Circuitry dynamics of the cerebellum inform differential therapeutic responses and patient stratification in essential tremor
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Essential tremor (ET) is the most common movement disorder, yet fewer than 50% of patients respond to current pharmacological treatments. This study identifies spatiotemporal cerebellar neurodynamics as key determinants of differential therapeutic responses in two clinically linked ET mouse models: harmaline-induced (harmane toxicity) and Grid2dupE3 (climbing fiber overgrowth) mice. In vivo electrophysiology and two-photon imaging revealed that harmaline mice exhibit regional PC synchrony and respond to propranolol, whereas Grid2dupE3 mice show global PC synchrony and resistance to propranolol. Computational models revealed that inferior olivary pacemaking via HCN and T-type calcium channels drives harmaline tremors, while Grid2dupE3 tremors arise from self-sustained circuitry oscillations independent of olivary pacemaking. The models not only predicted the outcomes of a preclinical drug trial, but also generated an electrophysiological biomarker of frequency dynamic index (FDI) for patient stratification. These findings uncover a neurodynamic mechanism and modeling platform for therapeutic discovery and biomarker development in ET.
