Neuronal firing patterns outweigh circuitry oscillations in parkinsonian motor control
Ming-Kai Pan, … , Wen-Sung Lai, Chung-Chin Kuo
Ming-Kai Pan, … , Wen-Sung Lai, Chung-Chin Kuo
Published October 31, 2016
Citation Information: J Clin Invest. 2016;126(12):4516-4526. https://doi.org/10.1172/JCI88170.
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Neuronal firing patterns outweigh circuitry oscillations in parkinsonian motor control

Abstract

Neuronal oscillations at beta frequencies (20–50 Hz) in the cortico-basal ganglia circuits have long been the leading theory for bradykinesia, the slow movements that are cardinal symptoms in Parkinson’s disease (PD). The beta oscillation theory helped to drive a frequency-based design in the development of deep brain stimulation therapy for PD. However, in contrast to this theory, here we have found that bradykinesia can be completely dissociated from beta oscillations in rodent models. Instead, we observed that bradykinesia is causatively regulated by the burst-firing pattern of the subthalamic nucleus (STN) in a feed-forward, or efferent-only, mechanism. Furthermore, STN burst-firing and beta oscillations are two independent mechanisms that are regulated by different NMDA receptors in STN. Our results shift the understanding of bradykinesia pathophysiology from an interactive oscillatory theory toward a feed-forward mechanism that is coded by firing patterns. This distinct mechanism may improve understanding of the fundamental concepts of motor control and enable more selective targeting of bradykinesia-specific mechanisms to improve PD therapy.

Authors

Ming-Kai Pan, Sheng-Han Kuo, Chun-Hwei Tai, Jyun-You Liou, Ju-Chun Pei, Chia-Yuan Chang, Yi-Mei Wang, Wen-Chuan Liu, Tien-Rei Wang, Wen-Sung Lai, Chung-Chin Kuo

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Figure 5

Bradykinesia is independent of the regularity of cortico-subthalamic transmissions.

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Bradykinesia is independent of the regularity of cortico-subthalamic tra...
(A) Schematic illustration of fiber optic cannula implanted in STN for the stimulation of cortico-subthalamic axonal terminals in Thy1-ChR2 mice. (B) Illustration of two illumination protocols: fixed 10 Hz stimulation and randomized frequency shuffles with the same stimulation loads (10 pulses/s). (C–I) Sample traces of locomotor behaviors and corresponding statistic results, showing that fixed-frequency and randomized (Rand) stimulation recapitulated bradykinesia with similar severity, quantified by (E–G) motion difficulties and (H and I) asymmetries (n = 4). Also refer to Supplemental Figure 5 for thermodynamic controls, which followed the same protocols with non-activating yellow light (589 nm) laser. Statistical analyses were performed using 1-way ANOVA with post-hoc Bonferroni correction. Data are presented as mean ± SEM; *P < 0.05, **P < 0.01, ***P < 0.001.