Tremor habituation to deep brain stimulation: Underlying mechanisms and solutions.

DBS of the ventral intermediate nucleus is an extremely effective treatment for essential tremor, although a waning benefit is observed after a variable time in a variable proportion of patients (ranging from 0% to 73%), a concept historically defined as "tolerance." Tolerance is currently an established concept in the medical community, although there is debate on its real existence. In fact, very few publications have actually addressed the problem, thus making tolerance a typical example of science based on "eminence rather than evidence." The underpinnings of the phenomena associated with the progressive loss of DBS benefit are not fully elucidated, although the interplay of different-not mutually exclusive-factors has been advocated. In this viewpoint, we gathered the evidence explaining the progressive loss of benefit observed after DBS. We grouped these factors in three categories: disease-related factors (tremor etiology and progression); surgery-related factors (electrode location, microlesional effect and placebo); and stimulation-related factors (not optimized stimulation, stimulation-induced side effects, habituation, and tremor rebound). We also propose possible pathophysiological explanations for the phenomenon and define a nomenclature of the associated features: early versus late DBS failure; tremor rebound versus habituation (to be preferred over tolerance). Finally, we provide a practical approach for preventing and treating this loss of DBS benefit, and we draft a possible roadmap for the research to come.