New Mechanisms Propel DBS for Movement Disorders

by James Cavuoto, editor

January 2017 issue

Advances in our understanding of the neural mechanisms involved with movement disorders—and in normal movement—promise to enhance DBS therapies for neurological disorders such as Parkinson’s disease, essential termor, dystonia, and Tourette’s syndrome.

In the initial stage of PD, patients’ movements are stiff and slow. This can be remedied with the drug L-dopa, but after a few years of treatment, patients usually develop uncontrolled jerking motions known as dyskinesias.

In recent years, several neurosurgeons and neuroengineers working on DBS for movement disorders have proposed potential brain signals that may be markers of abnormal brain activity giving rise to motor symptoms such as rigidity or bradykinesia. Investigators first looked at beta oscillation emanating from the basal ganglia as a potential indicator of dyskinesia. More recently, researchers have looked at the coupling between the phase of the beta rhythm in motor cortex and the amplitude of broadband activity in the brain. This abnormal synchrony, or “phase amplitude coupling,” is now seen as a more useful biomarker for movement disorders. In 2015, Phil Starr’s team at UC San Francisco published a paper in Nature Neuroscience that showed that DBS reduces PAC in Parkinson’s disease.

At the recent NANS meeting in Las Vegas, Kelly Foote from the University of Florida suggested that beta rhythms may “gate” motor function, acting as an abnormal suppressor that gives rise to rigidity and bradykinesia.

Investigators at Lund University in Sweden have recently made a similar suggestion about certain pathways in the striatum. “We know that the striatum plays an important role in movement control. But which neural pathways are most important has been hotly debated,” said Parkinson’s researcher Angela Cenci Nilsson in Lund.

The striatum has two principal types of cells forming distinct neural pathways, termed “direct pathway” and “indirect pathway,” respectively. The research debate has centered on whether both pathways are equally important in all situations, and whether they need to cooperate or can work independently. To address this, the Lund researchers applied a method called chemogenetics. Using a harmless virus, they introduced a new gene into one or the other type of striatal cell in laboratory mice. The gene coded for the production of a receptor protein activating the relevant neural pathway. However, the receptor became stimulated only when the animal was administered a particular substance whose effect lasted a couple of hours. Using this method, they were able to control the activity of cells forming the direct or indirect pathway while studying the animals’ behavior. Studies were conducted on both normal mice and animals with a Parkinson’s-like injury, and both with or without L-dopa.

The results showed that all types of movements were controlled by both pathways, which proved to function as a sort of “accelerator” (the direct pathway) and “brake” (the indirect pathway), respectively. In Parkinson’s mice treated with L-dopa, activation of the direct pathway produced faster movements but also more severe dyskinesias, mimicking both the advantages and the disadvantages of Parkinson’s therapy. On the other hand, activation of the indirect pathway gave slower movements but also eased the dyskinesias caused by L-dopa.

“We interpret these results to mean that the pathways need to interact in all situations, even in Parkinson’s-like conditions and upon L-dopa treatment. You can’t have only acceleration and no braking, but must instead balance both functions in a precise manner,” said Nilsson.

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