Colmant, L. | Search bioRxiv

bioRxiv2026

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.

neuroscience↗

bioRxiv2024

Erroneous compensation for long-latency feedback delays as origin of Essential Tremor

Essential tremor (ET), a movement disorder characterized by involuntary oscillations of the limbs during movement, remains to date not well understood. It has been recently suggested that the tremor originates from impaired delay compensation, affecting movement representation and online control. Here we tested this hypothesis directly with ET patients (N=24) and neurologically intact (NI) volunteers (N=28) in an upper limb postural perturbation task. After maintaining their hand in a visual target, participants experienced perturbations of unpredictable direction and magnitude, and were instructed to counter the perturbation and steer their hand back to the starting position. In comparison with NI volunteers, ET patients early muscular responses (Short and Long-Latency Responses, 20-50 ms and 50-100 ms respectively) were preserved or even slightly increased. However, they exhibited perturbation-dependent deficits when stopping and stabilizing their hand in the final target supporting the hypothesis that the tremor was generated by the feedback controller. We show in a computational model that errors in delay compensation accumulating over time produced the same small increase in initial feedback response followed by oscillations that scaled with the perturbation magnitude as observed in ET population. Our experimental results therefore validate the computational hypothesis that inaccurate delay compensation in long-latency pathways could be the origin of the tremor. Significance StatementEssential Tremor origin remains poorly understood. In the present study, we focused on motor impairments associated with feedback control. Following a mechanical perturbation applied to their arm, patients short and initial long-latency stretch responses were preserved. However, we observed clear impairments during the stabilization phase that scaled with the perturbation magnitude. These results were reproduced in a computational model where delay compensation was inaccurate, suggesting that the origin of the tremor may lie in an underestimation of the delays impacting the internal monitoring of the motor commands. Conflict of interestThe authors declare no competing financial interests.

neuroscience↗