Tuned to Tremor: Increased Sensitivity of Cortico-Basal Ganglia Neurons to Tremor Frequency in the MPTP Nonhuman Primate Model of Parkinson's Disease

Rest tremor is one of the most prominent clinical features of Parkinson's disease (PD). Here, we hypothesized that cortico-basal ganglia neurons tend to fire in a pattern that matches PD tremor frequency, suggesting a resonance phenomenon. We recorded spiking activity in the primary motor cortex (M1) and globus pallidus external segment of 2 female nonhuman primates, before and after parkinsonian state induction with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. The arm of nonhuman primates was passively rotated at seven different frequencies surrounding and overlapping PD tremor frequency. We found entrainment of the spiking activity to arm rotation and a significant sharpening of the tuning curves in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine state, with a peak response at frequencies that matched the frequency of PD tremor. These results reveal increased sensitivity of the cortico-basal ganglia network to tremor frequency and could indicate that this network acts not only as a tremor switch but is involved in setting its frequency.SIGNIFICANCE STATEMENT Tremor is a prominent clinical feature of Parkinson's disease; however, its underlying pathophysiology is still poorly understood. Using electrophysiological recordings of single cortico-basal ganglia neurons before and after the induction of a parkinsonian state, and in response to passive arm rotation, this study reports increased sensitivity to tremor frequency in Parkinson's disease. We found sharpening of the population tuning to the midrange of the tested frequencies (1-13.3 Hz) in the healthy state that further increased in the parkinsonian state. These results hint at the increased frequency-tuned sensitivity of cortico-basal ganglia neurons and suggest that they tend to resonate with the tremor.