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David Geffen School of Medicine

Zinging the Blues

By Kathy Svitil

By using magnetic or electrical stimulation to alter neural activity in the brain, neuromodulation joins medications and psychotherapy as a third domain for the treatment of difficult psychiatric disorders.

Magnetic or electrical stimulation to alter neural activity in the brain
Illustration: Superstock Images

For Junie Reypach, depression has been more than just a bad case of the blues. The 32-year-old mother of two was first diagnosed with major depressive disorder, or unipolar depression, when she was 13 years old. Over the years, she sought help from six different physicians and psychiatrists and tried more than a dozen medications, but her depression eventually darkened every aspect of her life, starting from the moment she — reluctantly — woke up every morning. “I was pretty much at my wit’s end,” Reypach recalls. “I didn’t know what to do anymore.”

A friend told Reypach about a promising new form of therapy underway at UCLA. Known as repetitive transcranial magnetic stimulation (TMS), it is one of a suite of therapies that falls under the umbrella of “neuromodulation” — the use of electrical or magnetic impulses to stimulate brain cells to alter, or modulate, their pattern of activity to achieve a therapeutic benefit. “When I first heard about TMS, I put it in the back of my mind,” she says, “and then when I was desperate to find something, I looked into it.”

Reypach was soon enrolled in the TMS treatment program at the UCLA Depression Research and Clinic Program. Within a week of starting a 30-session course of five-days-a-week treatments, her depression began to lift. “I’m able to get up every morning now and not have a problem,” she says. “Before I would dread getting up, hoping that tomorrow would be a better day. Now, tomorrow is actually going to be a better day because I feel a lot better.”

THE INTRODUCTION OF PSYCHIATRIC DRUGS in the mid-20th century revolutionized the treatment of mental illness, just as psychotherapy had done decades before. But neither drugs nor therapy are perfect fixes for all patients. Twenty-to-30 percent of patients suffering from depression do not respond to antidepressants, or they suffer from intolerable side effects. For such patients, neuromodulation offers hope.

Transcranial magnetic stimulation (TMS)  
Transcranial magnetic stimulation (TMS) uses a targeted magnetic pulse to stimulate areas of the brain that are underactive in depression.
Illustration: Courtesy of Neuronetics

“Neuromodulation is a huge developing field of psychiatric research and clinical treatment,” says psychiatrist Alexander Bystritsky, MD (FEL ’87), PhD, director of UCLA’s Anxiety Disorders Program. “Before, we had two main domains of psychiatric research and treatment: medication and psychotherapy. Neuromodulation now is the third domain.”

In TMS, which was approved by the U.S. Food and Drug Administration (FDA) for treatment of unipolar depression in 2008, an electromagnetic coil is positioned over a specific location above the patient’s scalp. When the magnet is activated, it delivers short, targeted electromagnetic pulses. The pulses, which are about the same strength as those used in magnetic resonance imaging (MRI), pass through the skin and skull and into the brain, to a depth of about 5 centimeters, or 2 inches, to areas believed to be involved in regulating depression and mood control. There, the magnetic field induces a directed current that activates nerve cells. Although the exact mechanism by which this helps to reduce depression is not yet fully understood, “we do know that the brain largely communicates by sending electrical signals, so when you bring a magnet to the brain, it is going to affect that signal transmission,” Dr. Bystritsky explains.

A typical course of treatment involves 30 sessions of 30-to-60 minutes each. The side effects are mild; patients may experience a headache and tingling in the scalp, and they may be irritated by the tapping noise generated by the device, which is much like that produced by an MRI machine.

“Depending on where they place the magnet, it can be annoying,” recalls Reypach. The procedure is not painful, she says, but “sometimes it’s a little uncomfortable.” After 10 or 15 minutes, “you get used to it.”

Like medications and psychotherapy, TMS doesn’t help all patients. But many, like Reypach, report remarkable success, says Ian Cook, MD (RES ’94, FEL ’91, ’96), professor of psychiatry and bioengineering and director of the UCLA Depression Research and Clinic Program. “It can get them to wellness when other treatments have failed. For example, we treated an individual who had to stop college because of his depression, and multiple medication attempts did not help; after TMS, he is back in school.” While the patient still is on some medications, “our hope is that he will be able to be on less,” Dr. Cook says. “It is really a beautiful thing to see.”

For most patients, the improvement following the end of their treatment regimen “tends to stick,” says Dr. Cook. For example, a follow-up study of subjects in the trial that led to the device’s initial approval in 2008 found that two-thirds of the patients whose depression was improved tended to stay in remission while taking just one antidepressant medication. “And most of those who did have some symptoms return were able to be brought back into wellness with just a few treatments — like five or 10, not the full 30,” Dr. Cook says. “Compared to medications, where once you stop the likelihood of relapse is very high, TMS seems to be a pretty durable treatment.”

IN ADDITION TO UNIPOLAR DEPRESSION, many people seek care for closely related conditions, such as depression as part of manic depression or depression coupled with post-traumatic stress (PTS), “and we have been able to offer them the option of clinical treatment with TMS,” Dr. Cook says. The treatment of other psychiatric conditions “is in an exploration phase,” Dr. Bystritsky says. “If we find tools to target the brain precisely to focus on the activation of disease-specific circuits, it would be conceivable to treat other psychiatric and medical disorders very effectively with this technique. We are just at the beginning. We are where pharmacology was about 40 years ago.”

Like TMS, another neuromodulation approach, trigeminal-nerve stimulation (TNS), aims to alter the pattern of electrical activity in the brain. In TNS, electrodes that deliver the pulses of energy are applied directly to the surface of the skin. TNS was invented by Dr. Cook, UCLA neurologist Christopher DeGiorgio, MD (FEL ’87), and colleagues, and licensed by UCLA to a Los Angeles-based neuromodulation company called NeuroSigma. The system has been approved for use in Canada and Europe but has not yet received FDA approval for general clinical use in the United States and is still considered experimental. (NeuroSigma is now working with the FDA to obtain approval for TNS to be used clinically in the U.S.) During TNS treatment, a patch connected by leads to a cell-phone-sized signal-generator box is attached to the forehead and worn for about eight hours at night, while the patient sleeps. The patch delivers a low-energy current of between 1 and 5 milliamps — much less energy than is used to power a light bulb — to stimulate branches of the trigeminal nerve. The trigeminal nerve normally transmits sensations from the face, mouth and the surface of the eyes into the brain; in TNS, this pathway is co-opted to send signals deep within the brain to a part of the frontal lobe called the anterior cingulate, which is involved in regulating mood and emotion.

“It allows us to get some information into the system that can cause very robust increases in the activity levels of these centers of the brain,” leading to therapeutic benefits, Dr. Cook says. (A related technique, vagus-nerve stimulation, involves the surgical implantation of a device in the front of the chest connected to an electrode that stimulates a nerve in the neck known as the vagus. FDA approved in 2005, it has also shown promise in the treatment of medication-resistant depression. The method, however, is not covered by most insurance plans or Medicare.)

Junie Reypach, pictured with daughters
Junie Reypach, pictured with daughters Natalia, 5, and Eva, 22 months, was diagnosed with major depressive disorder when she was 13 years old. Treatment at UCLA with transcranial magnetic stimulation has made her feel “tomorrow is actually going to be a better day because I feel a lot better.”
Photo: Ann Johansson

The first success of TNS treatment was described 2003 by Dr. DeGiorgio in patients with medication resistant wpilepsy; in 2010, Dr. Cook and his colleagues reported a 70-percent reduction in symptom severity in patients with major depression, that had not responded to medications.

More recently, UCLA researchers have begun testing the technique in people with PTS and in children and adolescents with attention-deficit hyperactivity disorder (ADHD). As reported last spring, subjects in the pilot ADHD study, led by James McGough, MD (FEL ’91), MS, professor of clinical psychiatry at the Jane and Terry Semel Institute for Neuroscience and Human Behavior at UCLA, showed encouraging improvements in behavior and on cognitive tests. “Aside from the sensation in the skin, which people often report as a tingling feeling or a buzzing, there is not much else that happens from a physical standpoint,” says Dr. Cook, a collaborator on the ADHD study.

“People don’t get high, they don’t get sedated; TNS doesn’t produce any kind of weird sensory effect,” Dr. Cook says. “If anything, subjects say that they are better able to focus, and that, plus findings from our neuroimaging work, is why we were led to do the study in ADHD.”

NEUROMODULATION METHODS LIKE TMS AND TNS have only recently come into use in psychiatry. However, the idea of producing a seizure in the brain to trigger a change in its activity can be dated back to the 16th century, when chemical agents were used to induce seizures in mentally ill patients — a practice that continued, in one form or another, into the 20th century. In the late 1930s, the first patients were treated with electroconvulsive therapy (ECT), which uses electrical energy to induce a seizure. ECT, once commonly known as electroshock therapy, uses two electrodes, placed at precise locations on the head, to induce a generalized seizure throughout the brain. The patient, who is under anesthesia and has been given muscle relaxants, has no awareness of the seizure. “ECT has a multitude of effects. Although we don’t have a precise understanding of its mechanism, it still is one of the best treatments that exist for refractory depression,” says Randall Espinoza, MD (RES ’94, FEL ’96), MPH, clinical professor of psychiatry and biobehavioral sciences and medical director of UCLA’s ECT program. As the largest academic ECT program west of the Mississippi, it performs more than 2,100 ECT treatments on approximately 180 patients each year.

Studies show that a typical course of ECT — generally six-to-12 treatments — is effective in patients with psychotic, catatonic or melancholic depression more than 90 percent of the time and helps 50-to-60-percent of patients with medication resistant depression.

The exact mechanism by which ECT reboots the depressed brain into a state of wellness is still not fully understood, but the neurophysiological effects of the induced seizure are well-documented, Dr. Espinoza says. They include alterations in the brain’s structural and functional connectivity, brain neurochemistry and normalization of blood flow to brain regions involved in depression, correction of neuroendocrine dysfunction and normalization of various brain neurotransmitter systems involved in depression. Studies also have shown that ECT — which appears to be useful not just for depression, but also for a variety of other treatment-resistant mental disorders — induces the growth of brain cells and nerve-cell synapses.

COMPARED TO GENERALIZED THERAPIES LIKE ECT, deep brain stimulation (DBS), a surgical procedure that involves the implantation of electrodes that deliver electrical impulses into specific areas of the brain, is a finely targeted treatment, shown to be effective for movement disorders such as Parkinson’s disease, dystonia and treatment-resistant epilepsy. It also is being investigated for chronic pain and headaches and, most recently, psychiatric conditions including depression, for which it is not yet FDA-approved.

  Dr. Nader Pouratian
  Dr. Nader Pouratian (MD ’03, PhD ’01): “Deep brain stimulation modifies [the] abnormal pattern of activity to make it a little bit closer to normal and help people’s symptoms come back to a more normal pattern.”
Photo: Reed Hutchinson

“When you have a condition like depression or Parkinson’s disease, it causes changes in the way that the brain functions and creates different patterns — or rhythms — of activity,” says neurosurgeon Nader Pouratian, MD ’03, PhD ’01, director of UCLA’s Neurosurgical Movement Disorders Program. “Deep brain stimulation modifies that abnormal pattern of activity to make it a little bit closer to normal.”

DBS is a two-stage procedure. In the first, electrodes are inserted, their placement guided by simultaneous MRI scanning, into particular regions of the brain that are chosen based on the patient’s condition. For treatment of depression, for example, the target area is a part of the cerebral cortex known as the subgenual cingulate cortex, or area 25. After the patient heals from that surgery, a generator to power the device is implanted in the chest and turned on.

When DBS is used for movement disorders such as Parkinson’s and epilepsy, “we turn on the device and see an almost immediate effect on the patient’s movement, stiffness and rigidity,” explains Dr. Pouratian. Such quick response is generally not the case with psychiatric disorders, “although some depression patients will say that there is a sensation of well-being, of feeling better. One patient said that he immediately felt this black cloud being lifted from over his head,” Dr. Pouratian says. “As soon as you turn the stimulator off, that black cloud comes back.”

In most patients, reaching a therapeutic level of stimulation may take a few weeks or a month of fine-tuning. “We try them at a certain level, then they come back in, and we re-evaluate them and keep turning the stimulation up until we see a therapeutic effect,” Dr. Pouratian says. “It is a much longer process of programming than we see with movement disorders.”

However, benefits of the therapy tend to be more durable in psychiatric patients than in those with movement disorders. “Assuming you have a therapeutic effect, in most people you will continue to see that for some period of time after you turn the stimulator off — one to two weeks — before the symptoms recur,” he notes.

IN ADDITION TO STUDYING THE USE OF DBS IN DEPRESSION, researchers at UCLA and elsewhere have begun investigating it for other psychiatric disorders, including Tourette’s syndrome, and to help persons with addictive behaviors, such as drug dependency and alcoholism. The FDA already has approved the use of DBS for the treatment of patients with obsessive-compulsive disorder (OCD), under its so-called humanitarian-device exemption.

“The FDA is not speaking to its efficacy, but it thinks it is safe, and OCD is a disease that doesn’t have many good therapeutic options, so it wanted to make this available,” Dr. Pouratian notes. “We’re also interested in treating patients with disorders of consciousness, people who have had brain injury or stroke or other neurological diseases and are either in a vegetative state or a minimally conscious state,” he says. “The goal is to use DBS or other forms of neuromodulation to awaken those patients and make them more functional and interactive.”

Despite the promise offered by neuromodulation, experts like Dr. Pouratian remain cautious. “A lot of effort has been taken to make sure that the advance of neuromodulation for psychiatric diseases has been done in an ethically appropriate manner, that we’re not taking advantage of people who are at a period of desperation,” he says. He adds, “I think that what is going to happen when we get over these hurdles, and we start showing that this can actually make a big difference in people’s lives, is that it will become increasingly accepted and adopted. Instead of saving it as a last-line therapy, we’ll be able to do it much earlier in peoples’ diseases as part of a multidisciplinary treatment, along with therapy and medication.”

From that standpoint, neuromodulation may be at the vanguard of “a new era for the treatment of brain disorders,” Dr. Cook says. “We’ve clearly restored many lives through medication and psychotherapy, but people do not do as well with medications as we would like, and unmet needs remain. Neuromodulation techniques — TMS, TNS and the like — really can give us more arrows in our quiver to help patients with forms of illness that don’t respond well to meds.”

At least one patient needs no convincing. “I’m glad I found TMS. It has helped a lot,” Junie Reypach says. “It feels good to want to get up and do things, compared to not wanting to get up at all.”

Junie Reypach, pictured with daughters
Neuromodulation uses magnetic or electrical stimulation to alter the patterns of electricity in the brain and has proven beneficial for many patients like Junie Raypach with intractable depression.
Photo: Ann Johansson

Kathy Svitil is a freelance writer and director of news for the California Institute of Technology.


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