Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been shown to be an effective treatment for movement disorders, including Parkinson's disease, essential tremor and dystonia. More recently, DBS has emerged as a treatment option for Tourette syndrome. However, the exact mechanisms that lead to successful DBS treatment remain undefined.
At Mayo Clinic in Rochester, Minnesota, neurologists and neurosurgeons offer DBS for selected patients while also researching the procedure's therapeutic mechanism, with a goal of personalizing and improving treatment. Mayo Clinic's large patient volumes and multidisciplinary approach provide a breadth of experience to enhance patient treatment and research efforts.
"DBS is not a cure for these movement disorders, and while the results of treatment aren't perfect, many patients have excellent results and for some, DBS can be life-changing," says Bryan T. Klassen, M.D., a consultant in Neurology at Mayo Clinic in Rochester, Minnesota.
"We have come so far," adds Kendall H. Lee, M.D., Ph.D., a consultant in Neurologic Surgery at Mayo Clinic's Minnesota campus. "Our research findings are helping us to better understand how DBS works and how to refine stimulation in our patients to ease symptoms of movement disorders."
Multidisciplinary patient selection
DBS is considered an option for patients with movement disorders refractory to medication. However, patient selection is key. Those with Parkinson's disease should be experiencing shorter duration of therapeutic effect from medication or medication intolerance after initial improvement of symptoms. Cognitive impairment is generally a contraindication for the surgery; speech and balance problems usually don't respond to DBS.
At Mayo Clinic, after initial evaluation by a neurologist, patients considered possible candidates for DBS have MRI, speech pathology testing, cognitive assessment and evaluation by a neuropsychiatrist, and consultation with a neurosurgeon. "We have a very integrated approach, and we're all in the same building," Dr. Klassen says.
A multidisciplinary committee discusses the test results to determine whether DBS is appropriate. "With our long experience, we understand the profile of a good candidate for DBS, and what we can expect from treatment of that particular patient," Dr. Klassen says.
The multidisciplinary approach continues in the operating room, where the patient's neurologist is present alongside the surgeon. "As neurologists, we have context for the patients — knowing how they functioned in the clinic and seeing how they respond to various voltage settings during surgery," Dr. Klassen says.
Although DBS doesn't always provide complete relief from symptoms, the outcomes can be striking. Dr. Lee cites the use of DBS for essential tremor: Microelectrode recording in the brain area can isolate what Dr. Lee calls "the tremor cells," facilitating correct application of DBS and, commonly, the cessation of tremor in the operating room. "We discover what is abnormal in the brain activity," Dr. Lee says, "and we stop it."
Searching for biomarkers
Mayo Clinic is pursuing several lines of research to understand the therapeutic mechanisms of DBS. One effort involves determining whether DBS evokes neurotransmitter changes — specifically, dopamine release. For the past decade, the Mayo Clinic Neural Engineering Laboratory has worked to develop a device that measures neurochemical changes in response to DBS. The ultimate goal is to drive changes in stimulation parameters based on stimulation-evoked neurochemical changes.
Wireless Instantaneous Neurotransmitter Concentration Sensing System
Mayo Clinic's Wireless Instantaneous Neurotransmitter Concentration Sensing System (WINCS) measures extracellular neurotransmitter concentration in vivo and displays the data graphically in nearly real time.
Funded in part by a grant from the National Institutes of Health Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, the researchers have tested a wireless system in laboratory animals as well as patients undergoing DBS surgery. In a study published in the June 1, 2016, edition of The Journal of Neuroscience, the researchers documented a peak in dopamine release in the caudate and putamen when stimulating the dorsolateral posterior border of the STN in nonhuman primates. The findings suggest that STN DBS provokes dopamine release and that its concentration varies depending on the site being stimulated.
"This novel system allows us to sense neurotransmitters in real time, and see exactly where in the brain we're activating dopamine," Dr. Lee says. "It's leading toward a closed-loop system."
A second line of research seeks an electrophysiological biomarker to guide changes in stimulation parameters for DBS implants. Dr. Klassen is participating in clinical trials of a Medtronic device that delivers DBS therapy while simultaneously sensing and recording brain wave activity in Parkinson's disease patients.
"Once we understand more about why DBS works, we can enhance the effectiveness of the settings and lower the amount of stimulation given to patients," Dr. Klassen says. "Lower stimulation settings may mean fewer side effects, because they result from electrical current spreading to structures other than the ones we want to stimulate."
"We've come to the point where we're very accurate at placing these electrodes," he adds. "When we know more about why DBS works, we can make the systems even smarter."
For more information
Min HK, et al. Dopamine release in the nonhuman primate caudate and putamen depends upon site of stimulation in the subthalamic nucleus. The Journal of Neuroscience. 2016;36:6022.