Like seismic sensors planted in quiet ground, hundreds of tiny electrodes rested in the outer layer of the 44-year-old woman’s brain. These sensors, each slightly larger than a sesame seed, had been implanted under her skull to listen for the first rumblings of epileptic seizures.
The electrodes gave researchers unprecedented access to the patient’s brain. With the woman’s permission, scientists at the University of California, San Francisco began using those electrodes to do more than listen; they kicked off tiny electrical earthquakes at different spots in her brain.
Most of the electrical pulses went completely unnoticed by the patient. But researchers finally got the effect they were hunting for by targeting the brain area just behind her eyes. Asked how she felt, the woman answered: “Calmer in my nerves.”
Zapping the same spot in other participants’ brains evoked similar responses: “I feel positive, relaxed,” said a 53-year-old woman. A 60-year-old man described “starting to feel a little more alive, a little more energy.” With stimulation to that one part of the brain, “participants would sit up a little straighter and seem a little bit more alert,” says UCSF neuroscientist Kristin Sellers.
Such positive mood changes in response to light neural jolts, described in the Dec. 17 Current Biology, bring researchers closer to an audacious goal: a device implanted into the brains of severely depressed people to detect a looming crisis coming on and zap the brain out of it.
It sounds farfetched, and it is. The project is “fundamental, pioneering, discovery neuroscience,” says Mark George, a psychiatrist and neurologist at the Medical University of South Carolina in Charleston. George has been studying depression for 30 years. “It’s like sending a spacecraft to the moon.”
Still, in the last several years, teams of scientists have made startling amounts of progress, both in their ability to spot the neural signatures that come with a low mood and to change a person’s feelings.
With powerful computational methods, scientists have recently zeroed in on some key features of depressed brains. Those hallmarks include certain types of brain waves in specific locations, like the one just behind and slightly above the eyes. Other researchers are focused on how to correct the faulty brain activity that underlies depression.
A small, implantable device capable of both learning the brain’s language and then tweaking the script when the story gets dark would be an immensely important clinical tool. Of the 16.2 million U.S. adults with severe depression, about a third don’t respond to conventional treatments. “That’s a huge number of people with a very disabling and probably underdiagnosed and underappreciated illness,” says neurologist Vikram Rao, who is working on the UCSF project with Sellers.
A disease of circuits
When George began studying depression decades ago, the field was still haunted by Sigmund Freud, who blamed the disorder on bad parenting and repressed anger. Soon after came the chemical imbalance concept, which held that the brain just needs a dash of the right chemical signal to fix itself. “It was the ‘brain is soup’ model,” George says. Toss in more of the crucial ingredient — serotonin, for instance — and the recipe would sing.
“We have a very different view now,” George says. Thanks to advances in brain imaging, scientists see depression as a disorder of neural circuits — altered connections between important brain regions can tip a person into a depressed state. “We’ve started to define the road map of depression,” George says.
Depression is a disorder, but one that’s tightly linked to emotion. It turns out that emotions span much of the brain. “Emotions are more widespread than we thought,” says cognitive neuroscientist Kevin LaBar. With his colleagues at Duke University, LaBar has used functional MRI scans to find signatures of certain emotions throughout the brain as people are feeling those emotions. He found the wide neural reach of sorrow, for instance, by prompting the emotion with gloomy songs and films.
Functional MRI allows scientists to see the entire scope of a working brain, but that wide view comes with the trade-off of lower resolution. And resolution is what’s needed to precisely and quickly sense — and change — brain activity. Implanting electrodes, like those used in the UCSF project, gives a more nuanced look into select brain areas. Those detailed recordings, taken from people undergoing epilepsy treatment, are what allowed neural engineer Maryam Shanechi to decode the brain’s emotions with precision.
As seven patients spent time in the hospital with electrodes monitoring brain activity, their emotions naturally changed. Every so often, the participants would answer mood-related questions on a tablet computer so that researchers could measure when the patients shifted between emotions. Then Shanechi, of the University of Southern California in Los Angeles, and her colleagues matched the brain activity data to the moods.
The task wasn’t simple. The implanted electrodes recorded an enormous pile of data, much of it irrelevant to mood. Shanechi and her team developed an algorithm to distill all that data into a few key predictive brain regions for each person. The resulting decoder could tell what mood a person was in based on brain activity alone, the team reported in the October Nature Biotechnology. “In every single individual, we can show how their mood changes in real time,” Shanechi says.
Data from electrodes monitoring brain activity helped researchers predict the moods of seven people over time (each icon shape represents one person). The closer an icon is to the diagonal line, the better the prediction matched self-reported mood.
Mood prediction versus self-reports
Source: O.G. Sani et al/Nature Biotechnology 2018
It’s possible that the brains of people with epilepsy might handle emotions differently, but researchers still think that the results will hold more generally. In the seven people tested, each brain had its own hot spots that predicted mood. But there were commonalities, too. In four patients, one of the most predictive spots was the orbitofrontal cortex — that spot just behind the eyes that the UCSF scientists stimulated to boost mood. “We were excited because we had arrived at those results independently,” Shanechi says. “They seem to all point to the important role of the orbitofrontal cortex.”
Among brain regions, the orbitofrontal cortex may be one of the top networkers. It has links to diverse brain systems, many of which may be important for mood. “We’re not saying that this is necessarily the best location to stimulate, but it’s definitely a way to tap into that network,” Sellers says. “There may be multiple different on-ramps to get on to this interstate.”
Other work at UCSF, led by neurosurgeon Edward Chang and psychiatrist Vikaas Sohal, turned up different changes thought to be involved in depression: brain waves that carry messages between the hippocampus and the amygdala. Those two brain structures “tend to be quiet, then have a whole bunch of brief bursts of activity,” Sohal says. For 13 of 21 patients with epilepsy, those bursts signaled lower moods, the researchers reported in the Nov. 29 Cell.
These studies add exquisite details to the brain map of depression, but on their own, these depression signatures are not enough, Shanechi says. “Let’s say I know somebody’s mood perfectly,” she says. “I still don’t know how to stimulate their brain to change their mood.”
Doctors and scientists have been using electricity to jolt brains out of depression for decades. Electroconvulsive therapy, first used in the 1930s, had become a common depression treatment by the 1950s. The modern form of the therapy, which somehow resets the brain by sparking seizures, is still one of the more effective treatments for people whose severe depression hasn’t responded to other interventions.
Other brain stimulation methods used for depression include transcranial direct current stimulation (tDCS), which relies on electrodes that rest on the surface of the scalp. Although still under study, tDCS is a favorite among home brain hackers eager to lift their moods or improve their minds (SN: 11/15/14, p. 22). Even deep-brain stimulation, which curbs some symptoms of Parkinson’s disease, has been tried. But the technique requires surgery, and the implanted stimulators have to be adjusted manually.
Old and new
Different stimulation methods deliver various amounts of electrical current to the brain. The oldest, electroconvulsive therapy, injects the most current compared with other methods, such as transcranial alternating current stimulation.
Electricity delivery approaches for depression over the years
Initial clinical attempts to treat depression with deep-brain stimulation were almost brute force sorts of stimulation. “We stuck the wire in and we turned it on all the time at high frequency,” George says. That constant, full-blast stimulation created a sort of jamming signal — with mixed results. It helped some people tremendously but not others. After some success in lifting depression in a handful of people, a larger clinical trial, reported in 2017 in the Lancet Psychiatry, showed no positive effect. (Some researchers who study deep-brain stimulation have argued the trial was flawed.)
“We need to have a smarter approach, rather than, ‘Put it in, turn it on and leave it on,’ ” says Darin Dougherty, a psychiatrist at Massachusetts General Hospital in Boston who is working on new stimulation methods. A system that can change its behavior depending on the patient’s needs would ultimately enable better levels of control, he says, by “driving the system in real time and steering it.”
Dougherty’s collaborator Alik Widge is working on the steering. He and colleagues are studying how to inject the right dose of electrical medicine, at the right time and in the right spot, to skillfully drive these complicated brain circuits. In unpublished work in people with epilepsy, Widge, Dougherty and colleagues were able to stimulate brains in a way that slightly changed their neural state, and as a consequence, people’s behavior, Widge says.
DARPA, a Department of Defense research agency, is funding this project plus work at UCLA on targeted brain stimulation. Now in its fifth and final year, the project, called SUBNETS, aims to help veterans with major depression, post-traumatic stress, anxiety and other psychiatric problems. “It is extremely frustrating for patients to not know why they feel the way they do and to not be able to correct it,” Justin Sanchez, the director of DARPA’s Biological Technologies Office, said in a Nov. 30 statement. “We owe them and their families better options.”
These next-generation systems, primarily being developed at UCSF and Massachusetts General Hospital, might ultimately deliver. After detecting altered brain activity that signals a looming problem, these devices, called closed-loop stimulators, would intervene electrically with what their inventors hope is surgical precision.
In contrast to the UCSF group, Widge, who is at the University of Minnesota in Minneapolis, and his collaborators don’t focus explicitly on mood. The researchers want to avoid categorical diagnoses such as depression, which they argue can be imprecise. Major depression is not the same disease for everyone. Causes and symptoms can differ greatly from person to person. Instead of grouping people by diagnosis, Widge and his team are going after brain circuits that are involved in traits that can be measured in the lab, such as cognitive flexibility (the ability to quickly shift strategies) and emotional regulation. These brain traits can then ultimately be tied to certain brain disorders, the researchers think.
In their trials, Widge, Dougherty and colleagues enlisted people who, like those in the UCSF trials, already had electrodes implanted for epilepsy treatment. Certain kinds of stimulation delivered to specific spots made participants slightly more likely to behave a certain way on computer tasks — emphasis on “slightly,” Widge cautions. “One of the fascinating things that we keep running into is that the brain really has some pretty hard ceilings on this,” he says. “You can move someone 5 percent or 10 percent, but you can’t totally change them.” A depressed person might begin to venture outside, take a short walk, visit a café, but a bigger shift is unlikely.
This type of influence might be able to nudge someone to choose chocolate ice cream over vanilla, for instance. “But if you hate nuts, there’s no way I’ll be able to make you choose butter pecan,” Widge says.
Animal studies and computer simulations by Widge take aim at characterizing the best ways to nudge neural circuits. Stimulation might be most effective when it works with the timing of the brain’s existing brain waves, he and colleagues reported December 5 in PLOS ONE. “It’s almost like trying to do aikido with the brain,” Widge says. “You’re trying to find this point at which the activity is perfectly poised so that all you have to do is give it a little bit of a push.” Deliver the right nudge at the right time to the right spot, and the hope is that “the whole thing will cascade in exactly the direction you want it to,” Widge says.
Shanechi’s group is also trying to learn how best to stimulate the brain. Using computational models, she and colleagues recently predicted how certain kinds of stimulation would change depression-related brain activity in controlled ways, keeping the relevant circuit behavior tightly within a healthy range. Shanechi has been testing those mathematical predictions, published in the December Journal of Neural Engineering, in people with implanted electrodes. She is delivering the sorts of electrical stimulation that her models pointed to and monitoring the effects.
Clues about how best to stimulate also emerged from the study in Current Biology, which described the 44-year-old woman’s calm mood during stimulation. Single and continuous electrical stimulation in the orbitofrontal cortex had different effects in neural tissue both near and far, the researchers found. This sort of neural tinkering — delivering certain kinds and doses of electrical current and seeing how the signals reverberate — is a crucial part of devising closed-loop systems.
The future isn’t now
It may seem unsettling for someone to go about daily life with a device that dwells in the brain and has the power to influence emotions. But researchers point out that lots of things change our moods, such as meditation, exercise and alcohol. Don’t forget the anti-depressants, taken by nearly 13 percent of people over the age of 12 in the United States. “We think nothing of taking a pill to change our mood and improve our emotions,” George says. “I don’t think it’s much different with a device.”
Of course, that device doesn’t exist yet. Scientists still aren’t certain where to stimulate and how — questions that probably have different answers for everyone, the data suggest. And even if the protocols were clear, the hardware that does the work still isn’t ready. In the recent mood-altering studies, wires emerging from under people’s skulls were attached to large external computers, not ideal for moving around.
To succeed, all of the hardware needs to fit under the skull, where it would perform lightning-quick assessments and figure out how to tweak neural behavior when needed. That goal is a long way off, Widge says. The whole system — including the electrodes, the processor and the power source — needs more refinement to be nimble enough to handle complex algorithms, durable enough to reside permanently inside a living person and powerful enough to avoid the need for frequent battery replacements.
Researchers imagine one day using such a device, and the theories that drive it, for problems other than depression. “If you find it works for mood, why not use it for other problems, like addictions?” asks George, who dreams of an implant that could detect an opioid craving and instantly counter it.
In fact, some of the brain circuits that Widge, Dougherty and colleagues are trying to influence are involved in a person’s predilection to seek new experiences. And that trait, called novelty-seeking, tracks closely with drug use. The ability to monitor and control that particular tangle of brain circuitry could ultimately lead to the device of George’s dreams.
For now, the possibilities are wide open, experts say. Chances are good that in the coming years scientists will gain the ability to tap into the brain and influence it in precise ways. After all, perhaps more than any other part of the body, the brain is designed to continuously transform.
“Evolution spent billions of years giving us a brain that’s fully capable of changing itself,” Widge says. The brain can get itself into a depressed state, but it is also capable of getting itself out of one. “The machinery is all there,” he says. “We just need to figure out how to work it.”