Deep brain stimulation (DBS) can improve symptoms of Parkinson disease when drug therapy fails, but exactly how the process works remains a mystery.
Because similar improvement can be achieved with surgical lesions, a process in which an electrical current or laser selectively destroys abnormally active locations in cerebral motor centers in Parkinson disease (PD), it has been thought that DBS works in a similar fashion.
However, a new study appearing online on July 23 before the Sept. 2 print edition of Neurology suggests that rather than inhibiting neuronal activity, DBS actually promotes metabolic changes in neurons that reduce the runaway electrical activity in the subthalamic nucleus (STN) and connected areas of the globus pallidus (GP) in the brain.
Led by Rüdiger Hilker, MD, a professor of neurology at Goethe-University, in Frankfort, researchers used 18-fluorodeoxyglucose (FDG) PET to measure glucose metabolism (regional normalized resting cerebral metabolic rate of glucose) before and after insertion of electrodes, and afterwards when stimulation was turned on and off.
While insertion caused a drop in metabolism similar to the effects of making a lesion, electrical stimulation appeared to excite the STN area and the directly connected pallidum by increasing neuronal output and slowing the overexcited motor areas, starting at the stimulation site and moving outward.
STUDY PROTOCOLS, RESULTS
Twelve patients were evaluated. Each had advanced PD and severe levodopa-associated on-off fluctuations and dyskinesias refractory to medication. The subjects included nine men and three women, with an average age of 65. Their results were compared with those in 10 healthy age-matched controls (six men, four women). Scans were performed two to four weeks before electrode implantation, and then at six weeks to two months after surgery under both on- and off conditions.
Electrode placement without stimulation initially led to significant FDG uptake reduction and slower glucose metabolism in the electrode region and the STN — a microlesional effect — but metabolism then increased sharply after stimulation was applied. This suggests that DBS promotes rather than inhibits metabolic activation in the STN region and the globus pallidus, according to the scientists.
“We conclude that subthalamic nucleus DBS has predominant excitatory properties and does, therefore, fundamentally differ from lesional neurosurgery,” the authors said. “Most important, our findings contradict the view of DBS as a suppressor of neuronal activity resembling a functional lesion of the target site. Our PET data indicate that DBS exerts uniform activation of the electrode area, the STN target region, and of the GP, which implies a mechanism of DBS action fundamentally different from lesional neurosurgery.”
A NEW VIEW OF DBS MECHANISM
While the findings appear to contradict current thinking that STN DBS suppresses neuronal activity, there remain many questions, noted W.R. Wayne Martin, MD, professor of neurology and director of the Movement Disorders Clinic at the University of Alberta-Edmonton in Canada, in an accompanying editorial.
“These data indicate that effective stimulation induces metabolic activation of the STN region and the downstream GP, consistent with local and remote excitation of neurons by high frequency stimulation,” he wrote.
The authors posit that this is most likely due to “tonic driving”— cellular current conduction mechanisms along ortho- and antidromic fibers — in both the target area (STN) and its projection site (GP). Although the observations “are compelling,” wrote Dr. Martin, “they do not completely resolve the mechanistic controversy since contradictory evidence also exists.”
David Eidelberg, MD, the Feinstein Professor of Neurology at New York University Medical Center and director of the Center for Neurosciences at the Feinstein Institute for Medical Research of the North Shore-LIJ Health System in Manhasset, NY, agreed, noting that while the data are robust, the study opens up broader areas for future research.
“The important point is that this is the first study to document a reduction in metabolism in areas specific to the electrode insertion site, but just putting in an electrode can change functional metabolism,” he told Neurology Today in a telephone interview. “It is important to note that while this is positive and useful information, and the researchers are the first to study metabolic changes at baseline and again after both on- and off-stimulation, the actual mechanics remain unclear,” he said.
“The fly in the ointment is that metabolism began and ended at the same point in the patients. Patients were better after the electrode was implanted, but not beyond the level at which they started before. This implies that stimulation has to involve other regions in the brain, not just the insertion site, and creates a conundrum. It forces us to look for other areas and pathways and opens up a whole new set of questions.”
NEWER IMAGING MODALITIES EXPLORE DBS ACTION
Other researchers, including Tipu Aziz, MD, a professor of neurosurgery at the University of Oxford and neurosurgeon at Radcliffe Infirmary in Oxford UK, are using newer imaging techniques to study the mechanics of DBS and its effect and neuronal activity in PD and chronic pain.
Dr. Aziz told Neurology Today in a telephone interview that steady progress is being made to fine-tune DBS by improving the technology and finding new targets for stimulation.
“This paper is really interesting because the researchers have shown that glucose activity decreases at the site of the electrode immediately after being implanted, but before stimulation, similar to what we've observed in surgical lesioning patients who have transient improvement for one or two weeks before falling off. With STN, however, this effect continues, and patients show improvement after a few weeks of stimulation. This paper offers one possible explanation.”
At Oxford, Dr. Aziz and his colleagues are using a newer imaging technique, magnetoencephalography (MEG), to study DBS for PD and chronic pain inhibition. MEG measures changes in magnetic fields associated with neuronal firing, with resolution in milliseconds, that is far more accurate, with greater resolution, and much faster. He said their findings will be published soon.
Dr. Aziz and his team are also working to develop ways to provide intermittent, or as-needed, stimulation in PD patients — similar to how newer generation cardiac pacemakers deliver stimulation to the heart. He noted that DBS devices today are where cardiac pacemakers were several decades ago.
“In Parkinson patients, DBS is currently provided continuously in an open-loop for 24 hours a day. Ideally we should find better targets and frequencies to provide stimulation less often, or only when patients experience early symptoms — or even before — just like pacemakers.”
Hilker R, Voges J, Weber T. STN-DBS activates the target area in Parkinson disease - An FDG-PET study. Neurology 2008;E-pub 2008 July 23.
Martin, WR, Wieler M. Subthalamic nucleus stimulation in Parkinson disease - Exciting or depressing? Neurology 2008;E-pub 2008 July 23.
Aziz T, Stein J. Oscillatory activity and deep brain stimulation in the pedunculopontine nucleus. Exp Neurol
Jenkinson N, Nandi D, Aziz T, et al. Pedunculopontine nucleus electric stimulation alleviates akinesia independently of domaminergic mechanisms. Neuroreport