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    The growing field of neurotherapeutics offers psychiatric patients new hope

    When all else fails, brain procedures help patients with treatment-resistant psychiatric disorders. But physicians who perform them still grapple with complex ethical questions and the lingering history of lobotomies.

    In transcranial magnetic stimulation (TMS), an external device is used to drive electromagnetic pulses through the skull to improve mood.

    In transcranial magnetic stimulation (TMS), an external device is used to drive electromagnetic pulses through the skull to improve mood.

    At 42, Sarah Miller* was plagued by strange fears and dark thoughts. She worried she would suddenly collapse while holding her baby. At the grocery store, the New Hampshire mom couldn’t make herself let go of the shopping cart. At times, she feared she might harm herself.

    By the time her son turned 2, Miller had been hospitalized more than five times. Medications and therapy hardly helped. So Miller decided to undergo surgery to help coax her brain onto a healthier course.

    Physicians implanted electrodes in her brain to modulate emotion-related neurons — a procedure called deep brain stimulation (DBS) — and the results were dramatic. “It almost felt like I snapped my fingers and got better,” she says of the surgery performed at Massachusetts General Hospital (MGH) in Boston.

    Four years later, the implants are still working. “I’m not scared to go for a walk or drive my car. I can volunteer in my son’s kindergarten,” says Miller. “I can’t believe how much my life has changed.”

    Miller benefited from the growing field of neurotherapeutics, which uses various types of invasive and non-invasive technologies to retrain misfiring neurons and reorganize neural pathways.

    The field — also known as interventional psychiatry — is often a last resort when other forms of psychiatric treatment, including medications and psychotherapy, have failed. So far, it has proven most effective for treatment-resistant depression (TRD) and treatment-resistant obsessive-compulsive disorder (OCD).

    These conditions are common. Roughly 30% of patients with major depression — about 2.8 million U.S. adults — are considered treatment-resistant. Rates of treatment-resistant OCD are similar.

    Of course, the notion of tampering with the brain can be disconcerting. “It can sound like we’re controlling the brain. Really, we’re just giving it a slight nudge,” says Darin Dougherty, MD, director of the Division of Neurotherapeutics at MGH.

    The disturbing history of lobotomy also hangs over the field, Dougherty says. “In the past, doctors would cut into a huge territory [of the brain]. Now, we work in an area that’s a cubic centimeter,” he says. “It’s an entirely different field.”

    Still, practitioners recognize the unique ethical issues involved. “We’re in the brain," says Dougherty. “This is the essence of who we are.”

    To address those issues, an international, interdisciplinary consortium released recommendations for psychiatric surgery in 2022. And the National Institutes of Health (NIH) funds research exploring the ethical questions raised by brain-related technologies.

    “It can sound like we’re controlling the brain. Really, we’re just giving it a slight nudge.”

    Darin Dougherty, MD
    Mass General Hospital

    Practitioners also acknowledge that the procedures are not appropriate for all patients and have potential side effects, but say they are at times crucial.

    “These are patients who have tried everything, and we have nothing else left to offer them,” says Ben Shofty, MD, PhD, a neurosurgeon at University of Utah Health in Salt Lake City. “These procedures can save lives.”

    Powerful procedures

    Brain procedures for mental illnesses started gaining ground in the 1990s, after it became clear that even the best medications and psychotherapy were failing many patients.

    The results were often impressive. “We’ve seen improvement in around 65% of patients with many of these procedures. That’s quite high,” says Shofty.

    “These procedures are not complete cures, so people generally still need medication and therapy, but they often can go back to normal life,” Shofty adds.

    Still, patients understandably harbor fears, including possible personality changes. “They ask, ‘Will I be a different person?’” says Shofty. “But all psychiatric interventions, including psychotherapy, change people. Here, the change is usually relief from suffering.”

    Neurotherapeutic approaches cover a spectrum, from noninvasive, outpatient procedures to more complex brain surgeries. But all share a common approach to psychiatric care.

    “Unlike pharmacology, which focuses on brain chemistry, we look at psychiatric illnesses as a matter of malfunctioning electrical circuits and try to impact those circuits for therapeutic effect,” says Dougherty.

    Brain stimulation sans surgery

    Among non-invasive neurological techniques are those that impact the brain via high-power magnets or electrical shocks.

    In transcranial magnetic stimulation (TMS), an external device drives electromagnetic pulses through the skull to alter brain activity. Side effects can include headache and scalp discomfort and twitching of facial muscles during the treatment.

    TMS can be time-consuming. At most centers, TMS patients attend 20-minute sessions daily for around six weeks. But a newer approach offers several brief sessions in one day, explains Martijn Figee, MD, PhD, director of the Interventional Psychiatry Program at Mount Sinai Hospital in Manhattan. “With that approach, it can take just a couple of days to get better. In psychiatry, it’s very unusual to see improvement that fast,” he says.

    So far, TMS is approved by the Food and Drug Administration (FDA) for OCD and TRD. Like other treatments, TMS is used off-label for additional psychiatric conditions, but with less supporting evidence.

    Exactly how TMS works isn’t clear, but it can be quite effective. For example, studies have found it can bring relief to 50% to 60% of TRD patients.

    David Kraft*, a writer in New York City, found TMS helpful for his OCD and depression. “I was constantly having fears of inadvertently harming others … and an urgent sense of needing to act to prevent the danger,” says the 70-year-old. “I still might have [such feelings] now, but TMS gave me the ability to resist the temptation of the OCD rituals.”

    For TRD patients with more severe symptoms, or for those not helped by TMS, another therapy — electroconvulsive therapy (ECT) — may be appropriate.

    ECT involves inducing a brain seizure via electrode pads placed on the scalp.

    “It’s not nearly as scary as it sounds,” says Amy Aloysi, MD, MPH, director of the Mount Sinai ECT Program. Unlike in the past, “it doesn’t involve actual convulsions because patients receive a muscle relaxant. Sometimes, it can be done on an outpatient basis.”

    ECT requires anesthesia so it’s usually performed in a hospital. Patients generally require treatment three times a week for 2-4 weeks, followed by a gradual tapering off and additional treatments later if necessary, says Aloysi.

    Side effects include headache, muscle aches, nausea, and temporary memory loss. Providers also now better understand how to mitigate any cognitive side effects, such as by using ultra-brief electrical pulses. And many patients find that any side effects are worth the benefits of the procedure. “We had a patient who kept needing hospitalization for severe depression,” Aloysi says. “Since starting ECT several years ago, he hasn’t needed hospitalization once.”

    Implants that alter mood

    When TMS and ECT don’t work or aren’t appropriate, physicians may suggest brain-stimulating implants, an approach that requires surgery.

    In vagus nerve stimulation (VNS), a surgeon wraps a wire around a nerve in the neck that sends signals to the brain. A battery implanted in the chest wall triggers 30-second pulses every few minutes that affect the activity of mood-related neurotransmitters. “It’s like a pacemaker for the brain,” explains Figee.

    Some potential VNS side effects are serious, such as infection and other surgical complications, while others are simply annoying, like hoarseness from the current. The procedure, which is FDA-approved for TRD, takes about one hour and is done on an outpatient basis, but it can take months to provide relief.

    In deep brain stimulation (DBS), the procedure that Miller underwent, implants are inserted directly in the brain.

    “Four electrodes about the size of a toothpick are placed through a tiny hole in the skull and connected via a wire to a battery in the chest,” explains Aloysi. Next, experts begin programming the implants, slowly ramping up the electrical signals over several months.

    “We turn the electrodes on and patients tell us how they feel using a slider indicator on an iPad,” says Aloysi. “Then we adjust the signal accordingly.”

    Some research suggests that DBS could be effective for depression, but the procedure is currently FDA-approved only for OCD. And it’s certainly not for all OCD patients, notes Shofty. “Some OCD patients are uncomfortable with the idea of something remaining in their body, plus some have behaviors like wound-picking that can increase the chance of infection.”

    Side effects include surgical site discomfort, infection, seizure, and possible movement of the battery. Mood-related changes such as mild mania are also possible, says Shofty. If some side effects aren’t tolerable, the device can be removed.

    Miller recalls her decision to try DBS. “I definitely had concerns, but I also wanted my pain to end,” she says. “I was willing to do whatever I could to get my life back.”

    Ablation: Permanently changing the brain

    Another type of surgery — ablation — permanently disconnects neural pathways in the brain that are known to be associated with certain psychiatric symptoms.

    Because ablation is irreversible, physicians vet prospective patients with great care. For example, Shofty requires OCD candidates to have had the condition for at least five years, and no patient receives ablation before first being approved by a panel of experts.

    Such vetting means the surgeries are rare. “There are maybe 100 in the United States each year,” says Dougherty.

    Patients sometimes opt for ablation if they live far from a center capable of providing DBS device programming, says Shofty. The approach also avoids the downsides of implants, such as device malfunction.

    Surgeons have several ablation options. One is radiosurgery — also called gamma knife — which shoots radiation from several directions to create a lesion in a precise location. Another destroys tissue with a laser beam delivered via a fiber that’s inserted into the brain using real-time MRI guidance. Studies suggest that ablation helps 70% of patients.

    Surgery does bring potential risks, including headache, seizures, and brain swelling, which can occur even months after surgery.

    But Dougherty highlights how far the procedures have come from psychosurgeries performed decades ago. “Physicians used to put a knife in and move it around indiscriminately. Now, sophisticated techniques allow for precise targeting, and we have a much greater understanding of how the brain works.”

    On the cutting-edge

    Researchers believe significant advances lie ahead for the neurological approach to psychiatric care.

    A “smart” DBS system, which would activate the implants only during abnormal activity, rather than run continuously, is currently undergoing trials.

    At his lab, Figee is exploring another neuropsychiatric approach: using sophisticated MRIs to map each patient’s brain. “The goal is to achieve individualized, precision targeting of neurons. Being able to personalize treatment would be a huge development,” he says. Researchers are about to launch mapping-based trials at 20 sites across the United States.

    Looking ahead, Dougherty also hopes to identify the neural pathways necessary to treat patients with other psychiatric conditions such as substance use addictions and eating disorders.

    Meanwhile, Kraft says he’s grateful for the benefits he’s gained, which include a restored sense of joy. “I go to a lot of theater, but [before TMS] it would be an opportunity to ruminate rather than experiencing it,” he says. “Yesterday I went to see a show with my daughter and I was filled with a sweet appreciation for the fact that this girl is in my life and that this show was in my life. I was able to think, ‘Aren’t I fortunate to be here?’”

    *Names have been changed and some details omitted to protect privacy.