Neurophysiologic Signatures of Essential Tremor and Implications for Deep Brain Stimulation

PROJECT SUMMARY / ABSTRACT Essential tremor (ET) is the most common movement disorder in adults, yet its underlying pathophysiology is poorly understood. Non-invasive neural recordings have implicated oscillations at tremor frequency in the cerebello-thalamo-cortical network of ET, yet peri-operative invasive thalamic recordings have not consistently shown such oscillations. Deep brain stimulation (DBS) to the ventral intermediate nucleus (Vim) of the thalamus is a treatment option for medically refractory tremor, and new DBS technology that chronically senses neurophysiologic signals from the stimulation site offers a novel window into studying neural signatures of ET and the effects of DBS. The central hypothesis of this proposal is that ET tremor is associated with the propagation of tremor frequency oscillations from the cerebellum to motor cortex via the Vim thalamus, and that thalamic DBS interrupts this propagation. The central hypothesis will be tested by pursuing three Specific Aims. Aim 1: Identify the relationship of chronically recorded Vim thalamus oscillatory activity to tremor intensity. Aim 2: Assess the directionality of oscillatory activity within the cerebello-thalamo- cortical network. Aim 3: Assess the effect of DBS on oscillatory activity within the cerebello-thalamo-cortical network and its relationship to tremor. To pursue these aims, this study will use multimodal neurophysiology, including novel methods such as chronically recorded thalamic local field potentials and combined cerebellar and motor cortex electroencephalography, to study the relationship of Vim oscillations with manifested tremor and other oscillations in the cerebello-thalamo-cortical network. Results from the proposed research will make significant contributions to our understanding of the underlying neurophysiology of ET, thus providing a framework for using sense-enabled DBS systems to further study mechanisms of DBS in ET and to improve DBS technology. This proposed project will provide career development training to Dr. Hammer, who is establishing herself as a physician-scientist conducting patient-centered research in the field of deep brain stimulation (DBS) for movement disorders. This K23 will propel Dr. Hammer towards scientific independence as she develops expertise in electroencephalography, cerebellar network physiology, network neuroscience, and trial design and statistics. She has assembled a multidisciplinary mentoring group including Dr. Brian Litt (expert in neural engineering in the setting of epilepsy), Dr. Casey Halpern (expert in DBS for novel indications in mental health), Dr. Sheng-Han Kuo (expert in cerebellar physiology in tremor and ataxia), and Dr. Svjetlana Miocinovic (expert in DBS for movement disorders). This K23 training will provide the foundation for a future R01 application using chronically sensed thalamic neural signals from DBS implants to study mechanisms behind declining efficacy of DBS for ET over time (i.e., “habituation”).