Circuit model may explain how deep brain stimulation treats Parkinson’s disease symptoms

Newswise – People with Parkinson’s disease and their doctors face many unknowns, including the answer to how exactly deep brain stimulation (DBS) relieves some of the motor symptoms patients experience. In a new study, scientists from Boston University and the Picower Institute for Learning and Memory at MIT present a detailed model that explains the underlying circuit dynamics and provides an explanation that, if confirmed experimentally, could further improve therapy.

One of the things that is known about Parkinson’s disease is that a deficiency of the neuromodulator dopamine is associated with abnormally high beta-frequency rhythms (brain waves with a frequency of about 20 Hz). DBS, in which high-frequency electrical stimulation is delivered to an area called the subthalamic nucleus (STN), apparently suppresses these elevated beta rhythms, restoring a healthier balance with other rhythm frequencies and better movement control.

The new biophysical based computational model described in the Proceedings of the National Academy of Sciences states that DBS’s beneficial effect stems from the way it interrupts a vicious circle that promotes runaway beta in a circuit loop between the STN and a region called the striatum. In 2011, co-author studied Michelle McCarthyresearch assistant professor of mathematics and statistics at BU, used mathematical models to show how, in the absence of dopamine, runaway beta can arise in the striatum from overexcitement between striatum-inhabiting cells that form medium spiny neurons (MSNs) are called.

The model, led by Picower Institute postdoc Elie Adam, builds on McCarthy’s finding. Along with Adam and McCarthy are co-authors Emery N. BrownEdward Hood Taplin Professor of Medical Engineering and Computational Neuroscience at MIT and Nancy KopelloWilliam Fairfield Warren Distinctive Professor of Mathematics and Statistics at the BU. The quartet’s work states that under healthy conditions, with enough dopamine, cells in the striatum called fast-spiking interneurons (FSIs) can produce gamma-frequency rhythms (30-100 Hz) that regulate the beta activity of the MSNs. But without dopamine, the FSIs are unable to limit MSN activity and beta dominates an entire circuit loop connecting the STN to the FSIs, to the MSNs, to other regions and then back to the STN.

“The FSI gamut is important to keep the MSN beta in check,” Adam said. “If the dopamine level drops, the MSNs can produce more beta and the FSIs lose their ability to produce gamma to quench that beta, so the beta goes wild. The FSIs are then bombarded with beta activity and become channels for beta themselves, leading to its amplification.

When DBS high-frequency stimulation is applied to the STN, the model shows that it replaces the overwhelming beta input received by the FSIs and restores their excitability. Revived and freed from those beta chains, the interneurons resume producing gamma oscillations (at about half the DBS pacing frequency, typically at 135 Hz) which then suppress the beta activity of the MSNs. Now that the MSNs are no longer producing too much beta, the loop going back to the STN and then to the FSIs is no longer dominated by that frequency.

“DBS stops the spread of the beta to FSIs so that it is no longer amplified, and then, through additional exciting FSIs, restores the ability of FSIs to produce strong gamma oscillations, which in turn will inhibit beta at the source, said Adam.

The model reveals another important wrinkle. Under normal circumstances, different levels of dopamine help shape the gamma produced by the FSIs. But the FSIs also get input from the cerebral cortex. In Parkinson’s disease, where dopamine is absent and beta becomes dominant, the FSIs lose their regulatory flexibility, but in the midst of DBS, with impaired beta dominance, the FSIs may instead be modulated by input from the cortex, even if dopamine is still absent. That allows them to reduce the gamma they deliver to the MSNs and allow harmonious expression of beta, gamma and theta rhythms.

By providing an in-depth, physiology-based explanation of how DBS works, the study may also provide clinicians with clues about how to make it work best for patients, the authors said. The key is finding the optimal gamma rhythms of the FSIs, which can vary a bit from patient to patient. If that can be determined, then tuning the DBS pacing rate to favor that gamma output should give the best results.

However, before that can be tested, the fundamental findings of the model must be validated experimentally. The model makes predictions necessary for such tests to proceed, the authors said.

The National Institutes of Health funded the research.


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