Neurophysiological activity patterns associated with excessive motor behaviors during long-term dopaminergic pharmacotherapy in a primate model of Parkinson’s disease
Neurophysiological activity patterns associated with excessive motor behaviors during long-term dopaminergic pharmacotherapy in a primate model of Parkinson’s disease
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Original abstract
Abstract Dopamine replacement therapy remains the main treatment for Parkinson’s disease (PD), but long-term use is associated with motor fluctuations and dyskinesia severely limiting therapeutic efficacy. In addition, late-stage PD patients often suffer from non-motor symptoms exacerbated by dopamine replacement therapy, such as PD-related psychosis (PD-P). In recent years, neurophysiological activity patterns associated with dyskinesia and psychosis have been identified in rodent models of PD, opening up opportunities for more mechanistic studies of these troublesome side effects. To determine whether long-term levodopa treatment in parkinsonian primates is associated with maladaptive circuit changes promoting pathophysiological brain activity similar to the rodent models, two unilaterally 6-OHDA-lesioned marmosets (Callithrix jacchus) were chronically implanted with recording electrodes in different parts of the cortico-basal ganglia-thalamic circuits, and behavior and neurophysiological activity were monitored in association with dopaminergic pharmacotherapy over one year. Levodopa alleviated signs of PD, but also induced excessive motor behaviors, including signs of PD-P. Concomitantly, beta-band local field potential activity was reduced and in one animal distinct narrow-band gamma oscillations developed in the subthalamic nucleus. Changes in subthalamic single-unit activity associated with levodopa treatment were dominated by increased firing rates that became more pronounced after a few months of treatment. Based on these observations, we propose that oscillatory activity in the high gamma-band and increased firing rates in a subgroup of subthalamic neurons should be further investigated as potential pathophysiological factors underlying drug-induced hyperkinetic and psychotic symptoms in PD.