of a brain region makes sense. The movement difficulties associated with Parkinson's, for example, stem from one particular area of the brain, and a deep brain stimulator is placed in that area in everyone. But with depression, symptoms vary widely, affecting things like sleep, memory and focus in addition to mood.

Influencing a circuit can help address all of those symptoms, he said.

In Sarah's case, the circuit ran from her amygdala, an area known to control fear and other strong emotions, to her ventral striatum, which is involved in decision-making.

"We're starting to recognize some of the complexity that's involved with how mood is regulated in the brain as a network ... interacting areas in the brain that give rise to really complex emotions that underlie things like depression and anxiety," Chang said.

Focusing on networks, he said, is "going to give us a lot more options and a lot more hope for thinking about how to tailor these therapies for patients in the future."

In the meantime, Sarah, her doctors and other experts in the field say experiments like this should help destigmatize depression and other mental illnesses.

When treatment after treatment didn't work, Sarah said, "I felt like it was my own personal moral failing." But when stimulating a circuit in her brain lifted her depression almost instantaneously, Sarah realized her black mood wasn't her fault.

"No one ever says to someone with Parkinson's that if you just have a positive attitude, you'll cure yourself," she said.

"The hardest part of living with depression is the stigma," she added. "That's why I've kept myself anonymous."

Suicide Lifeline: If you or someone you know may be struggling with suicidal thoughts, you can call the U.S. National Suicide Prevention Lifeline at 800-273-TALK (8255) any time of day or night or chat online.

Crisis Text Line provides free, 24/7, confidential support via text message to people in crisis when they dial 741741.

Contact Karen Weintraub at kweintraub@usatoday.com.

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This article originally appeared on USA TODAY: Targeted electrical brain circuit stimulation a hope for depression