The motor signs of Parkinson's disease (PD) have been linked causally to abnormalities in the spiking activity of neurons in the globus pallidus internus (GPi), a major output nucleus of the basal ganglia (BG). Likewise, deep brain stimulation (DBS) of the subthalamic nucleus (STN) may provide relief from parkinsonian signs by suppressing abnormalities in GPi activity. Efforts to refine DBS and develop new therapeutic targets for PD will be greatly enhanced by elucidation of the specific mechanisms by which abnormal GPi activity and its alteration under DBS impact parkinsonian signs. The experiments in this proposal focus on the idea that communication between GPi and BG-recipient thalamus is a central factor in the pathophysiology of Parkinsonism and its amelioration during DBS. Two hypotheses will be tested: the information hypothesis posits that a loss of independent signaling in the parkinsonian GPi reduces the information-carrying capacity of GPi-recipient neurons in thalamus, while an alternate hypothesis posits that certain firing abnormalities in GPi (e.g., low frequency oscillations or bursts) induce pathologic activity in thalamus, which disrupts function downstream (e.g. in the motor cortices). Each hypothesis predicts that the associated measures of neuronal activity will covary with the severity of parkinsonian signs and their rectification via DBS. These predictions will be tested through an innovative interdisciplinary research plan. Neuronal activity in GPi and GPi-recipient thalamus will be studied using multi-electrode single-unit and local field potential recordings in non-human primates, before and during the slow, progressive induction of parkinsonism, and during sub-therapeutic and therapeutic DBS in the STN. Independent signaling will be quantified as spike correlations, within and between nuclei, and as the specificity of neuronal responses to proprioceptive stimulation of different limbs. Parkinsonian signs will be measured using tasks that assay movement initiation (akinesia), movement kinematics (bradykinesia), and muscle tone (rigidity). Data from these experiments will be analyzed in collaboration with investigators (Rubin and Doiron) who have substantial computational experience, including work on parkinsonian BG dynamics and the propagation of information in neuronal networks. Computational and theoretical methods will tease apart specific ways that changes in GPi output alter thalamic function. Empirical results will be incorporated into Hodgkin-Huxley type neuronal models and mean field and information theoretic analyses to determine how GPi activity influences thalamic correlations and information coding, and to predict downstream effects of changes in thalamic firing properties across normal, parkinsonian and parkinsonian+DBS conditions. Results from these studies will advance our understanding of parkinsonian pathophysiology and test potential therapeutic mechanisms of DBS, suggesting targets for future therapeutic interventions including optimization of DBS. The results may also be relevant to the whole class of clinical disorders that involve BG-thalamic dysfunction as well as to the use of DBS for other neurologic conditions.

Public Health Relevance

The proposed experiments test central ideas about what causes the signs and symptoms of Parkinson's disease - that abnormal output from the parkinsonian basal ganglia disrupts the normal functions of motor control circuits. The experiments also test the idea that deep brain stimulation, a standard yet poorly understood surgical therapy for Parkinson's disease, works by normalizing function in the same brain circuits. Thus, results from these experiments will advance our understanding of what causes the symptoms of Parkinson's disease and of how a common surgical therapy provides clinical benefit. Results from these experiments may facilitate the optimization of DBS and suggest novel therapeutic interventions.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Sieber, Beth-Anne
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University of Pittsburgh
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