Model of the Pathological Changes in the Thalamo-Cortical Motor Circuit in Parkinsonism

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Movement in primates is, in part, controlled by brain circuits that involve three parts of the brain: the motor cortex, basal ganglia, and thalamus. Activity changes in these circuits contribute to the abnormalities seen in movement disorders such Parkinson’s disease. While activity changes in the basal ganglia are well defined, little is known about parkinsonism-associated changes in the primate basal ganglia-connected motor thalamus and cortex. To understand these changes in humans it is important to study the circuit dysfunction in primates, as these neuronal regions differ in both connections and composition from other species such as rodents. This project aims to enhance understanding of these network dynamics in ways that cannot be accomplished with conventional modeling approaches that often use an unwieldy number of coupled equations. Once the dynamics are described, new treatment approaches directed at normalizing thalamic activity in parkinsonian subjects may be developed and optimized for safety and effectiveness.Mathematical models of brain circuits are helpful to understand these abnormalities within the basal ganglia-thalamocortical network of connections. This project will generate a new multiscale model of the basal ganglia-thalamo-cortical pathways that will reflect the nonlinear nature of individual neurons while taking advantage of the inherent features of each nucleus. The first objective will be to create a fully functional thalamocortical loop model that can locate and examine the bifurcations between healthy and diseased brain activity states. Of particular interest are the trajectories in parameter space that could allow a parkinsonian subject to return back to the stable healthy state, allowing possibilities for researchers to identify new therapeutic opportunities. Next, since the primate-specific thalamic interneurons cannot currently be targeted with certainty in vivo, the model will be used to examine the roles that these interneurons have on the system. Finally, the model will be validated using an extensive dataset of neuronal recordings from healthy and parkinsonian nonhuman primates. Comparison to the recorded data will restrict the analysis of the mathematical model to a physiologically plausible region of the parameter space.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.