Objective: Tremor is an involuntary rhythmic movement. However, the frequency-coding mechanism of tremor remains unknown. This study aims to identify such mechanism in the central nervous system.

Background: Essential tremor (ET) is among the most common movement disorders. We have identified that ET patients have reduced expression of GluRdelta2 protein in the cerebellum, and develop synaptic pruning deficits and lateral crossing of cerebellar climbing fibers (CF). The overgrown climbing fiber causes excessive cerebellar oscillations and tremor. We also identified the Grid2^dupE3 mouse model with ET-mimicking pathophysiology spanning molecular (GluRdelta2 loss), structural (CF overgrowth), physiological (excessive cerebellar oscillations) and behavioral (tremor) levels.

Method: In this study, we used Grid2^dupE3 mouse model to explore the frequency-coding mechanism of tremor. We applied in-vivo electrophysiology to record neuronal activities and oscillations in the cerebral and cerebellar regions of awake-behaving mice. Optogenetic manipulation were applied to confirm the causal relationship between neuronal activities and tremor frequencies. Human evidence was collected by cerebellar encephalography (EEG) recordings in ET patients with thalamic deep brain stimulation (DBS).

Results: In Grid2^dupE3 mice, lidocaine-mediated neuronal silencing in thalamus, cerebellar cortex and deep cerebellar nucleus confirmed that the mouse tremor and associated neuronal oscillations are generated within the olivocerebellar circuit. Rhythmic optogenetic stimulation within the olivocerebellar circuit reliably generate tremor at the stimulating frequency. Single-unit neuronal activities further revealed that tremor frequency is generated within the coherent olivocerebellar circuitry, and determined by the periodic tuning of neuronal firing probabilities at the populational level. Cerebellar optogenetic stimulation in Grid2^dupE3 mice can instantaneously generate mouse tremor at the stimulation frequency and washout the innate tremor frequency. Thalamic DBS in ET patients with simultaneous cerebellar EEG recording also confirmed that the tremor-related neuronal oscillations can persistently generated within the cerebellar region.

Conclusion: The study shows the mouse evidence that tremor frequency is encoded by the populational neuronal activities within the olivocerebellar circuit, which is supported by the human DBS and cerebellar EEG recordings in ET patients.

References: 1. Pan M-K*, Li Y-S, Wang S-B, Ni C-L, Wang Y-M, Liu W-C, Lu L-Y, Lee J-C, Cortes EP, Vonsattel J-P, Sun Q, Louis E, Faust P, Kuo S-H*. Cerebellar oscillations driven by synaptic pruning deficits of cerebellar climbing fibers contribute to tremor pathophysiology. Science Translational Medicine. 2020 Jan 15;12(526):eeey1769
2. Chun-Lun Ni, Yi-Ting Lin, Liang-Yin Lu, Jia-Huei Wang, Wen-Chuan Liu, Sheng-Han Kuo, Ming-Kai Pan* Tracking motion kinematics and tremor with intrinsic oscillatory property of instrumental mechanics. Bioengineering & Translational Medicine. 2022. In press. https://doi.org/10.1002/btm2.10432
3. Ami Kumar, Chih-Chun Lin, Sheng-Han Kuo & Ming-Kai Pan*. Physiological recordings of the cerebellum in movement disorders. Cerebellum 2022 [Epub ahead of print].
4. Ming-Kai Pan* and Sheng-Han Kuo. Essential tremor: Clinical perspectives and pathophysiology. Journal of the Neurological Sciences 2022. Apr 15;435:120198
5. S-B Wong, Y-M Wong, C-C Lin, Scott Kun Geng, Nora Vanegas-Arroyave, Seth L. Pullman, S-H Kuo, M-K Pan*. Cerebellar Oscillations in Familial and Sporadic Essential Tremor. Cerebellum. 2021 Jun 21(3):425-431
6. Yueh-Chi Wu, Elan D Louis, John Gionco, Ming-Kai Pan, Phyllis L Faust, Sheng-Han Kuo*. Increased Climbing Fiber Lateral Crossings on Purkinje Cell Dendrites in the Cerebellar Hemisphere in Essential Tremor. Movement Disorders 2021. Jun;36(6):1440-1445

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MDS Abstracts - https://www.mdsabstracts.org/abstract/frequency-coding-mechanism-of-tremor-in-the-cerebellar-circuitry/