summary: A new computer model shows that the beneficial effects of DBS arise from the way it interrupts the beta-boosting cycle on the runway in a circular loop between the hypothalamic nucleus and the striatum.
source: Bakeware Institute for Learning and Memory
People with Parkinson’s disease and their doctors face many unknowns, including the answer to how well deep brain stimulation (DBS) can relieve some of patients’ motor symptoms.
In a new study, scientists at Boston University and the Beckware Institute for Learning and Memory at MIT present a detailed model that explains the underlying circuit dynamics and provides an explanation that, if confirmed empirically, could improve treatment further.
One of the things known about Parkinson’s disease is that a deficiency in the neuromodulator dopamine is associated with abnormally high beta-repetition rhythms (brain waves of around 20 Hz). DBS, which involves delivering high-frequency electrical stimulation to a region called the hypothalamic nucleus (STN), apparently suppresses elevated beta rhythms, restoring a healthy balance with other rhythm frequencies and better movement control.
The new computational model based on biophysics described in Proceedings of the National Academy of Sciences It is assumed that the beneficial effect of DBS arises from how a treadmill promoting runaway beta is interrupted in a circuit loop between the STN and a region called the striatum.
In 2011, study co-author Michelle McCarthy, associate research professor of mathematics and statistics at Boston University, used mathematical models to show how in the absence of dopamine, runaway beta in the striatum may arise from excessive excitation among cells that live in the striatum that Medium spinal neurons (MSNs) are called.
The model, led by Eli Adam, a postdoctoral researcher at the Becker Institute, builds on McCarthy’s discovery. Joining Adam McCarthy is co-authors Emery N. Brown, the Edward Hood Taplin Professor of Medical Engineering and Computational Neuroscience at MIT and Nancy Koppel and William Fairfield Warren distinct Professor of Mathematics and Statistics at Boston University.
The Quartet’s work hypothesizes that under healthy conditions, with sufficient dopamine, cells in the striatum, called fast-rising interneurons (FSI), can produce gamma-frequency rhythms (30-100 Hz) that regulate the beta activity of MSNs.
But without dopamine, FSIs cannot limit MSN activity and beta comes to dominate a complete circuit loop connecting the STN to FSIs, to MSNs, to other regions and then back to the STN.
“The FSI gamma is important to keep MSN beta in check,” Adam said. “When dopamine levels drop, MSN can produce more beta and the FSI loses its ability to produce gamma to quench this beta, thus becoming wild beta. The FSI is then bombarded with beta activity and becomes beta channels themselves, amplifying them.”
When high-frequency DBS stimulation is applied to the STN, a model emerges, which replaces the massive beta input received by FSIs and restores their excitability.
After being activated and freed from these beta restrictions, endogenous neurons resume producing gamma oscillations (at about half the DBS stimulation frequency, typically at 135 Hz) which then suppress the beta activity of the MSNs. Since MSNs no longer produce much beta, the loop leading to STN and then to FSIs is no longer controlled by this frequency.
“DBS stops beta propagating toward FSIs so that they are not amplified, and then, by additionally excited FSIs, restores the ability of FSIs to produce strong gamma oscillations, which in turn will dampen beta at their source,” Adam said.
The model reveals another important wrinkle. Under normal circumstances, different levels of dopamine help in the formation of the gamma produced by FSIs. But FSIs also receive input from the cerebral cortex.
In Parkinson’s disease, in which dopamine is absent and beta-dominant, FSI loses its regulatory flexibility, but amid DBS, with beta-dominance perturbation, FSI can instead be modulated by input from the cortex even with the persistent absence of dopamine. This gives them a way to lower the speed of the gamma they deliver to MSN, enabling the harmonious expression of beta, gamma, and theta rhythms.
By providing a deep physiology-based explanation of how DBS works, the study may also provide clues to clinicians on how to make it work better for patients, the authors said. The key is to find optimal gamma rhythms in FSIs, which may vary slightly from patient to patient. If this can be determined, adjusting the DBS stimulation frequency to enhance this gamma output should ensure the best results.
Before testing this, the underlying results of the model must be validated empirically. The authors said that the model makes predictions necessary to move forward with such a test.
The National Institutes of Health provided funding for the research.
About Parkinson’s Disease Research News and DBS
author: David Orenstein
source: Bakeware Institute for Learning and Memory
Contact: David Orenstein – Becker Institute for Learning and Memory
picture: The image is in the public domain
original search: Access closed.
“Deep brain stimulation in the hypothalamic nucleus of Parkinson’s disease can restore the dynamics of striatal networks” by Michael McCarthy et al. PNAS
Deep brain stimulation in the hypothalamic nucleus of Parkinson’s disease can restore the dynamics of striatal networks
Deep brain stimulation (DBS) of the hypothalamic nucleus (STN) is highly effective in relieving motor impairment in patients with Parkinson’s disease (PD). However, its therapeutic mechanism of action is unknown.
The healthy diagram shows rich dynamics resulting from the interaction of beta, gamma and theta oscillations. These rhythms are essential for the selection and execution of motor programs, and their loss or exaggeration due to dopamine (DA) depletion in PD is a major source of behavioral deficits.
Restoring normal rhythms may be helpful in the remedial procedure of DBS. We develop a biophysical retinal model of the BG pathway to study how abnormal beta oscillations can manifest throughout the BG in PD and how DBS can restore normal beta, gamma, and theta rhythms.
Our model includes STN projections on the striatum, the long known but poorly studied one, which has been found to preferentially target fast-spiking intrinsic (FSI) neurons. We found that DBS in the STN can normalize the activity of striatal mesenchymal spinal neurons by recruiting FSI dynamics and restoring the inhibitory potency of FSIs observed under normal conditions.
We also found that deep brain stimulation allows re-expression of gamma and theta rhythms, which are thought to be dependent on elevated DA levels and thus lost in PD, through cortical noise control. Our study highlights that the effects of DBS can go beyond the regulation of BG output dynamics to restore normal endogenous BG dynamics and its ability to be regulated.
It also suggests how gamma and theta oscillations can be utilized to complement and enhance the effectiveness of DBS treatment.