Emerging Deep Brain Stimulation Targets in the Cerebellum for Tremor

Deep brain stimulation (DBS) for essential tremor is remarkably effective, leading to over 80% reduction in standardized tremor ratings. However, for certain types of tremor, such as those accompanied by ataxia or dystonia, conventional DBS targets have shown poor efficacy. Various rationales for using cerebellar DBS stimulation to treat tremor have been advanced, but the varied approaches leave many questions unanswered: which anatomic target, stimulation settings, and indications seem most promising for this emerging approach. This article reviews the clinical experience published to date and explores some of the pre-clinical and human physiology data that might support a role for further systematic investigation of cerebellar DBS for clinical use. Four tremor disorders to date have been targeted with cerebellar DBS in humans: essential tremor, post-stroke tremor, dystonic tremor, and tremor associated with degenerative cerebellar ataxias, like spinocerebellar ataxia type 3. The dentate nucleus is the most frequently chosen target, but key stereotactic and imaging details are missing from many of the case reports. Interestingly, consensus on laterality has not been definitively established as there are conflicting models of the hypothesized mechanism of action of DBS of the dentate nuclei, and conflicting reports of benefit on the tremor ipsilateral to and contralateral toto the affected limb. Several points are highlighted, including the prediction from in vivo preclinical physiology studies and interventional studies, the remaining uncertainty regarding the preferred laterality of targets, and the lack of clear prioritization of tremor etiologies to be targeted in future rigorously designed interventional studies (e.g., preferably repeated n-of-1 or sham-controlled studies involving more than one patient).