Mapping Essential Tremor to a Common Brain Network Using Functional Connectivity Analysis

Background and Objectives:The cerebello-thalamo-cortical circuit plays a critical role in essential tremor (ET). However, abnormalities have been reported in multiple brain regions outside this circuit, leading to inconsistent characterization of ET pathophysiology. Here, we test whether these mixed findings in ET localize to a common functional network and if this network has therapeutic relevance.Methods:We conducted a systematic literature search to identify studies reporting structural or metabolic brain abnormalities in ET. We then employed ‘coordinate network mapping’, which leverages a normative connectome (n= 1000) of resting-state fMRI data to identify regions commonly connected to findings across all studies. To assess whether these regions may be relevant for treatment of ET, we compared our network to a therapeutic network derived from lesions that relieved ET. Finally, we investigated whether the functional connectivity of this ET symptom network is abnormal in an independent cohort of ET patients as compared to healthy controls.Results:Structural and metabolic brain abnormalities in ET were located in heterogeneous regions throughout the brain, but connected to a common functional network of brain regions, including the cerebellum, thalamus, motor cortex, precuneus, inferior parietal lobe and insula. The cerebellum was identified as the hub of this network as it was the only brain region that was both functionally connected to over 90% of studies’ findings, and significantly different in connectivity compared to a control dataset of other movement disorders. This network was strikingly similar to the therapeutic network derived from lesions improving ET, with key regions aligning in the thalamus and cerebellum. Further, functional connectivity between the cerebellar network hub and the sensorimotor cortices was significantly reduced in ET patients compared to healthy controls, and connectivity within this network was correlated with tremor severity and cognitive functioning.Discussion:The cerebellum is the central hub of a network commonly connected to structural and metabolic abnormalities in ET. This network may have therapeutic utility in refining and informing new targets for neuromodulation of ET.