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

Abstract

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.

Keywords: Amplitude; Cerebellum; Electroencephalogram; Essential tremor; Frequency; Motor control; Motor kinematics; Neuronal coding; Oscillations; Tremor.

Fig. 1

Description of tremor kinematics from the frequency domain. A Kinematics of tremors and corresponding frequency profiles. B–D Kinematic changes and corresponding effects in the frequency domain. Faster tremors lead to increased tremor frequency. Bigger tremors lead to increased tremor amplitude. Changing the shapes of the tremors leads to different profiles in the harmonic frequencies

Fig. 2

Mechanisms for tremor frequency formation. Neurons involved in tremor frequency formation exhibit unstable firing probability at the single cell level, but the combined firing probabilities of multiple neurons converge to a stable periodicity, resulting in a tuning frequency at the populational level. This populational coding mechanism is consistently presented across structures of the olivocerebellum, including IO neurons, PCs and DCN neurons, leading to stable circuitry oscillations at the tuning frequency. The circuitry oscillations cause tremors and can be picked up by cerebellar EEG, showing that the oscillatory frequency matches the tremor frequency

Fig. 3

Mechanisms for tremor amplitude modulation. A, B Increased IO-PC synchrony. CF overgrowth, or enhanced IO automaticity and coupling, increases synchrony between IO neurons and PCs, as well as within the IO and among PCs. C Enhanced PC-to-DCN transmission. Axonal torpedoes in PCs enhance the transmission from PCs to DCN neurons. D Cerebello-thalamo-cortical modulation. The thalamus modulates tremor amplitudes by gating cerebellar-to-cortical transmission, as well as through thalamo-cortical interactions. E Peripheral sensory modulation. Phasic sensory inputs from peripheral nerves influence tremor amplitudes in a frequency-dependent manner