Behavioral Markers of Essential Tremor Correlate with Distributed Alteration of Brain Functional Connectivity

Essential Tremor (ET) is a common motor disorder characterized by involuntary oscillations of the upper limbs during voluntary movement. Although increasing evidence implicates dysfunction of the cerebello-thalamo-cortical pathway, ET remains a diagnosis of exclusion, as no definitive biological marker currently exists. To better characterize ET, we recently hypothesized that impaired compensation of sensorimotor delays within the long-latency feedback pathways may generate the tremor-like oscillations observed in ET. This theory suggests that the mean spectral amplitude (MSA), derived from limb kinematics, may serve as a potential marker of ET. Here we investigated the relationship between MSA, standard clinical assessment (Fahn Tolosa Marin Tremor Rating Scale; FTM-TRS), and brain connectivity derived from resting state functional magnetic resonance imaging (rs-fMRI). Using seed-based analyses, we replicated previous findings of reduced functional connectivity between the dentate nucleus and components of the cerebello-thalamo-cortical pathway in ET patients compared with neurologically intact (NI) age-matched participants. Graph-theoretical analyses of whole-brain functional networks revealed distributed alterations in network topology across motor-related cortical and subcortical regions. Several graph metrics correlated with FTM-TRS scores and/or MSA, particularly within motor-related cortical and subcortical circuits, including the thalamus, basal ganglia, and cerebellum in ET. These findings indicate that ET is characterized by distributed alterations in functional brain networks beyond reduced connectivity of dentate nucleus and highlights MSA as a candidate quantitative marker linking altered brain connectivity to sensorimotor delay-driven tremor oscillations.