On February 4, 2019, before he was wheeled into the operating room, Tyler Hajjar, then age 28, hugged his mother and quipped, “It’s just brain surgery.” Hajjar, a resident of Johns Creek, Ga., had traveled to Emory University in Atlanta to outfit his brain with a device that might reset it in hopes of easing the depression that had severely diminished his quality of life—and, at times, threatened that life—for a decade. “Sometimes the best thing I could do was literally just lay in bed all day,” he recalls of his long illness, “but honestly, that was better than anything else that was going through my mind—which would have been irreversible.”

Hajjar wasn’t afraid of the surgery itself—only that it wouldn’t work. More than 20 medications, by his count, hadn’t helped him in any durable way; neither had electroconvulsive therapy, transcranial magnetic stimulation (TMS) or ketamine infusions.

But there was reason for optimism. Since the first trials in the early 2000s, deep-brain stimulation (DBS), in the hands of expert teams such as the one at Emory, has led to lasting relief in dozens of people with treatment-resistant depression. The technique, which remains experimental for depression—it did not meet the threshold for success in two large randomized controlled clinical trials—involves effectively rebooting the brain using implanted electrodes that stimulate it with pulses of electricity.

Though Hajjar hoped for a clinical benefit, his surgery was designed to also help uncover something novel: a wellness signal from the brain. He and nine others received a device that not only delivered electricity to the brain but also sensed neural activity. Analyzing that activity and correlating it with clinical ratings yielded a biomarker that signaled when a person was better in an enduring way.

The results, reported on September 20 in Nature, reveal a neural code that represents the first known signal of the presence or absence of depression in the brain. “This is to me, studying depression for more than 30 years, the closest clue to know, fundamentally, ‘What is depression, and how do we think about how the brain can be repaired?’” says Helen Mayberg, a neurologist at the Icahn School of Medicine at Mount Sinai, who was co-senior author of the study.

The new biomarker could improve the efficacy of the technology because it tells doctors when a person’s symptoms call for an adjustment in the stimulation and when they don’t—and, if tested further, it might even serve as a predictor of depression relapse. With such guidance, a larger number of doctors could capably care for people who have undergone DBS. “It could be very useful to bedside clinicians and to making the therapy more scalable, more effective and, frankly, helping the physician to do no harm,” says Michael Okun, a neurologist at the University of Florida, who was not involved in the study. Okun is a co-founder of the DBS Think Tank, an annual forum centered on cutting-edge issues involving the technology. Nearly three million people in the U.S. have treatment-resistant depression and stand to benefit from an approved therapy.

The work also could spur advances in less invasive treatments that modulate brain activity, such as TMS (which involves placing a coil on the scalp to create a magnetic field), says Gordon Baltuch, a neurosurgeon at Columbia University Irving Medical Center, who did not participate in the new research. “Neuromodulation could potentially help a cohort of people who have a disease which is not only disabling but is fatal” to tens of thousands of people each year in the U.S., Baltuch says.

Other biomarkers for depression could follow if, say, changes in a person’s face or voice, or in brain waves detected at the surface of the brain, correlate with the internal signal. Study investigators found a pattern of facial expressions that changed in tandem with the brain’s state, which is a promising sign. “There are probably many ways we will be able to read out from the brain, invasively and noninvasively,” says Christopher Rozell, a neuroengineer at Georgia Institute of Technology, who identified the wellness signal and was co-senior author on the new study. “It opens the floodgates for people to be able to look for these sorts of signals.”

The subcallosal cingulate, also known as “Brodmann area 25,” is embedded deep in the brain, above and behind the eyes. It is a critical crossroads for four major nerve fiber tracts and thus an intersection of brain traffic coming from areas that control all the functions that go awry in depression—emotional regulation, sleep, appetite, reward, motivation and memory, among others.

Two decades ago Mayberg was mapping brain circuits involved in depression and noticed that every time an antidepressant worked, area 25 became less active. So she decided to see if stimulating the brain there could modulate the area’s activity and ease depression in the most intractable cases, where other treatments had failed. Over the course of 20 years, she and her teams found that it could. In a 2019 follow-up study on 28 people treated with DBS, for example, Mayberg and her colleagues reported that half or more of the individuals significantly improved, and about 30 percent achieved remission and stayed well two to eight years later. One patient of Mayberg’s has stayed in remission for 18 years. “People just don’t get better; they stay better,” Mayberg says. Response rates have now climbed to about 80 percent as new techniques enable better targeting of area 25 in individual brains, Mayberg says.

Although Mayberg knew the treatment worked, at least in her patients, she did not know how. In 2013 Mayberg, then at Emory, heard about prototype stimulators made by the medical device company Medtronic that could also record from the brain, and she applied to receive 10 of them. She teamed up with Rozell and his colleagues, who had the skills to make sense of what the sensors were picking up.

In 2015 Emory neurosurgeons implanted the first of the new devices by threading one electrode into area 25 in each hemisphere and connecting these to a pacemaker. Each electrode has four contacts, places where it interfaces with brain tissue around area 25. Four years later Hajjar was the last member of this cohort to have the operation. In the operating room, he was awakened briefly, and he reported that stimulation of one of the contacts on the left side of the brain brought on a new feeling of emotional lightness—one that would, if he weren’t bolted in, enable him to go out with his father to a shooting range to participate in an activity that they both enjoyed.

It was a promising sign. Over the course of six months, the device collected data from Hajjar’s brain and picked up a constellation of brain waves that reflected the combined activity of thousands of neurons. “Like a symphony where you have some high-pitched instruments and some low-pitched instruments, we can take these brain signals and decompose them into frequencies in different ranges,” Rozell says.

Hajjar and the others in the study also had a weekly clinical assessment, which was videotaped. Within a couple of months, most participants felt somewhat better. After six months, symptoms had diminished by at least half in nine of the 10 individuals, and seven achieved remission. Only six of them, however, had usable brain data, and five of the six showed the typical pattern of improvement.

Using data from those five people, Rozell and his team built artificial intelligence software to compare participants’ brain wave patterns at the start of the study, when they were sick, with those patterns at the end, when they were better. The researchers found a coordinated change in a few frequency bands that could distinguish a sick brain from a brain that was well with 90 percent accuracy. “It’s the very first time that we’ve really been able to get a brain readout of recovery,” Rozell says.

The signal was the same for all the participants, but it showed up at different times: at eight weeks in one person and at 20 weeks in another, for example. When a doctor sees it, they know that regardless of their patient’s current state of mind, they can leave the stimulation as is, says Patricio Riva-Posse, the study’s lead psychiatrist. “There is an objective biomarker beyond my impression as a psychiatrist that can tell me, ‘Oh yes, this patient is slowly getting better,’” Riva-Posse says. It can also provide people being treated reassurance that they are on the right path. “We have a goal line for recovery,” Mayberg says.

The sixth participant with usable brain data showed an atypical trajectory after treatment. She felt better after the operation and stayed well for four months, but then she relapsed. The scientists looked for the wellness signal in her after the fact. She had it at the start of her treatment, but it disappeared a month before she relapsed—and so it could have served as a warning sign. “If we would have had it, we would have turned up [her stimulation] a month earlier. She might not have gotten into trouble,” Mayberg says.

Using artificial intelligence software, the researchers also found changes in a person’s face that paralleled the appearance of the brain’s wellness signal. Those changes fell short of a clinically useful biomarker, Rozell says, because the study was too small to define a pattern that was both specific for depression and common to all participants. Still, the finding points to the possibility of a more universal indicator of recovery. “We will build models that aren’t just for my small cohort of lucky patients but that could generalize to everybody,” Mayberg says.

Brain scans might also offer clues to wellness. Scans of the study participants’ brain before their surgery showed that the degree of damage to certain nerve fiber tracts correlated with the severity of their depression. The researchers could not look for a change in those tracts with the treatment, however, because the participants could not be put in a brain scanner once the implant was in place.

The latest DBS technology is compatible with brain imaging. A team at Mount Sinai has now implanted some of these new devices in another group of 10 participants and will look not only for the wellness biomarker but also for evidence of a repaired brain circuit, Mayberg says.

Formal approval of DBS for depression requires randomized controlled clinical trials. One earlier such trial targeting area 25 did not demonstrate a benefit over a sham procedure when its sponsor, St. Jude Medical (now Abbott), halted it in 2013 at the halfway point. Yet some people improved after the stopping point, and the accumulated results and lessons from small trials leave a lot of room for hope, experts say. (Another trial targeting a different place in the brain using a DBS system from Medtronic also had disappointing results.)

Despite these setbacks, the technology has not been abandoned as a depression treatment. “It’s a multibillion-dollar industry. People are going to keep trying until they get it,” Okun says. “They are getting closer, and the data is getting better and better as they see these groups improving their outcomes.”

Abbott is gearing up for a do-over. In July 2022 the U.S. Food and Drug Administration granted the company a breakthrough device designation for the use of the company’s DBS system in treatment-resistant depression, thereby expediting its development and, if all goes well, eventual approval. Abbott is now working with the FDA on a plan for a clinical trial, according to Jenn Wong, the company’s divisional vice president of global clinical and regulatory affairs in their neuromodulation business.

At the six-month mark, Hajjar went into remission. He started hanging out with friends he hadn’t seen in a while and was able to take on some temporary work. “I felt like I could get back into the world,” he recalls. He still struggled with anxiety, however, and in 2021 his depression began to reemerge. But adjustments to the stimulation brought him back.

Hajjar is now employed part-time and has had several speaking gigs in which he has shared his story with surgeons, scientists and medical students at conferences or over Zoom. He is even making tentative plans for the future—including pursuing his long-term interest in mechanical drafting. Perhaps most importantly, he has a new outlook on life. “I look forward to waking up in the morning,” he says.