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


Summary: A new computer model shows that the beneficial effects of deep brain stimulation arise from the way it interrupts the cycle favoring the beta track in a circuit loop between the subthalamic nucleus and the striatum.

Source: Picower Institute for Learning and Memory

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.

“The FSI gamma is important for controlling the MSN beta,” Adam said. “When 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. The ISPs then get bombarded with beta activity and become them themselves conduits for beta, leading to its amplification.

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 to its source,” Adam said.

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). Image is in public domain

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.

About this DBS and Parkinson’s disease research news

Author: David Orenstein
Source: Picower Institute for Learning and Memory
Contact: David Orenstein – Picower Institute for Learning and Memory
Picture: Image is in public domain

Original research: Access closed.
“Deep brain stimulation in the subthalamic nucleus of Parkinson’s disease can restore the dynamics of striatal networks” by Michelle McCarthy et al. PNAS


Abstract

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Deep brain stimulation in the subthalamic nucleus of Parkinson’s disease can restore the dynamics of striatal networks

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is highly effective in alleviating movement disability in patients with Parkinson’s disease (PD). However, its mechanism of therapeutic action is unknown.

The healthy striatum exhibits rich dynamics resulting from an 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.

The restoration of natural rhythms can then play a decisive role in the therapeutic action of DBS. We are developing a networked biophysical model of a BG pathway to study how abnormal beta oscillations can emerge throughout the BG in PD and how DBS can restore normal beta, gamma, and theta striatal rhythms.

Our model incorporates long-known but understudied STN projections to the striatum, which preferentially target fast-spiking interneurons (FSI). We find that DBS in the STN can normalize the activity of striatal middle spiny neurons by recruiting FSI dynamics and restoring the inhibitory potency of FSI observed under normal conditions.

We also find that DBS allows reexpression of gamma and theta rhythms, which are thought to be dependent on high levels of DA and therefore lost in PD, through cortical noise control. Our study highlights that DBS effects may go beyond regulating blood glucose outflow dynamics to restoring normal internal blood glucose dynamics and the ability to regulate them.

It also suggests how gamma and theta oscillations can be harnessed to complement DBS treatment and improve its effectiveness.


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