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.