Cortico-thalamic tremor circuits and their associations with deep brain stimulation effects in essential tremor.

Essential tremor is one of the most common movement disorders in adults. Deep brain stimulation (DBS) of the ventralis intermediate nucleus of the thalamus and/or the posterior subthalamic area has been shown to provide significant tremor suppression in patients with essential tremor, but with significant inter-patient variability and habituation to the stimulation. Several non-invasive neuromodulation techniques targeting other parts of the CNS, including cerebellar, motor cortex or peripheral nerves, have also been developed for treating essential tremor, but the clinical outcomes remain inconsistent. Existing studies suggest that pathology in essential tremor might emerge from multiple cortical and subcortical areas, but its exact mechanisms remain unclear. By simultaneously capturing neural activities from motor cortices and thalami and recording hand tremor signals via accelerometers in 15 human subjects who had undergone lead implantations for DBS, we systematically characterized the efferent and afferent cortico-thalamic tremor networks. Through the comparisons of these network characteristics and tremor amplitude between DBS off and on conditions, we also investigated the associations between different tremor network characteristics and the magnitude of the DBS effect. Our findings implicate the thalamus, specifically the contralateral hemisphere, as the primary generator of tremor in essential tremor, also with a significant contribution of the ipsilateral hemisphere. Although there is no direct correlation between the cortico-tremor connectivity and tremor power or reduced tremor by DBS, the strength of connectivity from the motor cortex to the thalamus and vice versa at tremor frequency predicts baseline tremor power and effect of DBS. Interestingly, there is no correlation between these two connectivity pathways themselves, suggesting that, independent of the subcortical pathway, the motor cortex appears to play a relatively distinct role, possibly mediated through an afferent/feedback loop in the propagation of tremor. DBS has a greater clinical effect in those with stronger cortico-thalamo-tremor connectivity involving the contralateral thalamus, which is also associated with bigger and more stable tremor measured with an accelerometer. Interestingly, stronger cross-hemisphere coupling between left and right thalami is associated with more unstable tremor. This study provides important insights for a better understanding of the cortico-thalamic tremor-generating network and its implication for the development of patient-specific therapeutic approaches for essential tremor.