Elucidating the Temporality of Structural and Functional Connectivity Changes in Essential Tremor after successful Deep Brain Stimulation to the dentato-rubro-thalamic tract

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Project Summary The symptoms of Essential Tremor (ET), the most common movement disorder in adults, are seriously disabling and are only marginally improved by medication alone. Tremor control has improved greatly with the use of deep brain stimulation (DBS) to the ventrointermediate nucleus (Vim) of the thalamus, a node along a circuit of abnormal rhythmic output in ET that travels from the cerebellar dentate nucleus to the contralateral red nucleus and cortex via the dentato-rubro-thalamic tract (DRTt). Recent advances in diffusion imaging have led to the development of tractography techniques where the structural connectivity of fiber tracts such as the DRTt can be illustrated and then, as we have shown, directly targeted during DBS surgery for excellent clinical effect. Despite such novel targeting methodology and initial tremor improvement, however, the development of side effects such as progressive gait ataxia and waning efficacy after years of chronic stimulation points to the fact that the pathology of essential tremor is poorly understood. Such incomplete knowledge of the network effects of chronic stimulation in ET is a major barrier that needs to be overcome through understanding the dysfunction and modulation of the connectivity of the cerebellar-thalamic-cortical (CTC) network over time. Resting state functional MRI (rsfMRI) has emerged as a powerful tool to explore the functional connectivity between different brain regions and has improved the idea of ET as a network-based disease not confined to the motor circuit, including parietal visuomotor processing cortices; however, comparisons pre- and post- DBS have not been performed. The use of positron emission tomography (PET) has correlated ataxic side effect with cerebellar metabolic changes after chronic DBS; however, associated changes seen with rsfMRI are unknown. Our long-term goal is to understand how stimulation of the DRTt causes network-level effects over time. Our central hypothesis is that structural and functional connectivity of the DRTt correlates with clinical response to DBS in a time-dependent fashion. In pursuit of this hypothesis, we will recruit new ET patients already undergoing DBS and additionally perform imaging analysis to elucidate the effects of stimulation and define DRTt connectivity. In Aim 1, we seek to define the structural connectivity of the DRTt by using tractography methods and compare over time diffusivity changes correlated with clinical response and/or ataxic side effect. In Aim 2, we seek to detect functional network changes due to DBS by using rsfMRI obtained serially in ON/OFF states, where we will track the evolution of altered connectivity changes over time. In Aim 3, we seek to confirm the cortical mediators of tremor identified in Aims 1 and 2 by use of intraoperative electrocorticography during DBS. This innovative combination of using a novel targeting technique and serial imaging across DBS states will advance our understanding of the larger network response to DBS, which is essential to develop more specific stimulation of fibers to improve response and avoid side effects in ET.