Targeting the fundamentals for tremors: the frequency and amplitude coding in essential tremor

Essential tremor (ET) is one of the most common movement disorders with heterogeneous pathogenesis involving both genetic and environmental factors, which often results in variable therapeutic outcomes. Despite the diverse etiology, ET is defined by a core symptom of action tremor, an involuntary rhythmic movement that can be mathematically characterized by two parameters: tremor frequency and tremor amplitude. Recent advances in neural dynamics and clinical electrophysiology have provided valuable insights to explain how tremor frequency and amplitude are generated within the central nervous system. This review summarizes both animal and clinical evidence, encompassing the kinematic features of tremors, circuitry dynamics, and the neuronal coding mechanisms for the two parameters. Neural population coding within the olivocerebellum is implicated in determining tremor frequency, while the cerebellar circuitry synchrony and cerebellar-thalamo-cortical interactions play key roles in regulating tremor amplitude. Novel therapeutic strategies aimed at tuning tremor frequency and amplitude are also discussed. These neural dynamic approaches target the conserved mechanisms across ET patients with varying etiologies, offering the potential to develop universally effective therapies for ET.