Essential tremor: Clinical perspectives and pathophysiology

Abstract

Essential tremor (ET) is one of the most common neurological disorders and can be highly disabling. In recent years, studies on the clinical perspectives and pathophysiology have advanced our understanding of ET. Specifically, clinical heterogeneity of ET, with co-existence of tremor and other neurological features such as dystonia, ataxia, and cognitive dysfunction, has been identified. The cerebellum has been found to be the key brain region for tremor generation, and structural alterations of the cerebellum have been extensively studied in ET. Finally, four main ET pathophysiologies have been proposed: 1) environmental exposures to β-carboline alkaloids and the consequent olivocerebellar hyper-excitation, 2) cerebellar GABA deficiency, 3) climbing fiber synaptic pathology with related cerebellar oscillatory activity, 4) extra-cerebellar oscillatory activity. While these four theories are not mutually exclusive, they can represent distinctive ET subtypes, indicating multiple types of abnormal brain circuitry can lead to action tremor. This article is part of the Special Issue "Tremor" edited by Daniel D. Truong, Mark Hallett, and Aasef Shaikh.

Keywords: Cerebellum; Electroencephalogram; Essential tremor; Oscillation; Physiology; Tremor.

Fig. 1.

Climbing fiber synaptic pathology in ET. (A) In a control subject, climbing fiber synapses, as visualized by the vesicular glutamate transporter type 2 immunohistochemistry, usually do not extend to the outer 20% of the molecular layer (dash line), which is the parallel fiber synaptic territory. (B) In a ET patient, climbing fiber synapses abnormally extend to the parallel fiber synaptic territory (arrows).

Fig. 2.

Summary of ET pathophysiology. (A) Climbing fiber overgrowth and hyperinnervation. Reduction of GluRδ2 protein in the Purkinje cells causes climbing fiber synaptic pruning deficits, which lead to hypersynchrony and excessive oscillations in Purkinje cells. (B) Increased inferior olive automaticity and synchrony. β-carboline alkaloids, such as harmaline, lead to augmented T-type calcium channel function and potentially increased inferior olive synchrony via gap junctions. (C & D) GABA dysregulation. GABA receptor knockout in Purkinje cells and reduced GABA receptors in the deep cerebellar nucleus can lead to abnormal oscillations in the circuitry. DCN: deep cerebellar nucleus; IO: inferior olive; PC: Purkinje cell.