This application proposes studies that build upon our findings in the previous grant period on the role of aging, dry eye and blink adaptation in the development of the eyelid dystonia, benign essential blepharospasm (BEB). These studies explained important features that characterize BEB: (1) disease onset typically occurs after age 50; (2) trigeminal reflex blinks are hyperexcitable; (3) dry eye frequently precedes disease onset; and (4) repetitive bursts of eyelid muscle contractions create involuntary spasms of lid closure. We found that aging significantly increased trigeminal reflex blink excitability after age 60 in humans. This increased excitability pointed to reductions in trigeminal inhibition with aging as a contributing factor in the development of BEB. In humans, we demonstrated that the blink adaptations in response to dry eye included increased trigeminal reflex blink excitability and the generation of multiple blinks to a single trigeminal stimulus, blink oscillations. Because shortening the interval between the occurrences of the blink oscillations of dry eye would create the spasms of lid closure present in BEB, disturbing the blink adaptations to dry eye might generate BEB. We confirmed this hypothesis by creating a rodent model of blepharospasm. Thus, our previous work revealed that a disturbance in blink adaptation, motor learning, was a critical component of the origin of BEB. The primary goals of this application are to characterize the two error signals that initiate and modulate blink adaptation and to determine the role of the cerebellum in the origin and maintenance of BEB. We propose to: (1) determine what blink adaptations a single error signal engenders in humans; (2) establish the neural changes in the cerebellum and trigeminal complex initiated by these error signals in rodents; and (3) characterize the role of the cerebellum in initiating and maintaining BEB using our animal model. The data from these experiments may establish the neural underpinnings of and point toward new treatments.
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