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Treating Depression with Transcranial Magnetic Stimulation

Rewiring the Brain's Circuits to Relieve Depression

“Electricity is the real currency of the brain.”
              —Mark S. George, M.D.

Neuroplasticity, the brain’s capacity to reorganize itself by forming new neural connections throughout life, is a novel paradigm in brain research studies, one that is replacing a long-held belief that the brain’s circuits are hard-wired by adulthood and that little can be done to change them. If specific circuits involved in psychiatric disorders can be identified, rewiring them could offer hope for patients who thought they had run out of options.

“If we know the circuit, and can modify it, we can potentially come up with a new treatment for any disease of the brain,” says Mark S. George, M.D., McCurdy Endowed Distinguished Professor in the Departments of Psychiatry, Radiology, and Neurology and Director of the Brain Stimulation Laboratory at MUSC’s Institute of Psychiatry. “With sophisticated brain imaging, we can more accurately identify and target those circuits.”

What are the faulty circuits responsible for major depressive disorder? How can those circuits be reset in the 30% to 50% of patients who do not respond to or cannot tolerate pharmacological therapy with antidepressant agents like selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors?

Electroconvulsive therapy (ECT) has been the workhorse for treating severe depression since its development in the 1930s, and new developments have reduced the likelihood of side effects like memory loss. Transcranial magnetic stimulation (TMS), pioneered by Dr. George and other scientists at MUSC and approved by the U.S. Food and Drug Administration for treatment of this patient population in 2008, more specifically targets the faulty circuits specific to depression, achieving impressive response rates with few side effects and without the need to anesthetize the patient.

Electroconvulsive Therapy

The exact mechanism by which ECT works is unknown, but it is believed that passing currents through specific regions and then producing a seizure “resets” the brain circuitry and chemistry, allowing for a reduction in depressive symptoms. It has demonstrated efficacy in treating patients with refractory depression; the vast majority of these patients—as many as 65% to 80%—show improvement after ECT treatment.

Although ECT still arouses concern in some patients because of its early negative portrayal in the media, treatment delivery has evolved significantly since its invention. It is used only in patients with severe drug-refractory conditions. ECT involves anesthetizing the patient (with methohexital or etomidate), administering a muscle relaxant (succinylcholine), and using an electrical stimulus transmitted through electrode patches on the head to induce a seizure. Studies have found ECT to be equally effective in treating bipolar disorder.¹ Other indications for ECT include mania, schizophrenia, and catatonia.

ECT remains the most effective acute treatment for severe major depression. “Advances in ECT, including better equipment, more experienced and better trained physicians, changes in the placement of electrodes, and changes in the pulse-width of the current have all helped significantly reduce the cognitive side effects associated with ECT,” notes Baron Short, M.D., M.S., Director of the MUSC Institute of Psychiatry’s Brain Stimulation Service. “The Brain Stimulation Laboratory is further refining ECT methods so that we can maintain efficacy while dramatically reducing side effects,” continues Dr. Short.

A 2013 article in Brain Stimulation (May-June 2013) reports the initial results of a study conducted jointly at MUSC and Columbia University in New York to assess the efficacy of a novel form of precise ECT called FEAST (Focal Electrically Administered Seizure Therapy).² This new form of ECT uses pulsed direct current stimulation, with the bulk of the electrical charge delivered directly under one electrode that is placed about two inches above the right eye. Traditional ECT uses alternating current, which flows in both directions and is thus harder to direct and target. Patients undergoing FEAST became fully oriented just five minutes after they first opened their eyes, an important finding since longer orientation times typically predict longer-term cognitive effects. After an average of ten sessions over the course of four weeks, 8 of 17 study patients saw a reduction in their depressive symptoms, and five patients were largely symptom free.

Identifying the Faulty Circuit in Depression

FIGURE 1. Dr. Mark George, demonstrating transcranial magnetic stimulation therapy,
which he helped pioneer to treat depression.

Early in his career, Dr. George, a pioneer in biomedical imaging, set out to identify the regions of the brain associated with depression, comparing imaging studies of the brain in patients who were depressed and those who were not. In depressed patients, far less activity was observed in the frontal cortex. This is not surprising, given that this area of the brain is associated with cognition, motivation, and executive function such as planning.

“What do we do with the frontal cortex? We think about our role in the future, we plan, we hope, we understand how we fit into the world. If you think about depression, it’s hopelessness (I can’t see any future), helplessness (I’m not empowered to change the world), and worthlessness (I am not worth anything), so the normal role of the prefrontal cortex in realistically evaluating where you are is totally gone,” explains Dr. George.

The frontal cortex submits the sensory and emotional stimuli from the limbic system to a reality test. The limbic system is a primitive region of the brain associated with primal emotions like fear and anger that are integral to the fight or flight response and so key for survival. Is a noise in the night a sign of real danger that should provoke flight, or can it be rationally traced to an unthreatening cause? It is the frontal cortex that runs through the possible scenarios to decide whether action is required.

FIGURE 2. Transcranial Magnetic Stimulation. Illustration by Bryan Christie Design, used with permission.

When this portion of the brain is not functioning properly, our interpretation of sensory and emotional stimuli can become irrational and inflexible. Whereas an “undepressed” person might be able to entertain any number of plausible explanations for the failure of a coworker to greet him or her (eg, the coworker was having a bad day, was under the pressure of a deadline, was not feeling well that day), the depressed person immediately assumes it is evidence of that colleague’s anger toward and dislike of him or her. The capacity to reason and think of alternative interpretations is compromised, leaving the depressed person with an overly negative and reductive perspective on the world.

Transcranial Magnetic Stimulation

As early as 1995, Dr. George wondered whether we “might be able to tickle or stimulate this part of the brain that is not working in depressed people, and whether, if we could restore this regulatory system, we could get people undepressed.” From that germinal idea developed TMS, now available in more than 500 clinics nationwide. In open-label clinical trials, one in two patients suffering with depression improved significantly after undergoing TMS targeted to the frontal cortex, known to be underactive in depressed patients, and one in three patients was completely free of depressive symptoms after six weeks of treatment. TMS is proving even more effective in real-world clinical settings, with a reported response rate of 50% to 60%.³ As evidence of its efficacy and effectiveness grows, insurers are becoming more willing to cover the procedure. In South Carolina, Medicare and Blue Cross Blue Shield are currently writing for coverage.

During TMS, a small curved device, about the size of a cupped hand, rests lightly on the head of a patient reclining comfortably in a spa chair, delivering focused magnetic stimulation directly to the area of the brain thought to be involved with regulating mood (Figures 1 and 2). The magnetic field pulses are the same strength as those used in magnetic resonance imaging (MRI) machines—on the order of 1.5 T—but very brief. Unlike ECT, which must be given under anesthesia and which induces a seizure, TMS can be performed while the patient is awake and is targeted only at those areas of the brain thought to be involved in depression.

Typically, patients receive four to six weeks of daily treatment, each session lasting 30 to 45 minutes, and some patients receive regular intermittent treatments thereafter to alleviate low mood. Patients are awake, can read or listen to music during the treatment, and can even return to work after treatment, an advantage over ECT, after which patients need time to recover.

TMS also has an attractive side effect profile, and early studies suggest better durability than that obtained with ECT.⁴ Unlike pharmacological therapies that can result in weight gain and sexual dysfunction, TMS has few side effects, and those are typically minor (ie, mild scalp irritation, a very slight risk of seizure). Its response rate of 50% to 60% may be somewhat lower than that achieved in ECT, but the durability of that response may be superior (80% for TMS at one year vs 50% for ECT). The only real disadvantage posed by TMS is the need to undergo treatments for a period of several weeks. To address this issue, Dr. George and his team are currently experimenting with shorter, more intensive protocols (such as that described in “Reducing Suicidal Thinking With TMS”), which thus far have proven to have similar efficacy with no additional burden of side effects.

Reducing Suicidal Thinking With TMS

New evidence suggests that TMS can reduce suicidal thinking, an important finding because few therapeutic options exist for this population. According to Dr. George, “We don’t have a treatment for when someone comes off of the bridge. We can talk with them or change medicine, but that takes time. There has been little available in the way of an acute treatment.”

In a study led by Dr. George and conducted jointly at the Ralph H. Johnson VA Medical Center in Charleston, SC, and Walter Reed National Military Medical Center in Bethesda, MD, veterans in immediate danger of committing suicide received TMS, using a shortened protocol of nine treatments over the course of three days. TMS was found to halve the incidence of suicidal thinking in these patients in the first 24 hours of treatment. When asked at the end of the nine treatments whether they were currently bothered by thoughts of suicide, study patients receiving TMS reported 40% less depression than at baseline.

The availability of an acute treatment for these patients could revolutionize the management of suicide, mirroring the evolution seen in the management of patients experiencing stroke or myocardial infarction once acute treatments— like tissue plasminogen activator for ischemic stroke and cardiac catheterization for heart attack—became available. Educational campaigns were launched to teach the public how to recognize the warning signs, and protocols were developed to ensure the timely administration of treatment, greatly improving outcomes. Likewise, more suicides may be prevented with the advent of an acute treatment for suicide and educational campaigns reminding people that suicidal crisis is a brain disease and can be treated.

Other Potential Research and Clinical Applications

The potential applications of TMS extend beyond treatment-resistant depression and suicide. TMS is a valuable research tool as well as an important clinical advance. Because it can turn on or off certain regions of the brain, or dial down or dial up the intensity of their activity, TMS can be used, together with sophisticated brain imaging, to identify the faulty circuits that characterize a range of disorders. Once those faulty circuits have been identified, TMS can be used to help repair that wiring. “We are not wedded to any one disease,” says Dr. George. “Researchers here at the MUSC Brain Stimulation Lab are experimenting with TMS as a treatment for chronic and acute pain management and addiction disorders in the hopes of better understanding the circuits in the brain and targeting them for new treatments.”

Learn more about the Brain Stimulation Service at MUSC. To enroll a patient in a clinical trial, contact research assistant Jkeonye Moss at mosjk@musc.edu

References

¹ Daly JJ, et al. ECT in bipolar and unipolar depression: differences in speed of response. Bipolar Disorders 2001;3(2):95-104.

² Nahas Z, et al. A feasibility study of a new method for electrically producing seizures in man: focal electrically administered seizure therapy [FEAST]. Brain Stimul 2013;6(3):403-8.

³ Carpenter LL, et al. Transcranial magnetic stimulation (TMS) for major depression: a multisite, naturalistic, observational study of acute treatment outcomes in clinical practice. Depress Anxiety 2012;29(7):587-96.

⁴ Mantovani A, et al. Long-term efficacy of repeated daily prefrontal transcranial magnetic stimulation (TMS) in treatment-resistant depression. Depress Anxiety 2012;29(10):883-890. dx.doi.org/10.1002/da.21967.

This article originally appeared in the November 2013 issue of Progressnotes.

KEY POINTS

  • The brain’s circuits are not completely hard-wired in adults, and so faulty circuits can still be rewired.
  • Sophisticated brain imaging has helped to identify the faulty circuits responsible for a variety of psychiatric and neurological disorders.
  • Electroconvulsive therapy has long been used to “reset” the brain’s circuits, and recent advances have minimized the likelihood of side effects like memory loss.
  • Transcranial magnetic stimulation (TMS), approved by the U.S. Food and Drug Administration for the treatment of patients who have failed to respond to treatment with at least two separate antidepressants, delivers focused magnetic stimulation directly to the area of the brain thought to be involved with regulating mood.
  • In real-world clinical settings, 50% to 60% of patients with treatment-resistant depression respond to TMS, and early studies suggest that the response is more durable than that achieved with ECT, with fewer side effects.

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