Essential tremor: Clinical perspectives and pathophysiology.

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.