Cerebellar TMS for postural instability in progressive supranuclear palsy

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PROJECT SUMMARY/ABSTRACT This project uses PSP as a model disorder to study early interventions for symptomatic treatment to improve balance and postural instability in parkinsonian disorders. The goal of this research is to develop effective therapies for postural instability and falls in progressive supranuclear palsy (PSP). PSP is a form of parkinsonism classically characterized by early and severe balance deficits, primarily backward postural instability. Injuries related to this debilitating postural instability in PSP, or risk-avoidance aimed at preventing such incidents, limit mobility and physical therapy, which, in turn, leads to a further decline in function. The traditional symptomatic treatments for bradykinesia and rigidity in parkinsonism (dopaminergic medication and stimulation of the basal ganglia circuitry via deep brain stimulation) are not helpful for backward postural instability in PSP, or in advanced Parkinson’s disease. We know that the cerebellum’s normal ability to inhibit and modulate motor output for postural control is diminished in parkinsonian disorders. The objective of this proposal is to investigate the effect of non-invasive repetitive cerebellar transcranial magnetic stimulation (rTMS) on postural instability in progressive supranuclear (PSP). The central hypothesis is that augmenting cerebellar inhibition via cerebellar rTMS will decrease postural instability in patients with PSP by increasing functional connectivity between the cerebellum, thalamus, and primary motor cortex. Aim 1 uses a specialized force plate platform and wearable sensors to evaluate objective posturography measures of postural stability before and after rTMS. Aim 2 identifies changes in cerebellar, thalamic, and motor cortex functional activity before and after resting state fMRI. If successful, this proof-of-concept study for cerebellar neuromodulation in PSP will lead to better rehabilitation strategies, and cerebellar neuromodulation via TMS may also lead to more durable neuromodulation approaches for postural instability, such as cerebellar targeting for future deep brain stimulation paradigms. The candidate for this K23 Career Development Award has a long-term goal of becoming an independent clinical investigator in the field neuromodulation for symptomatic management of balance impairment and of other untreatable aspects of parkinsonism. With the outstanding mentorship of Dr. Fay Horak (quantitative gait and balance research), and co-mentored by Dr. Bill Rooney (fMRI), Dr. Joseph Quinn (clinical trials and PSP), and Dr. Mark George (neuromodulation), a comprehensive training plan for quantitative research methods and fMRI analysis is proposed. In a future RO1, Dr. Dale will pair cerebellar rTMS with rehabilitation programs for postural instability and expand investigations of TMS as a probe of the neural circuitry for motor control in parkinsonism.