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Surgical Technique Halts Cell Loss, Parkinson Disease
09/02/2008
Deep-brain stimulation, a surgical technique often viewed as a last resort for people with Parkinson disease, halts the progression of dopamine-cell loss in animal models, according to preliminary research by a team of UC scientists that includes Michael Behbehani, PhD professor emeritus of molecular and cellular physiology and of anesthesia.
The scientists also discovered clues to why the technique works. The act of stimulating neurons with electrodes boosted the amount of an important protein in animalsÕ brains. The protein, a trophic factor known as BDNF (brain-derived neurotrophic factor), is a nurturing, growth-promoting chemical. Parkinson disease is a degenerative neurological disorder involving the death of dopamine-producing brain cells, or neurons.
"Demonstrating that deep-brain stimulation halts the progression of dopamine-cell loss was basically a confirmation and extension of previous findings," says Caryl Sortwell, PhD, associate professor of neurology at UC and the study's lead investigator. "But finding the mechanism is a novel discovery that is even more critical. We now know not only that it works, we also are beginning to understand how it is working." The study was unveiled at a conference held by the Cleveland Clinic and the National Institute of Neurological Disorders and Stroke.
The research holds important implications for patients with Parkinson disease and could alter the current recommended timetable for surgical intervention. In a typical treatment scenario, a patient has lost about 50 percent of his or her dopamine-producing neurons when symptoms first appear and a diagnosis is made. The typical patient then waits an average of 14 additional years before undergoing deep brain stimulation surgery. During that 14-year span, medications can offer symptomatic relief, but cell loss continues unabated. There is at present no cure for the disease.
The UC research study was a response to an observation by physicians, including co-investigator George Mandybur, MD, associate professor of neurosurgery, who have long been able to neutralize, in certain patients, some of the most debilitating symptoms of Parkinson disease, including tremor, stiffness, and slowness, by stimulating an area deep within the brain.
"The surgery for Parkinson disease has been available for over 10 years, and in that time we have noticed that in some patients the disease does not seem to progress as rapidly after surgery as it did before the surgery," says Mandybur, a neurosurgeon with the Mayfield Clinic. As a result, he and others theorized that deep-brain stimulation not only alleviated symptoms, but also provided neuroprotection.
The UC study, Mandybur says, "helps us understand why this is going on and what may be happening in the brain. It also gives some evidence to support performing the surgery earlier to slow the overall progression of Parkinson disease."
Sortwell's study, which is continuing, is supported by a $120,000 grant from the Sunflower Revolution fundraiser, a partnership of the University Hospital Foundation and the Davis Phinney Foundation. The initial study platform was funded by UC's Millennium Fund and subsequently by the Neuroscience Institute.
During the study, researchers implanted high-frequency stimulating electrodes in the subthalamic nucleus, an area of the brain associated with movement, in rats and then induced dopamine neuron loss. When the rats had experienced a 50% loss of dopamine neurons, the researchers initiated brain stimulation in half of the group. Measurements of surviving, functioning dopamine neurons in rats implanted with active stimulators were then compared to a control group implanted with inactive stimulators. While the control group's loss of dopamine neurons increased to 75% after two weeks, the rats implanted with active stimulators experienced no further loss of cells during that time.
Subsequent tissue analysis revealed that in rats implanted with active stimulators the trophic factor BDNF had tripled in the striatum, a part of the brain that houses dopamine terminals and 'receives' the dopamine neurotransmitters that are produced in the substantia nigra.
The study has brought together investigators from four academic disciplines: joining Sortwell, Behbehani and Mandybur on this study were Timothy Collier, PhD and doctoral student Anne Spieles-Engemann, from UCÕs department of neurology, Jack Lipton, PhD from the department of psychiatry. Behbehani established the method for implanting the electrodes in the rat's tiny subthalamic nucleus.
Michael Behbehani, PhD, Caryl Sortwell, PhD and a team of UC investigators found that deep-brain stimulation can help halt the progression of Parkinson disease.
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