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Stimulating the Brain: Researchers are studying the use of deep brain stimulation to treat Alzheimer's disease, stroke, and depression, among other disorders. Here's a look at the latest clinical trials.

Shaw, Gina

doi: 10.1097/01.NNN.0000526574.46535.14
Departments: Clinical Trial Watch

Researchers are testing deep brain stimulation for disorders other than tremor and Parkinson's disease.

WEB EXTRA: For more about DBS clinical trials, including questions to ask before volunteering, go to http://bit.ly/NN-MoreDBS.

For more than 40 years, LaVonne Moore hosted a radio talk show in Bucyrus, OH, on the station she co-owned with her husband, Tom. About 13 years ago, she began forgetting questions and asked Tom to take her off the air. He initially dismissed her concerns, but her memory problems persisted. After a local physician diagnosed LaVonne with Alzheimer's disease, the Moores sought care at the Ohio State University (OSU) Wexner Medical Center. For several years, under the care of neurologist Maria Kataki, MD, PhD, LaVonne took medications aimed at slowing her cognitive decline, including memantine (Namenda) and rivastigmine (Exelon).

ZEPHYR/SCIENCE PHOTO LIBRARY

ZEPHYR/SCIENCE PHOTO LIBRARY

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CLINICAL TRIAL OPPORTUNITY

In mid-2010, after an appointment with Dr. Kataki, the Moores were asked to meet with Douglas W. Scharre, MD, director of the division of cognitive neurology at OSU. Dr. Scharre was conducting a small clinical trial to test whether Alzheimer's disease could be treated safely with deep brain stimulation (DBS), which involves implanting a neurostimulation device into the brain to block the abnormal electrical signals that cause neurologic symptoms. Would LaVonne be interested?

After saying yes, LaVonne underwent two surgeries to place the device in her brain. The first surgery was upsetting for LaVonne, Tom recalls. She was sometimes confused about where she was and contnually tried to get out of bed. “I stayed in the hospital with her overnight to help keep her calm,” Tom says. “By the time she was released, she was doing much better. After the second surgery, her recovery was much easier.”

For the next four years, as part of the trial, LaVonne and Tom returned to OSU every three months for tests: MRI and PET scans, electroencephalograms (EEGs), and neuropsychological exams.

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POTENTIAL FOR ALZHEIMER'S

The phase 1 trial, which was published in Neurology in 2016, was designed to test whether using DBS to target an area of the brain called the ventral capsule/ventral striatum (VC/VS) in order to regulate behavior in the brain's frontal lobe was safe and effective in patients with Alzheimer's disease. The procedure was not considered a cure. In fact, the researchers expected the disease to progress despite the intervention. Nonetheless, the authors noted that all three patients in the study “tolerated the DBS well without significant adverse events.” The participants had less performance decline—and two significantly less decline—after 18 to 28 months on a standard measure of mental and functional performance in dementia compared with a matched comparison group of people who did not receive DBS.

The study was very small and the findings preliminary, and it's difficult to say how much more LaVonne might have declined without DBS. But the findings could provide new insights into potential targets for Alzheimer's disease. Until more research is done, DBS is not approved for use in Alzheimer's disease outside of a clinical trial.

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MOVEMENT CONTROL

In 1997, DBS was approved by the US Food and Drug Administration (FDA) to help treat the rhythmic trembling of the hands, head, voice, legs, or body associated with essential tremor, and for the tremor associated with Parkinson's disease. In 2002, the approval was expanded to treat other symptoms of Parkinson's disease, including rigidity and slowness of movement, as well as the abnormal movements known as dyskinesias that result from long-term use of dopamine replacement medications. And in 2003, the approval was expanded to include dystonia, a condition that causes involuntary, sometimes painful muscle spasms.

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FINE-TUNING TREATMENT

Within the past decade, researchers have been studying the safety and potential effectiveness of DBS for a wide variety of other neurologic disorders, including depression, stroke, and traumatic brain injury (TBI). Hundreds of clinical trials involving DBS are now either recruiting, underway, or recently completed.

Why are researchers interested in examining DBS for so many different conditions? “DBS can be fine-tuned to target different areas of the brain thought to be involved with different conditions,” explains Ali Rezai, MD, endowed chair of neuromodulation at OSU. “As we learn more about the brain circuitry involved in many conditions, we are able to identify network-based imbalances that DBS may improve by modulating these networks—increasing or reducing their activity, depending on the underlying cause.” Dr. Rezai was co-investigator with Dr. Scharre on the DBS Alzheimer's study, and is on the board of directors and has equity ownership in Autonomic Technologies, a medical device company for the treatment of severe headache, and Neurotechnology Innovation Translator, a group that develops neurotechnology for patient care.

Researchers have used DBS in clinical trials to target two areas of the brain implicated in Parkinson's disease: the subthalamic nucleus and the globus pallidus interna. Both are part of the brain's basal ganglia, which are involved in switching the body's motor systems on and off, Dr. Rezai explains. In Alzheimer's disease, researchers have targeted the fornix, a bundle of nerve fibers that carries output from the hippocampus, a pathway that has been linked to memory decline in the disease, as well as the VC/VS.

Researchers are also focusing on how DBS can be fine-tuned to target the electrical current more precisely at the structures they want to treat while avoiding areas that might cause side effects.

Because DBS involves significant risks and side effects, including bleeding in the brain, stroke, infection, seizures, changes in mood, and problems with the device hardware, investigators are limited in their ability to recruit larger pools of participants. This is also why many trials are open label, meaning they do not involve a comparison group of participants undergoing sham therapy. Therefore, both researchers and participants know who is receiving DBS and who is not.

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CONTROLLING SEIZURES

“Our early successes with Parkinson's disease and other movement disorders helped us evolve from thinking about DBS for a particular disease to thinking about it for a particular symptom,” says Michael S. Okun, MD, FAAN, chair of the department of neurology and co-director of the Center for Movement Disorders and Neurorestoration at the University of Florida in Gainesville and national medical director of the Parkinson's Foundation.

In 2013, the FDA approved the responsive nerve stimulator (RNS), a DBS system made by NeuroPace for adults with seizures that failed to improve with two or more antiepileptic drugs. This system continuously monitors brain activity, learning the unique electrical signals in each individual's brain that mark the start of a seizure, and interrupts that pattern with a series of mild stimulations. The NeuroPace device was approved after a multicenter trial involving 191 patients showed significant reduction in seizure frequency among patients receiving DBS. In long-term results presented at the annual meeting of the American Epilepsy Society in December 2016, people who had been using the system for seven years reported a 70 percent reduction in the frequency of their seizures, with 29 percent of patients reporting at least one six-month period entirely free from seizures.

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TREATING DEPRESSION

Helen Mayberg, MD, professor of psychiatry, neurology, and radiology and endowed chair of psychiatric neuroimaging and therapeutics at Emory University School of Medicine in Atlanta, has been studying the use of DBS for treatment-resistant depression since 2003. Her original trials focused on the subcallosal cingulate (SCC), an area of the brain that helps regulate mood.

“These patients had failed at least four classes of antidepressants, as well as psychotherapy and electroconvulsive therapy,” she explains. “In our first cases, and in other open-label experimental studies, we had excellent results.” But larger clinical trials of DBS for depression, run by device manufacturers Medtronic and St. Jude Medical, failed to produce the same dramatic results.

ZEPHYR/SCIENCE PHOTO LIBRARY

ZEPHYR/SCIENCE PHOTO LIBRARY

More recently, Dr. Mayberg has been studying the bundles of neural fibers that connect the SCC to other brain regions. In a small trial published in Molecular Psychiatry in April 2017, she described a group of 11 patients who underwent DBS targeting these bundles; after one year, nine of the patients were classified as responding to treatment, with six of them in remission.

Implanting the electrode exactly is key. For depression, researchers are developing new imaging technology that would allow for more refined methods of surgical targeting and improved outcomes.

Dr. Mayberg's group at Emory University has received donations of non-commercial DBS devices from both St. Jude Medical and Medtronic for use in experimental studies. The companies have no input on the study design, data acquisition, or analysis or interpretation of results. Other organizations that support Dr. Mayberg's research include the National Institutes of Health (NIH), the Dana Foundation, the Woodruff Fund, the Stanley Medical Research Foundation, and the Hope for Depression Research Foundation.

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TAMING TICS

Several research teams, including Dr. Okun's, have reported promising results in using DBS to treat Tourette syndrome, a condition that causes people to make involuntary movements and/or loud noises known as tics. In April 2017, a group from Tufts University Medical Center and NYU Langone Medical Center published findings in the Journal of Neurosurgery from a small trial in which DBS was used to treat 13 patients whose symptoms had not responded well to other treatments. The severity of these patients' tics declined by an average of 37 percent post-surgery; over time, the tics decreased by 50 percent.

Dr. Okun is now leading an NIH-funded clinical trial of DBS in Tourette syndrome, using a responsive DBS system. Like NeuroPace's RNS system for epilepsy, it is designed to detect the “signal” of an impending tic and stop it before it starts. (Dr. Okun receives no compensation related to the trial.) Four patients are currently enrolled, and the trial is still recruiting new patients. (For more information, go to http://bit.ly/CTG-Tourette.)

ALFRED PASIEKA/SCIENCE PHOTO LIBRARY (RIGHT)

ALFRED PASIEKA/SCIENCE PHOTO LIBRARY (RIGHT)

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TARGETING TRAUMATIC BRAIN INJURY

DBS was first tested in TBI a decade ago, when Cornell University neuroscientist Nicholas Schiff, MD, led a team that used it to treat a 38-year-old man with TBI who had been in a minimally conscious state for years. After surgery, the patient, who had previously only been able to make slight eye or finger movements, was able to communicate with words and gestures, respond to questions, and even chew and swallow his food, no longer requiring a feeding tube.

In 2016, Dr. Rezai published the results of a small study in Neurosurgery that investigated the effects of DBS on four patients who had sustained TBIs from car accidents that occurred between six and 21 years earlier. All four had significant functional difficulties and couldn't be alone overnight. Three of them needed help with dressing, grooming, and using the bathroom. After two years of DBS treatment, three of the four participants were significantly more independent and were doing better behaviorally and emotionally. Within the next three years, Dr. Rezai plans to launch a multicenter trial of the procedure for patients with TBI.

With the expanded use of DBS, doctors are looking at treating the brain circuits underpinning neurologic symptoms. “The better we understand these circuits, the more specific we can be in our targeting,” says Dr. Okun. “In the brain, if you miss your target by a millimeter, that can be like the distance between Florida and California.”

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Assess the Risks

The use of deep brain stimulation (DBS) for Parkinson's disease, dystonia, and essential tremor is well established, but the procedure is still brain surgery. “Even though it is somewhat minimally invasive and patients often go home the next day, DBS still involves drilling a hole in the skull,” says Michael S. Okun, MD, FAAN, chair of the department of neurology and co-director of the Center for Movement Disorders and Neurorestoration at the University of Florida in Gainesville and national medical director of the Parkinson's Foundation.

The operation itself is risky and may cause serious complications such as a stroke, seizures, or bleeding. Other complications include infection and temporary pain and swelling at the site where the device was implanted. The hardware can also malfunction. People who undergo DBS sometimes experience mood and behavioral disturbances such as depression, reckless behavior, and cognitive decline, as well as problems with speech. In some cases, the doctor can adjust the stimulation settings to minimize these side effects.

It's also important to understand that some trials of DBS—especially larger, randomized trials—involve “sham” stimulation. This means that some patients will still undergo the surgery, but the implanted device will not be turned on.

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PROCEED WITH CAUTION

Bear in mind that while recent research has been tantalizing, all other uses of DBS—including for Alzheimer's disease, depression, stroke, and traumatic brain injury—remain unapproved and unproven, says Janis Miyasaki, MD, director of the Movement Disorders Program at the University of Alberta in Canada. No one should undergo DBS for any of these new indications outside the setting of a clinical trial, and everyone should have a clear understanding of the risks.

“Many of these newer indications have demonstrated benefit in anecdotal or case series only,” says Dr. Miyasaki. “Furthermore, studies of the placebo effect demonstrate that the more expensive and intensive the proposed treatment, the greater the placebo effect. Therefore, recommending an invasive procedure with potential long-lasting problems needs to be done with great care. I have seen amazing results with DBS for movement disorders, but also devastating complications,” she says.

Candidates for the device need to be chosen carefully by a multi-disciplinary team, and the skills of the surgeon and device programmer need to be top-notch, Dr. Miyasaki adds. “The research is exciting, but we need to proceed with caution.”

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The Mechanics

Deep brain stimulation (DBS) devices have three main components, according to the National Parkinson Foundation:

  • A lead: a thin, insulated wire that is implanted by a neurosurgeon into the targeted brain area through a small opening in the skull;
  • An extension: another insulated wire that passes from the lead under the skin of the head, neck, and shoulder to connect with the third component, the neurostimulator;
  • A neurostimulator: a battery-operated device about the size of a large stopwatch that is implanted under the skin near the collarbone.

The lead must be placed in exactly the right spot; being off by even a millimeter could produce adverse effects, such as new or worsening problems with walking, balance, coordination, speech, mood, and cognition. The procedure is usually done while the patient is awake so the surgeons can ask questions and instruct the patient to engage in specific tasks, making sure the placement is accurate. More recently, MRI-guided DBS placement has also become available, making DBS an option for patients who are uncomfortable with the idea of being awake during brain surgery.

Once the lead is in place, the neurostimulator sends electrical pulses to precise areas in the brain, blocking the abnormal signals that cause neurologic and neuropsychiatric symptoms. A specialized remote control can be used by the patient, the doctor, or both to program the stimulator's settings. Some people have the stimulator on 24 hours a day, while others are advised by their doctor to turn it off and on at specific times.

© 2017 American Academy of Neurology