Cortical Oscillatory Dynamics in Parkinsonian Networks: Biomarkers and the Potential of Theta Frequency Stimulation
June Jung1, Donald W Doherty1, Adam Newton1, Adriana Galvan5, Thomas Wichmann5, Salvador Dura-Bernal1, Hong-Yuan Chu4, Samuel Neymotin3, William W Lytton1,2
1Department of Physiology and Pharmacology, SUNY Downstate Medical Center, NY,2Kings County Hospital, Brooklyn, NY, USA3Nathan Kline Institute, Orangeburg, NY, USA,4Georgetown University, DC, USA,5Emory University, Atlanta, GA, USA
Introduction
Parkinson’s disease (PD) is marked by characteristic motor symptoms including tremors, stiffness, slowed movement, and balance issues, along with non-motor symptoms like cognitive challenges and difficulty making decisions. Symptom onset and severity vary among individuals. While dopaminergic neuron degeneration in the substantia nigra pars compacta (SNc) is a primary cause of motor dysfunction, recent studies highlight the critical role of disrupted oscillatory activity in the primary motor cortex (M1) in PD pathology. Mouse models of PD, including 6-OHDA mouse, and mitoPark mouse have shown reduced excitability in corticospinal pyramidal tract (PT) neurons.
Methods
We adapted an established mouse primary motor cortex (M1) framework, to make a Parkinsonian motor cortex (PD M1) computational model to investigate changes in neural oscillatory activity. The model incorporated experimental observations from the MitoPark mouse including decreased PT intrinsic excitability and reduced thalamocortical synapse strength to PT neurons (decreased 25% at 16–18 weeks; 50% at 25–28 weeks), correlating with disease progression. Multiple oscillation measures were analyzed as potential biomarkers for tracking disease severity.
Results
In vitro results were used to simulate in vivo Parkinsonian cortical activity, revealing progressively disrupted neuronal firing and increased beta oscillations (~20 Hz) with disease progression.Beta-gamma coupling and modulation index were two oscillatory measures that were significantly reduced under Parkinsonian conditions, with the modulation index progressively declining as the disease advanced. Theta-frequency stimulation suppressed beta bursts, enhanced beta-gamma coupling, and partially restored disrupted cortical network activity caused by PD pathophysiology.
Discussion
These findings suggest that the modulation index may serve as a biomarker for tracking Parkinsonian disease severity. Moreover, theta-frequency stimulation of inhibitory interneurons may help restore imbalanced cortical oscillations and could offer an alternative or complementary strategy to current high-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) in PD patients.
AcknowledgementsThis research was funded in part by Aligning Science Across Parkinson’s [ASAP-020572] through the Michael J. Fox Foundation for Parkinson’s Research (MJFF). For the purpose of open access, the author has applied a CC BY public copyright license to all Author Accepted Manuscripts arising from this submission.
References
1. Chen, L., Daniels, S., Kim, Y., & Chu, H.-Y. (2021). Decreased excitability of motor cortical neurons in parkinsonism. Journal of Neuroscience, 41(25), 5553–5565.https://doi.org/10.1523/JNEUROSCI.2694-20.2021
2. Dura-Bernal, S., et al. (2023). Multiscale model of M1 circuits. Cell Reports, 42(6), 112574.https://doi.org/10.1016/j.celrep.2023.112574
