People with Parkinson’s disease and their doctors face many unknowns, including the exact answer to the question of how deep brain stimulation (DBS) relieves some of the motor symptoms experienced by patients. In a new study, scientists from Boston University and MIT’s Picower Institute for Learning and Memory present a detailed model explaining the circuit’s underlying dynamics, providing an explanation that, if confirmed experimentally, could further improve therapy.
Among the things that are known about Parkinson’s disease, 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 an area called the subthalamic nucleus (STN), apparently suppresses these elevated beta rhythms, restoring a healthier balance with other rhythmic frequencies and better control of movements.
The new biophysics-based computer model described in the Proceedings of the National Academy of Sciences postulates that the beneficial effect of DBS arises from the way it interrupts a vicious circle promoting beta runaway in a circuit loop between the STN and a region called the striatum. In 2011, study co-author Michelle McCarthy, assistant research professor of mathematics and statistics at BU, used mathematical models to show how, in the absence of dopamine, runaway beta could arise in the striatum at cause of excessive excitation among cells living in the striatum called middle cells. spiny neurons (MSN).
The model, led by postdoc Elie Adam of the Picower Institute, builds on McCarthy’s discovery. Adam and McCarthy join co-authors Emery N. Brown, Edward Hood Taplin Professor of Medical Engineering and Computational Neuroscience at MIT and Nancy Kopell, William Fairfield Warren Distinct Professor of Mathematics and Statistics at the BU. The quartet’s work posits that under healthy conditions, with adequate dopamine, striatal cells called fast-spiking interneurons (FSIs) can produce gamma frequency rhythms (30-100 Hz) that regulate MSN beta activity. But without dopamine, the ISPs are unable to limit MSN activity, and beta comes to dominate a whole circuit loop linking the STN to the ISPs, to the MSNs, to other regions, and then to the STN.
Gamma FSI is important for controlling MSN beta. 0When dopamine levels drop, MSNs can produce more beta and ISPs lose their ability to produce gamma to turn off that beta, so the beta goes wild. ISPs are then bombarded with beta activity and themselves become conduits for beta, leading to its amplification.”
Elie Adam, postdoctoral fellow at the Picower Institute
When the high frequency DBS stimulation is applied to the STN, the model shows that this replaces the overwhelming beta input received by the FSIs and restores their excitability. Invigorated and freed from these beta shackles, the interneurons begin to produce gamma oscillations again (at about half the DBS stimulation frequency, typically 135 Hz) which then suppress beta activity from the MSNs. Since MSNs no longer produce too much beta, the loop leading back to the RTC and then to the ISPs is no longer dominated by this frequency.
“DBS prevents the beta from propagating to the ISPs so that it is no longer amplified, and then, by additionally exciting the ISPs, restores the ability of the ISPs to produce strong gamma oscillations, which in turn will inhibit the beta at its source,” Adam said.
The model reveals another significant wrinkle. Under normal circumstances, different levels of dopamine help shape the gamma produced by ISPs. But ISPs also receive information from the cerebral cortex. In Parkinson’s disease, where dopamine is absent and beta becomes dominant, FSIs lose their regulatory flexibility, but in the middle of DBS, with beta dominance disrupted, FSIs may instead be modulated by input from the cortex even with dopamine still absent. This allows them to limit the gamma they provide to MSNs and allow harmonious expression of beta, gamma, and theta rhythms.
By providing a deep physiology-based explanation of how DBS works, the study may also offer clinicians clues about how to make it work best for patients, the authors said. The key is to find the optimal gamma rhythms of ISFs, which can vary quite a bit from patient to patient. If this can be determined, adjusting the DBS stimulation rate to favor this gamma output should ensure the best results.
Before this can be tested, however, the fundamental results of the model must be validated experimentally. The model makes the predictions necessary for such tests to proceed, the authors said.
The National Institutes of Health funded the research.
Adam, EM, et al. (2022) Deep brain stimulation in the subthalamic nucleus of Parkinson’s disease can restore the dynamics of striatal networks. PNAS. doi.org/10.1073/pnas.2120808119.
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