For release: Wednesday, June 17, 2009
Electrical stimulation of the spinal cord relieves symptoms of Parkinson's disease in rodents, according to a new study published in Science*. The procedure might provide a safe, effective alternative to deep brain stimulation (DBS), a relatively invasive treatment for Parkinson's disease that is used when medication fails.
"This could be a completely new avenue for treating patients," says Miguel Nicolelis, M.D., Ph.D., the study's senior author and a neurobiologist at Duke University Medical Center in Durham, N.C. The study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of Mental Heath (NIMH), both components of the National Institutes of Health (NIH).
People with PD typically develop involuntary shaking, slowness of movement, stiffened muscles and impaired balance. The disease is caused by the destruction of brain cells that produce the chemical dopamine. Researchers do not know exactly how loss of these cells relates to the symptoms of PD, but they have seen telling patterns of abnormal electrical activity in patients’ brains.
Most patients benefit from the drug L-dopa, a relative of dopamine, in early stages of the disease. In later stages, L-dopa tends to become less effective and patients may turn to DBS, which involves surgically implanting electrodes deep within the brain and using them to deliver stimulation to specific regions such as the substantia nigra – the home of the lost dopamine-producing cells. Although DBS was first tested nearly 30 years ago, scientists still do not understand precisely how it works.
The technique developed by Dr. Nicolelis and his co-authors is called dorsal column stimulation (DCS). The dorsal column is a part of the spinal cord that connects to movement centers in the brain. In their new study, the researchers implanted electrodes over the dorsal column, near the shoulder blades, in mice and rats with parkinsonism. They found that DCS produced dramatic increases in the rodents’ speed and range of movement during behavioral tests – up to 26 times faster than without DCS.
The surgical procedures involved in DCS are low risk compared to those involved in DBS. DBS requires penetrating the brain and targeting the electrodes to small regions in the brain. By contrast, “the dorsal column is one of the largest bundles of nerve fibers in the body, and we can use it to alter the brain’s circuitry without trying to find a magic spot inside the brain,” Dr. Nicolelis says. Those aspects of DCS could make it safer and more broadly available than DBS.
Two pieces of research laid the groundwork for DCS. The first piece was the identification of abnormal brain activity patterns associated with PD, which are mostly seen in the motor cortex – a region at the top and front of the brain. In experiments on mice with parkinsonism, Dr. Nicolelis was able to examine these activity patterns in unprecedented detail, to the level of individual brain cells. In normal mice, the activity of individual cells in the motor cortex looks chaotic, but in mice with parkinsonism, the cells’ activity is more synchronized.
“These activity patterns reminded me of low-amplitude epileptic seizures,” Dr. Nicolelis says.
That was when the second piece of DCS research fell into place. About 10 years ago, Dr. Nicolelis developed a nerve stimulation treatment for epilepsy that has since entered pilot trials. He showed that in mice, it was possible to suppress seizure activity in the brain by delivering mild electrical stimulation to nerves in the face. He reasoned that a similar treatment might be effective against PD.
Making those logical connections and developing the technology for DCS required an outside-the-box approach, notes Yuan Liu, Ph.D., a program director at NINDS. “This study would not have been possible without the expertise that Dr. Nicloelis’s research team has in computational analysis and bioengineering. It is a prime example of how developing potential therapies for neurological disease sometimes requires a multidisciplinary approach that brings in fields besides neurology.”
Dr. Nicolelis and his co-authors first tested their technique in rodents with acute symptoms of PD. The researchers induced those symptoms by using a combination of drugs and genetic techniques to temporarily deplete dopamine in the animals’ brains. DCS by itself increased the animals’ mobility within seconds. DCS combined with L-dopa was even more effective, and less L-dopa was needed to relieve the animals’ symptoms. To reach the same level of mobility, mice receiving the combined treatment needed 80% less L-dopa than mice on the drug alone.
Next, the researchers tested DCS in rodents with a chronic condition that more closely resembles PD. Rather than temporarily shutting down the animals’ dopamine-producing cells, the researchers used a toxin to destroy the cells. Like the animals with acute symptoms, the animals with chronic symptoms gained mobility during DCS.
In addition to introducing DCS as a possible alternative to DBS, the study also sheds light on how both techniques work, Dr. Nicolelis says. He and his team found that DCS had effects on the activity within the rodents’ brains that preceded its effects on behavior. The activity – or firing – of cells in the motor cortex became less synchronized, approaching the firing pattern seen in a healthy brain.
“We think that by adding some noise to the system, DCS disrupts the synchronized pattern [in the cortex] and allows the brain cells to fire in a more distributed way,” Dr. Nicolelis says. DBS probably has a similar effect, he says.
Recently, another NIH-funded team also reported in Science** that DBS appears to act on cells in the cortex. Through a technique called optogenetics, which involves inserting light-sensitive proteins into cells, the researchers were able to use light to either stimulate or inhibit cells within the substantia nigra. Neither of those approaches mimicked the effects of DBS. Instead, using light to stimulate cortical cells that extend down into the substantia nigra was the key to reproducing the effects of DBS.
*Fuentes R et al. “Spinal Cord Stimulation Restores Locomotion in Animal Models of Parkinson's Disease.” Science, March 20, 2009, Vol. 323 (5921), pp. 1578 – 1582.
**Gradinaru V. et al. “Optical Deconstruction of Parkinsonian Neural Circuitry.” Science, April 17, 2009, Vol. 324 (5925), pp. 354 - 359.
-By Daniel Stimson, Ph.D.
Last Modified June 17, 2009