People with Parkinson’s disease and their doctors confront many unknowns, including the answer to exactly how deep brain stimulation (DBS) relieves of the motor symptoms patients experience.
In a new study, scientists at Boston University and The Pi cower Institute for Learning and Memory at MIT present a detailed model explaining the underlying circuit dynamics, providing an explanation that, if experimentally confirmed, could improve the therapy further.
Among the things that are known about Parkinson’s disease is that a deficit of the neuromodulator dopamine is associated with abnormally high beta-frequency rhythms (brain waves at a frequency of about 20 Hz). DBS, involving the delivery of high-frequency electrical stimulation to a region 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 bio physically-based computational model described in the Proceedings of the National Academy of Sciences posits that the beneficial effect of DBS arises from how it interrupts a vicious cycle promoting runaway beta in a circuit loop between the STN and a region called the striatum.
In 2011, study co-author Michelle McCarthy, research assistant professor of mathematics and statistics at BU, used mathematical models to show how, in the absence of dopamine, runaway beta might arise in the striatum from excessive excitement among striatum-dwelling cells called medium spiny neurons (MSN).
The model, led by Pi cower Institute postdoc Elie Adam, builds on McCarthy’s finding. Joining Adam and McCarthy are co-authors Emery N. Brown, Edward Hood Tapeline Professor of Medical Engineering and Computational Neuroscience at MIT and Nancy Koppel, William Fairfield Warren Distinguished Professor of Mathematics and Statistics at BU.
The quartet’s work posits that under healthy conditions, with adequate dopamine, cells in the striatum called fast-spiking interneurons (FSI) can produce gamma-frequency rhythms (30-100 Hz) that regulate the beta activity of the MSN's,
But without dopamine, the FSI are unable to limit the MSN activity and beta comes to dominate a whole circuit loop connecting the STN to the FSI, s to the MSN, s to other regions and then back to the STN.
“The FSI gamma is important to keep the MSN beta in check,” Adam said. “When dopamine levels go down, the MSN's can produce more beta and the FSI lose their ability to produce gamma to quench that beta, so the beta goes wild. The FSI's are then bombarded with beta activity and become conduits for beta themselves, leading to its amplification.”
When DBS high-frequency stimulation is applied to the STN, the model shows, that replaces the overwhelming beta input received by the FSI, s and restores their excitability. Reinvigorated and freed from those beta shackles, the interneurons resume producing gamma oscillations (at about half the DBS stimulation frequency, typically at 135 Hz) that then suppress the beta activity of the MSN's. With the MSN's no longer producing too much beta, the loop leading back to the STN and then to the FSI's is no longer dominated by that frequency.
“DBS stops the beta from propagating towards FSI, s so that it is no longer amplified, and then, by additionally exciting FSI, restores the ability of FSI, s to produce strong gamma oscillations, that will in turn inhibit beta at its source,” Adam said.
Among the things that are known about Parkinson’s disease is that a deficit of the neuromodulator dopamine is associated with abnormally high beta-frequency rhythms (brain waves at a frequency of about 20 Hz). Image is in the public domain
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