Abstract
Objective
Holmes' tremor is a debilitating movement disorder with limited treatment options. Lesions causing Holmes' tremor can occur in multiple different brain locations, leaving the neuroanatomical substrate unclear. Here we test whether lesion locations that cause Holmes' tremor map to a connected brain circuit and whether this circuit might serve as a useful therapeutic target.
Methods
Case reports of Holmes' tremor caused by focal brain lesions were identified through a systematic literature search. Connectivity between each lesion location and the rest of the brain was computed using resting state functional connectivity MRI data from 1,000 healthy volunteers. Commonalities across lesion locations were identified. This Holmes' tremor circuit was then compared to neurosurgical treatment targets and clinical efficacy.
Results
We identified 36 lesions causing Holmes' tremor, which were scattered across multiple different brain regions. However, all lesion locations were connected to a common brain circuit with nodes in the red nucleus, thalamus, globus pallidus, and cerebellum. In cases with effective neurosurgical treatment, the treatment target was connected with the lesion location, indicating that a second hit to the same circuit might be beneficial. Commonly used deep brain stimulation targets such as the ventral intermediate nucleus and subthalamic nucleus fell outside our Holmes' tremor circuit, while the globus pallidus target was close, consistent with published clinical response rates for these targets.
Interpretation
Lesions causing Holmes' tremor are part of a single connected brain circuit that may serve as an improved therapeutic target.
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