Objective: Identify differential therapeutic responses in essential tremor (ET) models.

Characterize the spatiotemporal neural dynamics and circuitry features in these models.

Elucidate neuronal mechanisms underlying drug-response dynamics to inform ET treatment.

Background: Essential tremor (ET), the most common movement disorder, is characterized by action tremor. Despite its prevalence, therapeutic responses vary, suggesting heterogeneous pathophysiologies. Less than 50% of ET patients respond to pharmacological treatments, and no new medications have been developed in 25 years. Elevated harmane levels and cerebellar climbing fiber (CF) overgrowth due to GluRd2 protein loss represent distinct ET pathophysiologies.

Method: We investigated differential therapeutic outcomes in two ET mouse models: harmaline-induced tremor, mimicking harmane-related pathophysiology, and Grid2dupE3, capturing GluRd2-dependent CF overgrowth. Multi-electrode arrays were implanted in freely moving mice with simultaneous tremor tracking. Two-photon calcium imaging assessed inter-neuronal synchrony of cerebellar Purkinje cells (PCs).

Results: Harmaline-induced tremors responded to propranolol and primidone, whereas Grid2dupE3 tremors were drug-refractory. Both models exhibited similar cerebellar population frequency coding, suggesting frequency alone does not explain drug responses. Two-photon calcium imaging revealed that Grid2dupE3 mice exhibited global PC synchrony, whereas harmaline-treated mice displayed regional synchrony. Computational modeling supported these findings and predicted differential responses to T-type calcium channel blockers, validated through preclinical trials.

Conclusion: Harmaline-treated and Grid2dupE3 mice represent distinct ET subtypes, one responsive and the other refractory to propranolol and primidone. Our neural dynamics approach demonstrated that drug responses correlate with distinct PC synchrony patterns, confirmed via two-photon imaging and computational modeling. The model also predicted differential efficacy of T-type calcium channel blockers, underscoring the potential for precision medicine in ET treatment.

References: 1. Ming-Kai Pan*. Targeting the fundamentals for tremors: the frequency and amplitude coding in essential tremor. Journal of Biomedical Science. 2025 Feb 10;32(1):18
2. Yi-Mei Wang, Chia-Wei Liu, Shun-Ying Chen, Liang-Yin Lu, Wen-Chuan Liu, Jia-Huei Wang, Chun-Lun Ni, Shi-Bing Wong, Ami Kumar, Jye-Chang Lee, Sheng-Han Kuo, Shun-Chi Wu, Ming-Kai Pan*. Neuronal population activity in the olivocerebellum encodes the frequency of essential tremor in mice and patients. Science Translational Medicine. 2024 May 15;16(747):eadl1408
3. Yin-Tzu Hsieh, Kai-Chun Jhan, Jye-Chang Lee, Guan-Jie Huang, Chang-Ling Chung, Wun-Ci Chen, Ting-Chen Chang, Bi-Chang Chen, Ming-Kai Pan*, Shun-Chi Wu*, Shi-Wei Chu* TAG-SPARK: Empowering High-Speed Volumetric Imaging with Deep Learning and Spatial Redundancy. Advanced Science 2024 Nov; 11(41):e2405293.
4. 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

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MDS Abstracts - https://www.mdsabstracts.org/abstract/spatiotemporal-neural-dynamics-of-the-cerebellum-underlie-differential-therapeutic-outcomes-in-essential-tremor-subtypes/