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 1

Behavioral and real-time neuronal abnormalities in 6-OHDA–lesioned parkinsonian rat model.

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Behavioral and real-time neuronal abnormalities in 6-OHDA–lesioned parki...
(A) Scheme of the experimental design. Rats received surgical placements of drug infusion cannula coupled with a stimulating electrode, and recording electrodes in STN and cortex. Implanted rats received part or all of the following evaluations, including locomotor behaviors (open-field free movements and rotarod forced movements), single-unit recordings, and LFPs, before and after pharmacological and/or electrical manipulations. inj., injection; Str, striatum; GP, globus pallidus; SNc, substantia nigra pars compacta. (B and C) Locomotor behaviors. 6-OHDA rats developed motor deficits, especially slow movements (bradykinesia), in both (B) free-moving and (C) forced-moving paradigms (n = 11 in both paradigms). (D) STN firing patterns. 6-OHDA rats developed excessive burst firings in STN, while the intra-burst profiles remained unchanged (n =10). (E–G) Oscillatory profiles. (E and F) In situ synchronization of oscillatory activities presented as LFPs. STN and cortical power in beta frequencies (20–50 Hz) were pathologically increased in both resting and moving conditions in 6-OHDA rats (n = 11). (G) Long-range cortico-subthalamic oscillations presented by time-coherence plot. 6-OHDA rats developed robust oscillations in beta frequencies (n = 11). Statistical analyses were performed using a nonparametric Wilcoxon signed-rank test. Data are presented as mean ± SEM; **P < 0.01.