A Brain Implant Fights Depression
Pam Belluck, New York Times, 10/5/2021

     Driving home from work in Northern California five years ago, a young woman was so overwhelmed with depression that all she could think about was ending her life. "I couldn't stop crying," recalled Sarah, now 38. "The thought that consumed me the entire way on that road was just driving my car into the marshland so I can drown." She made it home, but soon after, moved in with her parents because doctors considered it unsafe for her to live alone. No longer able to function at work, she quit her health technology job.She tried nearly every treatment: roughly 20 different medications, months in a hospital day program, electroconvulsive therapy, transcranial magnetic stimulation. But as with nearly a third of the more than 250 million people with depression world­wide, her symptoms persisted.
     Then Sarah became the first participant in an unusual study of an experimental therapy. Now, her depression is so manageable that she's taking data analysis classes, has moved to her own place and helps care for her mother, who suffered a fall. "Within a few weeks, the suicidal thoughts just disappeared," said Sarah, who asked to be identified by only her first name to protect her privacy. "Then it was just a gradual process where it was like my lens on the world changed."
     Researchers at the University of California, San Francisco, surgically implanted a battery-operated, matchbook-sized device in Sarah's brain — a "pacemaker for the brain" some call it — calibrated to detect the neural activity pattern that occurs when she is becoming depressed. It then delivers pulses of electrical stimulation to stave off depression. Twelve days after Sarah's device was fully operational in August 2020, her score on a standard depression scale dropped to 14 from 33, and several months later, it fell below 10, essentially signaling remission, the researchers reported. "The device has kept my depression at bay, allowing me to return to my best self and rebuild a life worth living," Sarah said.
     Sarah’s is the first documented case of personalizing a technique called deep brain stimulation to successfully treat depression. Much more research is needed before it's clear how effective the approach could be and for how many patients. But several teams of scientists are now working on ways to essentially match the electrical stimulation to what happens in a patient's brain. Deep brain stimulation is used to treat Parkinson's and several other disorders, but isn't approved by federal regulators for depression because results have been inconsistent. While some previous studies suggested benefits, two trials sponsored by U.S. device companies were stopped in the last decade because stimulation seemed no better than the placebo effect of a "sham" implant that provided no stimulation.
     But those studies didn't target individualized locations or patterns of electrical activity in people's brains. It was "one size fits all," said Dr. Darin Dougherty, director of neurotherapeutics at Massachusetts General Hospital, who worked on one of the halted trials. He called the personalized approach with Sarah, which he wasn't involved in, "very exciting."" One person's depression might look very different from another person's depression," said Dr. Katherine Scangos, an assistant professor of psychiatry at U.C.S.F. and an author of a report about Sarah's case, published Monday in the journal Nature Medicine. The senior authors were Dr. Andrew Krystal, an expert in neuro-modulation and mood disorders, and Dr. Edward Chang, whose work includes brain implants for paralyzed patients who cannot speak.
     To identify the specific brain activity pattern linked to Sarah's depression, researchers conducted an intensive 10-day exploration of Sarah's brain, placing multiple electrodes in it and asking about her feelings when they applied stimulation to different locations in varying doses.Sarah remembers an "aha moment" when she felt like "the Pillsbury Doughboy," emitting a "giant belly laugh," which she said was "the first time I spontaneously laughed and smiled" in five years. Another feeling resembled "being in front of warm fire and reading a comforting book," while a negative sensation felt like "nails on a chalkboard."
    Eventually, the team identified a specific pattern of electrical activity that coincided with Sarah becoming depressed. The exploratory phase guided the researchers to place the stimulation device in Sarah's right brain hemisphere linked to electrodes in two regions. One was the ventral striatum, involved in emotion, motivation and reward, where stimulation "consistently eliminated her feelings of depression"; and the other was the amygdala, where changes could "predict when her symptoms were most severe," Dr. Scangos said.
     While deep brain stimulation is typically delivered continuously, Sarah's device is set to supply only a six-second burst when it recognizes her depression-linked brain activity pattern. The goal, said Dr. Dougherty, is that stimulation will disrupt or shift the neural activity to produce a healthier pattern that will ease depressive symptoms. Sarah has continued taking psychiatric medications, and the stimulation hasn't eliminated depression-causing activity in her brain. But she can manage her illness much better, she said, instead of being unable to make even the smallest decisions, like what to eat. Now, "you're experiencing that whole negative, depressive, whatever the triggering thing is, and then it's like suddenly the ultra-rational side of you comes on and those emotions can be separated," she said in an interview, wearing a T-shirt that said "Take it easy lemon squeezy."
     That separation helps her productively use tools from talk therapy, like staying calm and maintaining perspective.About 30 percent of people with depression don't respond to standard treatments or find the side effects intolerable. Deep brain stimulation wouldn't be appropriate for all because it costs tens of thousands of dollars and brain surgery to implant the device carries risks like infection. But if the new attempts work, it might help a significant number, experts said. Dr. Chang said the research may also lead to noninvasive approaches that would help more people." Our job now is really to figure out what is it that identifies who needs this kind of intervention," said Dr. Helen Mayberg, director of the Center for Advanced Circuit Therapeutics at the Icahn School of Medicine in New York City, who pioneered the concept of deep brain stimulation for depression nearly 20 years ago.
     Dr. Mayberg uses a different method of individualization. With imaging, she finds the location in each person's brain where four white matter bundles intersect near a key depression-related region. After implanting electrodes and a stimulation device, "we pretty much set it and forget it," delivering stimulation continuously, while also helping patients with conventional therapy.Neural activity is monitored "to learn the brain signature that heralds an impending depressive relapse or need for a dose adjustment or just indicates that the person is just having a bad week," Dr. Mayberg said. She led one of the halted trials, but her work has also allowed patients to experience improvements that continue for years if stimulation is sustained.
     In another approach, Dr. Sameer Sheth, an associate professor of neurosurgery at Baylor College of Medicine, and colleagues study a patient's specific brain activity pattern to identify which of billions of combinations of stimulation characteristics, like frequency and amplitude, improve that patient's depression. He then tunes electrodes in two regions and applies that specific combination as continuous stimulation. Dr. Sheth said the first patient, given the device in March 2020, "is remarkably well" now, maintaining a relationship and becoming a father. To test for a placebo effect, researchers gradually stopped stimulation to one brain region without the patient knowing when. His depression "got worse and worse" said Dr. Sheth, until he needed a "rescue." After stimulation restarted, he improved, suggesting the effect "is definitely stimulation-related."
     Several months ago, Sarah needed a rescue too. Shortly after entering a study phase where the device is either turned off or left on for six weeks without the participant knowing which, "the suicidal thoughts were back," Sarah said."She did have a very severe worsening of her depression," said Dr. Scangos. She said she couldn't disclose whether stimulation had been off or on, but said a device company technician was sent to Sarah's home to "make a rescue change." Afterward, Sarah said, she improved again.
     Over the year, the number of times a day that Sarah's device has detected depression-linked brain activity and delivered stimulation has decreased somewhat, but is still substantial, Dr. Scangos said. Still, some days Sarah doesn't need the maximum amount the device is set to provide: 300 times or 30 total minutes daily. (It stops around 6 p.m. because evening stimulation made her too alert to sleep.) Longer-term and more detailed data on Sarah will be published later, said the researchers, who have two other participants so far.The device is intentionally tuned so Sarah cannot feel the stimulation, but she believes she knows that it's occurred because she subsequently develops a sense of "emotional distance" that keeps negative feelings "compartmentalized," she said. Also, "I feel alert," she said. "I feel present." That's "a really good sign," said Dr. Dougherty, who is considering using a similar approach for depression and possibly addiction. "The emotions are still there, but instead of sticking like mud, it's running off like water.
     "To help researchers correlate brain activity with emotional states, two or three times a day, Sarah holds a doughnut-shaped magnet to her head, triggering the device to save the next 90 seconds of neural activity, and she completes a mental health survey. She's been encouraged to pick moments "when she's in a very good mood or a bad mood," Dr. Scangos said. Also, twice daily, 12 minutes of neural data are automatically relayed to the device company and researchers.One question, experts said, is whether Sarah's results support the theory that stimulating briefly whenever depression begins works because it keeps the brain from becoming accustomed to the treatment. Or, Dr. Sheth asked, does Sarah's need for many daily doses after a year suggest continuous stimulation would be as or more effective? Another question is whether the therapy can prompt lasting brain changes to eventually avert depression with little or no continuing stimulation.
     Researchers, several of whom consult for device companies or have patents related to deep brain stimulation, expect it will take years to learn if individualized approaches are effective enough to be approved. Different methods might work for different people's depression, and individualized stimulation might eventually help other psychiatric disorders, researcher say. When depressed, Sarah, a passionate cook and foodie, had such slow reflexes and trouble functioning that she'd cut or burn herself in the kitchen and doctors told her it wasn't safe to cook anymore. Foods had little flavor. But after receiving the device, she ate Vietnamese pho in the hospital cafeteria and was thrilled she could taste "the brightness and the herbs," she said. -While being driven home from the hospital, she saw the marshes and exclaimed: "God, the color differentiation is gorgeous." Now, she said, she's "seeing things that are beautiful in the world, and when I was in the depths of depression, all I saw was what was ugly.

How Do You Serve A Friend in Despair?
David Brooks, New York Times, 2/12/2023

My friendship with Peter Marks was created around play. Starting at age 11, we played basketball, softball, capture the flag, rugby. We teased each other, pulled pranks, made fun of each other's dance moves and pretty much everything else. We could turn eating a burger into a form of play, with elaborate smacking of lips and operatic exclamations about the excellence of the cheese. We kept it up for five decades.

     My wife has a phrase that got Pete just right — a rare combo of normal and extraordinary: masculine in the way you're supposed to be masculine, with great strength and great gentleness. A father in the way you're supposed to be a father, with great devotion, fun and pride. A husband the way you are supposed to be a husband, going home at night grateful because the person in the whole world you want to talk with the most is going to be sitting right there across the dinner table.

     Over the years, Pete and I often spoke about the stresses he was enduring over the management of his medical practice, but I didn't see the depths of what he was going through until we spent a weekend with him in the spring of 2019. My wife noticed a change immediately. A light had gone out; there was an uncharacteristic flatness in his voice and a stillness in his eyes. One bright June afternoon, he pulled us aside and told us he wasn't himself. He was doing what he loved most — playing basketball, swimming in the lake — but he couldn't enjoy anything. He was worried for his family and himself and asked for our continued friendship and support. It was the first time I had seen such pain in him — what turned out to be severe depression. I was confronted with a question for which I had no preparation: How do you serve a friend who is hit with this illness?

     I tried the best I could, but Pete succumbed to suicide last April. This article flows from what I learned from those agonizing three years and that senseless tragedy. It reflects a hard education with no panaceas.

     First, I need to tell you more about Pete. We met as kids at Incarnation Camp in Connecticut. We were campers and counselors together for a decade and remained close for life. At camp, Pete was handsome, strong, athletic and kind. There was an exuberant goof-ballism about him.

     I remember once, in a fit of high silliness, he started skipping around the dining hall, singing, and leaping higher and higher with each skip. He tried to skip right out of the room, but there was a doorframe, probably about seven feet tall, and Pete slammed into the top of the frame and fell flat on his back. The rest of us, being 16-year-old junior counselors, found this utterly hilarious. Pete, also being 16, found this utterly hilarious, too. I remember him lying there in a fit of giggles, with a doorframe-shaped bruise forming on his brow.

     One summer, Pete and I led a team of 12-and 13-year-olds in a softball game against a team of 14- and 15-year-olds. Our team miraculously won. In the celebration afterward, Pete, the boys and I piled on one another on the mound in a great wriggling heap of disproportionate ecstasy. We hugged and screamed and high-fived. I think our celebration lasted longer than the game — a volcano-like pile of male self-approval that is lodged in my memory as one of life's moments of pure joy.

     As the years went by, Pete did well in college, joined the Navy, went to medical school and became an eye surgeon. On evenings before surgery, Pete took great care of himself, didn't stay out, made sure he had enough sleep to do the job that he loved. On evenings after surgery, he'd call his patients to see how they were feeling. His wife, Jen, a dear friend who was also at camp with us, used to linger around just to hear the gentleness of his tone on those calls, the reassuring kindness of his manner.

     He seemed, outwardly, like the person in my circle least likely to be afflicted by a devastating depression, with a cheerful disposition, a happy marriage, a rewarding career and two truly wonderful sons, Owen and James. But he was carrying more childhood trauma than I knew, and depression eventually overwhelmed him.

      At first, I did not understand the seriousness of the situation. That's partly temperamental. Some people catastrophize and imagine the worst. I tend to bright-icize and assume that everything will work out. But it's also partly because I didn't realize that depression had created another Pete. I had very definite ideas in my head about who Pete was, and depression was not part of how I understood my friend.

     Over the next months, severe depression was revealed to me as an unimagined abyss. I learned that those of us lucky enough never to have experienced serious depression cannot understand what it is like just by extrapolating from our own periods of sadness. As the philosophers Cecily Whiteley and Jonathan Birch have written, it is not just sorrow; it is a state of consciousness that distorts perceptions of time, space and self. The journalist Sally Brampton called depression a landscape that "is cold and black and empty. It is more terrifying and more horrible than anywhere I have ever been, even in my nightmares."

     The novelist William Styron wrote brilliantly about his own depression in "Darkness Visible." He wrote that "the madness of depression is, generally speaking, the antithesis of violence. It is a storm indeed, but a storm of murk. Soon evident are the slowed-down responses, near paralysis, psychic energy throttled back close to zero." He continued: "I experienced a curious inner convulsion that I can describe only as despair beyond despair. It came out of the cold night; I did not think such anguish possible."

     During the Covid pandemic, Pete and I spoke by phone. In the beginning, I made the mistake of trying to advise him about how he could lift his depression. He had earlier gone to Vietnam to perform eye surgeries for those who were too poor to afford them. I told him he should do that again, since he found it so tremendously rewarding. I did not realize it was energy and desire that he lacked, not ideas about things to do. It's only later that I read that when you give a depressed person advice on how to get better, there's a good chance all you are doing is telling the person that you just don't get it.

     I tried to remind Pete of all the wonderful blessings he enjoyed, what psychologists call "positive reframing." I've since read that this might make sufferers feel even worse about themselves for not being able to enjoy all the things that are palpably enjoyable.

     I learned, very gradually, that a friend's job in these circumstances is not to cheer the person up. It's to acknowledge the reality of the situation; it's to hear, respect and love the person; it's to show that you haven't given up on him or her, that you haven't walked away. Time and again Pete would talk about his great fear that he would someday lose his skill as a surgeon, that he would cease to be a healer, that he would lose his identity and self.

     As Pete spoke of his illness, it sometimes seemed as if there were two of him. There was the one enveloped in pain and the other one who was observing himself and could not understand what was happening. That second self was the Pete I spoke to for those three years. He was analyzing the anguish. He was trying to figure it out. He was going to the best doctors. They were trying one approach after another. The cloud would not lift.

     I am told that one of the brutalities of the illness is the impossibility of articulating exactly what the pain consists of. Pete would give me the general truth, "Depression sucks." But he tried not to burden me with the full horrors of what he was going through. There was a lot he didn't tell me, at least until the end, or not at all.

     I never told him this, but there were moments during that hard plague year of 2020 that I feared that my own mind was slipping. Cheerfulness is my normal default state, but that year my moods could be dark and troubled. When your oldest friend is battling his demons, it's natural to wonder about your own.

     While I've devoted my life to words, I increasingly felt the futility of words to help Pete in any meaningful way. The feeling of impotence was existential. After a while, I just tried to be normal. I just tried to be the easygoing friend who always had been to him and he had been to me. I hoped this would slightly ease his sense of isolation. Intellectually, Pete knew that his wife and boys lavishly loved him, that his friends loved him, but he still felt locked inside the lacerating self-obsession that was part of the illness.

     Perhaps the most useful thing I did was send him a video. My friend Mike Gerson, a Washington Post columnist, had been hospitalized with depression in early 2019. He had delivered a beautiful sermon at the Washington National Cathedral about his experience before he died of complications of cancer last November. Depression, he said, was a "malfunction of the instrument we use to determine reality." Then he talked about the lying voices that had taken up residence in his mind, spewing out their vicious clichés: You are a burden to your friends, you have no future, no one would miss you.

     That resonated with Pete and gave him a sense of validation. He, too, would describe the obsessive-compulsive voices that would attack him from inside his own head. Mike also talked about the fog eventually thinning, at the glimpse of beauty or of love, and reminded Pete that "there is something better on the far side of despair."

     Still the clouds refused to lift. Jen had some wise words when I asked her what she learned being around him during those years. "I was very aware this was not the real Pete," she said. "I tried not to take his periods of negativity and withdrawal personally."

     I wish I had bombarded Pete with more small touches. Just small emails to let him know how much he was on my mind. Writing about his own depression in The Atlantic last year, Jeffrey Ruoff mentioned that his brother sent him over 700 postcards over the years, from all 50 states, Central America, Canada and Asia. Those kinds of touches say: I'm with you. No response necessary "There are moments in our lives," Honore de Balzac wrote, "when the sense that our friend is near is all that we can bear. Our wounds smart under the consoling words that only reveal the depths of pain."

     The years went by and medications and treatment programs continued to fail. Pete and Jen began to realize how little the medical community knows about what will work. They also began to realize that mental health care is shockingly siloed. Pete saw outstanding doctors who devoted themselves to him, but they work only within their specific treatment silo. When one treatment didn't work, Pete would get shuttled off to some other silo to begin again. Jen recently emailed me that when she had a cancer recurrence, in the middle of Pete's depression, she had a "tumor board" —three different cancer experts (a surgeon, an oncologist and a radiation on­cologist) — who coordinated her care.

     "In our experience, there is none of this in mental health," she wrote me. In many places, there is no one looking at the whole picture and the whole patient. "If one more mental health professional tells me 'Everyone did their best,' I will scream," Jen wrote. "If this is our best, it is not nearly good enough."

     Pete developed theories to explain why this had happened to him. He pointed to a series of traumas and neglect he had suffered at home as a child — events he had vaguely referred to during our friendship but had never gone into in detail with me until his final years. He thought part of his illness was just straight biology. Think of it like brain cancer, he'd say. A random physical disease. I agree with some of that, but I'm also haunted by the large nunber of medications doctors put him on. He always seemed to be getting on one or getting off another as he ran through various treatment regimens. His path through the mental health care system was filled with a scattershot array of treatments and crushing disappointments.

     Pete and his family joined us for Thanksgiving in 2021. By this point I was just trying to be as I always had been toward him, in hopes that he might be able to be as he always had been toward me. We all played basketball and board games and enjoyed the weekend. I felt some hope. But Pete appears in one of the photos that were taken that weekend, sitting on the couch, still-faced, enveloped in shadow. One afternoon, he asked my wife to pray over him in the kitchen, plaintively, grasping for hope.

     The experts say if you know someone who is depressed, it's OK to ask explicitly about suicide. The experts emphasize that you're not going to be putting the thought into the person's head. Very often it's already on her or his mind. And if it is, the person should be getting professional help.

     When Pete and I gestured toward the subject of suicide, we just talked about what a magnificent family he had, how much they, all loved one another. Like Jen, I tried to tell him that this darkness would lift, though as the years went by and the therapies failed, his faith in this deliverance waned.

     Pete was always the braver of the two of us. He was the one who would go cliff diving or jump over bonfires without fear. And he was never more courageous than over his last three years. He fought this malady with astonishing courage and steadfastness against a foe that would bring anybody to his knees. He fought it minute by minute, day by day — over a thousand days. He was driven by his selfless love for his family, which he cherished most in the world.

     We had dinner a few days before he died. Jen and I tried to keep the conversation bouncing along. But, apparently, their car ride home was heart-rending. "How can I not be able to talk to my oldest friend?" Pete asked. "Brooksie can talk to people. I can't."

     Depression can be bitterly ridiculous. Pete died a few weeks before his younger son's college graduation, enmeshed by loving relationships and friendships. It's ridiculous that we still know so little about the illness and how to treat it. I find it unfathomable that it's been well over a century since Sigmund Freud started writing about psychology. We've had generations of scholars and scientists working in this field, and yet suicide rates in 2020 were 30% higher than they were in 2000 and one in five American adults experience mental illness each year. We need much more research funding to figure this out.

     If I'm ever in a similar situation again, I'll know that you don't have to try to coax somebody out of depression. It's enough to show that you are trying to understand what this troubled soul is enduring. It's enough to create an atmosphere in which the sufferer can share her experience. It's enough to offer him or her the comfort of being seen.

     My friend Nat Eddy, who also accompanied Pete through those final years, wrote to me recently: "Do whatever it is you do to give the wives and children a break — an hour or two when they don't have to worry that the worst will happen (and pray that it doesn't happen on your watch, because that isn't a given). Do whatever it is you do so you can look at yourself in the mirror. True friendship offers deep satisfactions, but it also imposes vulnerabilities and obligations, and to pretend it doesn't is to devalue friendship."

     I feel sorrow that I didn't know enough to do this more effectively with Pete. I might have kept him company more soothingly. I might have made him better understand what he meant to me. But I do not feel guilt.

     Pete had teams of experts walking with him through this. He had his wonderful wife and kids, who accompanied him lovingly and steadfastly every day. I've talked to Jen about this. Pete used to say he found talking to Jen more helpful than talking to any of the experts. So there is no reason for any of us to feel like failures because we could not alter what happened. Every case of depression is unique, and every case is to be fought with as much love and endurance and knowledge as can be mustered. But in this particular case, the beast was bigger than Pete; it was bigger than us.

     I feel like I've read a lot about the grieving process for family members but not so much about what grieving is like when your friends die. Death and I were too well acquainted last year. I lost three good friends — Pete, Mike Gerson and my longtime "NewsHour" partner, Mark Shields. I've been surprised by how profound and lasting the inner aches have been.

Pete's death has been a cause of great disorientation. He'd been a presence for practically my whole life, and now the steady friendship I took for granted is gone. It's as if I went to Montana and suddenly the mountains had disappeared.

     One great source of comfort has been the chance to glimpse, from time to time, how heroically Pete's boys, Owen and James, have handled this loss. In their own grief, they have rallied forcefully and lovingly around their mother. Two months after Pete's passing, my eldest son married. To my great astonishment and gratitude, Jen and the boys were able to make the trip to attend. At the reception, the boys gently coaxed their mother to join us on the dance floor. It felt appropriate since this is what we did at camp; dancing skeined through the decades of our lives. I have a sharp memory of those two fine young men dancing that evening, and a million memories of the parents who raised them so well.