Brain stimulation poised to move from last resort to frontline treatment

Researchers hope to hone noninvasive approaches to better treat depression and other neurological conditions.

Given the way that Mark S. George describes the early days of his experiments with transcranial magnetic stimulation (TMS), potential patients might be wary. A professor of psychiatry at the Medical University of South Carolina and a pioneer of TMS, George recounts, for example, how the electrical circuits delivering current to coils would explode “with a blue flame” not all that far from the subject and the scientist.

Decades after its first use, TMS is now considered an effective and safe treatment for major depressive disorder in adults for whom medications have failed. Image credit: ScienceSource/Garo/Phanie.

Four decades later, after much equipment innovation and procedural refinement, TMS is considered an effective and safe treatment for major depressive disorder in adults for whom standard treatment has failed. About two-thirds of them experience remission or at least have their symptoms abate by half (1). And by using brain imaging to “neuro navigate” during stimulation, remission rates for depressed patients have neared 80% in trials. In 2018, TMS achieved US regulatory clearance for people with obsessive-compulsive disorder and, in 2020, to help tobacco smokers quit.

Even so, proponents say that TMS and other noninvasive brain-stimulation methods—which include updated forms of electroconvulsive therapy (ECT) and transcranial direct-current stimulation—have yet to achieve their full potential, both as research tools and as clinical treatments for a range of neurological conditions. To get there, researchers want to fully understand the biological mechanisms behind these techniques, along with finding more rigorous ways to test them in the lab, all with a view toward making treatments more tailored and reliably successful. With its demonstrated benefits and lack of serious side effects, Colleen Loo, a neurostimulation pioneer at the University of New South Wales, says, “there’s no reason TMS can’t be used as a frontline treatment” for major depression.

Battling “Brain as Soup”

The idea of zapping the brain with electric and magnetic fields—without piercing the skin—dates back nearly 100 years, when neurologists placed electrodes on either side of the head to induce a seizure, which worked for mentally ill patients by “resetting” their brains (3). But side effects were serious—most notably, amnesia—and negative media portrayals of forced treatment rankled the field. Coupled with advances in antidepressants such as Prozac in the 1980s, ECT was left on the sidelines.

Attention shifted to magnetic fields in 1985, when Anthony Barker of the University of Sheffield placed a coil carrying an alternating current on the top of the scalp, targeting the motor cortex. Subjects visibly twitched their limbs, indicating that the pulsed magnetic field affected their brains (4).

But doubts persisted that TMS could be used in the clinic. Back then, neurotransmitters such as serotonin and GABA (gamma-aminobutyric acid) were the relevant treatment targets, George recalls. “In psychiatry, it was ‘brain as soup.’” No one was embracing the model that the brain worked in circuits, he says, and that disease arose from dysfunction within those circuits. Moreover, the prevailing dogma, based on ECT, was that seizures were necessary to produce a therapeutic effect. And TMS at the levels used did not induce seizure.

While the shape of the TMS coil and the target areas on the skull have changed somewhat in recent years, the basic approach remains roughly the same. Clinicians apply a painless magnetic pulse to the skull by means of a coil. The flux induces an electric field that modifies neuronal activity. Image credit: Shutterstock/Pepermpron.

TMS Takes Off

Things started to shift in the 1990s, when research showed that induced electrical currents from magnetic fields at the surface of the cortex can cascade along a circuit pathway deeper into the brain and effect change.

Researchers experimented with coil shapes—circular rings, figure-eights, and other variations—to achieve different focal areas and improve targeting. Advances in electronics enabled scientists to vastly increase the pulsing frequency from a few hertz to thousands of hertz without the equipment blowing up.

TMS formally reached the clinic in 2008, when the US Food and Drug Administration (FDA) approved its use for depressed adults who failed to respond to at least one antidepressant, which is not uncommon. For such treatment-resistant cases, TMS has been a boon, with two-thirds seeing remission or major improvement in symptoms, George says—although most responders do need more treatment later, such as additional sessions, medication, or talk therapy. Continued hardware improvements and new ways of applying magnetic fields have proved crucial: The shape of the pulse applied to the coil, the amplitude, frequency, duration, and other parameters often make the difference in whether patients respond (5).

But the most critical advance for generating faster responses to TMS and extending remission periods is precision targeting. In the past, experimenters just used a literal rule of thumb: Find the motor cortex by moving the coil until the patient’s thumb twitched, then use a tape measure to slide the coil 5–6 centimeters forward to get to the sweet spot (5). Although easy to implement, individual anatomy varies enough that results were hit or miss. “In the early days, it was one size fits all,” says Sarah H. Lisanby, director of the Noninvasive Neuromodulation Unit at the National Institute of Mental Health. “With that approach, response rates were similar to that seen in antidepressant medications.” Reliably and selectively identifying the target was a challenge (6).

Learning how much and how often to apply the magnetic fields has made treatment much more practical. Early on, the protocol consisted of 6 weeks or more of TMS sessions at a clinic, three to five times a week for an hour at a time—hardly convenient, especially when compared with prescription pills taken at home. But a key insight from Nolan Williams of Stanford University and director of the Stanford Brain Stimulation Lab changed things. He noticed that in patients with severe cases of treatment-resistant depression, increased pulse dose, coupled with personalized targeting, would improve the speed and efficacy of TMS. Williams realized that the brain can handle more stimulation without ill effects and that the conventional TMS protocol, based on safety concerns, was likely underdosing patients. They decided to “take a dose–response curve approach to TMS,” he says, and “apply a neurobiologically informed, patterned increase in pulse dose over a compressed period.” In 2021, Williams and his colleagues developed a significantly faster protocol: 10 sessions a day for 10 minutes each for 5 days with the pulses increased threefold. Moreover, they used functional MRI to make sure that the placement of the coils targeted the subgenual cingulate, a brain area associated with depressed mood (7).

The results were astonishing: In a randomized controlled trial, 11 of 14 patients experienced remission within 4 weeks of treatment, compared with 2 of 15 in a control group. What’s more, Williams says, most patients do not need the full 5 days of treatment; most feel better in 2.6 days, on average. In 2022, the FDA cleared the rapid procedure, now called the Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT). The approval was “a landmark event,” Lisanby says, and “is the first time neuroimaging is part of an FDA-cleared treatment for psychiatry,” which may be key to maximizing the clinical impact of TMS. This “neuro navigating” using functional MRI, as well as positron emission tomography scans, along with more sophisticated modeling of the electric field, has been instrumental in accurately dosing and directing pulses, George says.

Although TMS still has side effects—it can cause short-term headache and dizziness and may induce seizures in some populations, such as those with epilepsy—regulators consider it safe and effective overall (8). And, as a practical matter, so do insurers (including Medicare), which have increasingly covered TMS since the mid-2010s (9).

Next-Generation Noninvasiveness

Valuable insights from TMS have started to inform other noninvasive methods. ECT, the only other FDA-approved brain-stimulation treatment for severe depression, tends to relieve depression more effectively and more quickly than conventional TMS. Speedy treatment can be especially important for patients at risk for suicide (10). Because of the “convulsive” aspect of the treatment, however, ECT requires significant preparation, such as general anesthesia and muscle paralyzers, and it typically comes with memory loss, which is short-term for most patients, but possibly permanent in others. And there is the lingering burden of negative public perception.

But experience with TMS—showing that memory-blasting seizures aren’t a necessary by-product of effective treatment—has led to a rethinking of ECT. One small study in 2015 found that current applied below the threshold of causing seizure helped 8 of 11 depressed patients, with 6 of them classified as in remission (11). Other studies found that memory can be spared by placing both electrodes on one side of the head, rather than on the temples of either side, or by shortening the duration of the electrical pulses (12).

The lessons learned from TMS have also led researchers to re-examine a simpler, lower-cost technology to stimulate the brain, transcranial direct-current stimulation (tDCS). It uses two electrodes, typically placed on different parts of the head, to send a weak current, in the milliampere range. (By comparison, ECT typically uses nearly 1 ampere.)

Hints that tDCS could relieve depression date back to the 1960s, but research did not take off until around 2000. Definitive conclusions are still lacking—labs often used different methods and standards, complicating comparisons and results—but a 2020 meta-analysis by Loo and collaborators in Brazil looked at 23 randomized controlled trials in people with acute depression and concluded that tDCS “is modestly effective in treating depressive episodes” (13).

Perhaps the greatest promise of tDCS, with its low intensity and simple electronics, is the prospect of moving it out of the clinic and into patients’ homes, making brain stimulation much more convenient. In a 2023 study, neuropsychologist Leigh Charvet, of New York University, and colleagues found that 16 patients, with the help of telehealth supervision, mindful meditation, and background music, could effectively apply tDCS to themselves over the course of a 10-week treatment protocol. Three-quarters of patients started responding during the intervention, and 81% were in remission at the end of the trial (14).

An MRI scan reveals the neural activity of a patient with major depression (Left). One week of treatment with TMS, using an FDA-cleared protocol, significantly altered brain activity (Right), revealing how magnetic stimulation provides relief. Image credit: Reprinted with permission from ref. 2.

Lab Foot Forward

Even as clinical evidence suggests that noninvasive brain stimulation is just as safe and effective as current frontline treatments, understanding how the techniques work at a cellular level remains a challenge. Researchers know that the energy affects action potentials in neurons, altering the cells’ activity in ways that produce beneficial change over time (6). Brain stimulation like TMS seems to bolster some connections between neurons, making those connections stronger or even boosting their numbers. “We are talking about synaptic plasticity,” George says.

The effect of stimulation on the directional flow of neural signals along circuits may also matter—both as a potential marker for treatment-resistant depression and for its response to TMS. In a 2023 study, Williams and colleagues reported that in depressed people, signals to the anterior cingulate cortex, an emotion center in the brain, flow in the wrong direction, and the SAINT protocol can correct this flow (2).

“The technology is far outstripping the neuroscience. We have so many more tools than we have good ideas on how to use them.”

—Mark S. George

But some details remain unclear. What other ways might the neural circuitry be affected? How might stimulation-induced changes influence, say, the blood–brain barrier or neurotransmitters? One obstacle to getting answers: devising effective hardware to conduct exploratory work in animals. “The coil geometry to do studies in mice and rats is really tough,” Williams explains. “Coil technology will need to improve for the geometry to match the spatial aspects of the rodent brain.” But researchers also point to the gap between the lab and the clinic. Williams notes that an understanding of TMS at the molecular level will require multidisciplinary skills—work that pairs serious basic neuroscience with clinical trials.

And devising controls, or sham conditions, for clinical tests isn’t always easy or straightforward. Scalp sensations from fake coils and clicking noises made by the machinery during discharge turned out to induce brain activity that confounded the interpretation of the brain activity induced by TMS. Understanding these artifacts, and engineering quieter systems, would help researchers better understand their experimental results. Lisanby notes that measuring clinical outcomes by focusing on changes in what the targeted network actually does could be more objective than diagnoses based on the Diagnostic and Statistical Manual of Mental Disorders, or DSM, which rely on self-reported symptoms and may not map well onto the targeted circuit.

Scanning, the Future

If brain stimulation is going to become a reliable frontline approach, clinicians will have to determine, among other things, who responds best to which treatments. About 30% of people with depression do not respond to conventional drug and talk therapies (15); the most resistant cases are less likely to respond to brain-stimulation therapy as well. “We don’t have good tests for individuals,” George says, although researchers are looking for predictive biomarkers, such as changes in blood-flow activity, electroencephalograms, and heart rate, as they develop the emerging field of “precision psychiatry” to address the underlying biological mechanisms of mental disorders. The SAINT protocol results show the promise of a personalized approach: By using brain scans to find the ideal coil placement, the Stanford team improved remission to nearly 80% in their small study, compared with the one-third remission rate seen with conventional TMS.

Understanding who benefits and why might also elucidate a longstanding mystery: why adolescent brains seem to resist TMS. Williams says that, anecdotally, some teens do report relief after undergoing the SAINT protocol, but a randomized, double-blind trial in 2020 found that standard TMS did no better than sham treatment (16). Loo and colleagues came up with similar results when testing tDCS on adolescents (17). Some researchers speculate that distinct characteristics of the developing adolescent brain—teen depression typically involves anger and irritability rather than sadness—point to different dosing regimens compared with adults.

Resolving the question of why some populations and individuals respond and others do not may just come down to more trials. At this point, “the technology is far outstripping the neuroscience,” George says. “We have so many more tools than we have good ideas on how to use them.”

That growing array of tools for noninvasive brain stimulation includes transcranial ultrasound (TUS), which can reach deeper into the brain, where the problematic neural circuits reside, than TMS and tDCS can; the technique was first shown in 2013 to relieve pain (18). Like electrical and magnetic energy, the acoustic energy also seems to improve mood by modulating neuronal plasticity. Human studies have accelerated since 2020, targeting chronic pain, dementia, epilepsy, traumatic brain injury, and depression, in the hope that TUS will prove a relatively low-cost treatment with a good safety profile (19).

Although noninvasive brain-stimulation methods can be pricey, their economics may start to be competitive with the continued refinement of the protocols and development of the technology, especially when absences from work and other forms of lost productivity are factored into the equation. And broader adoption could lead to an entirely different paradigm. Instead of treating depression in the acute phase, after patients have already endured a great deal of suffering, clinicians would implement preventive strategies, Lisanby says. Perhaps brain stimulation could be conducted in combination with medication and cognitive therapy, in the same way that physicians manage cardiovascular risks with lifestyle modifications, drugs, and diet—all tailored to individual needs. “When you think about it,” she says, “the way you really want to deal with depression is through prevention.” Considering that rates of suicide in the United States have not abated for decades, despite new antidepressants, the potential speed of relief from the latest forms of brain stimulation, Lisanby adds, could make a difference that is nothing less than “transformative and life-saving.”