Emily K. Plowman, Ph.D. - US grants

PROJECT SUMMARY Speech and swallowing impairments occur in 90% of individuals with Parkinson's Disease (PD) and aspiration pneumonia constitutes the leading cause of death in this patient population. While current pharmacological and surgical interventions are effective in alleviating general limb motor symptoms of PD, they have failed to provide significant benefit for cranial motor functions controlled by corticobulbar tracts such as speech and swallowing. This suggests that cranial motor and limb motor deficits are mediated by different underlying neural pathologies in PD, however the nature of these differences are not currently understood. The central goal of this proposal is to investigate differences in the neural mechanisms mediating corticobulbar versus corticospinal impairments in an animal model of PD. Using intracorticial microstimulation and a comprehensive behavioral testing battery consisting of both cranial motor and limb motor tasks, the proposed studies will (1) determine the differential effects of unilateral versus bilateral striatal dopamine depletion on cranial and limb motor function and corticobulbar and corticospinal circuits; (2) determine the differential responses of cranial and limb motor function in PD to targeted motor rehabilitation and dopamine replacement therapy; and (3) determine the differential effects of targeted motor rehabilitation and dopamine replacement therapy on the integrity of corticobulbar and corticospinal circuits. The results have the potential to guide the development of neurobiologically informed therapies that specifically target cranial motor impairment that can be translated to the human patient population. More effective treatment strategies of cranial motor dysfunction in PD will improve patient quality of life, reduce individual health care cost, aspiration pneumonia and ultimately morbidity in this disease population.

DESCRIPTION (provided by applicant): Bulbar dysfunction in the form of progressive speech, swallow and respiratory impairment are highly prevalent in Amyotrophic Lateral Sclerosis (ALS) and together account for 95% of disease mortality. Although progressive muscle weakness is the primary sign of ALS, the effects of exercise and strength training in this patient population i controversial. While exercise in persons with ALS has historically been discouraged due to fear that muscle overburden may execrate physical decline, recent animal and human data suggest that moderate intensity exercise applied early in the disease may serve a neuroprotective role in ALS. Indeed, exciting preliminary data from our laboratory indicate that a regimen of expiratory muscle strength training (EMST) in persons with mild-moderate ALS has a positive effect on expiratory force generating abilities, airway protection and cough during swallowing, swallow kinematics, self-reported swallow severity and swallow- related quality of life. The central goal o this proposal is to investigate the effects of an eight-week regimen of EMST on bulbar function in persons with mild to moderate ALS using a blinded, sham-controlled, randomized clinical trial. The central hypothesis of this proposal is that eight-weeks of daily moderate intensity resistance EMST exercise will actively engage the expiratory and submental musculature, deter disuse atrophy and prolong function of airway protection, swallowing and functional oral intake in persons with ALS. The proposed study is designed to specifically determine the effect of EMST on: 1) expiratory force generating ability (maximum expiratory pressure); 2) swallow physiology and airway safety during swallow; 3) cough function; 4) functional oral intake, swallow-related quality of life and self-reported swallow severity; 5) and subsequent disease progression in persons with mild to moderate ALS. The results will provide valuable insight into the potential role of muscle strength training for improving bulbar function in persons with ALS and will help guide the future direction of research and treatment for this devastating disorder.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease causing progressive muscle weakness and impairments in swallowing (dysphagia). Dysphagia leads to malnutrition, dehydration, tracheal aspiration and pneumonia that contribute to 26% of ALS mortality. The current proposal is strongly motivated by fundamental knowledge gaps that have contributed to sub-optimal clinical care of individuals with ALS and a lack of formal practice guidelines in the management of progressive swallowing impairment in ALS. The overarching goal of this work is to improve clinical practice by 1) increasing our understanding of governing mechanisms and progression of dysphagia in ALS and 2) identification of sensitive biomarkers of swallowing dysfunction to build a clinical dysphagia risk index tool. We will perform serial instrumental swallowing evaluations in 100 individuals with ALS (50 bulbar-onset, 50 spinal-onset) from disease diagnosis to feeding-tube dependence and provide critical longitudinal data to help establish the first time-course model of ALS swallowing decline. Such a model is needed to guide best practice recommendations, optimal timing of interventions, for planning and design of future clinical trials, and for interpretation of experimental treatment effects. We will also test the discriminant ability and clinical utility of a set of promising clinical markers of swallowing decline that are pragmatically designed for easy dissemination into ALS clinical settings. Our long- term goal is to improve clinical care of swallowing disorders in ALS. The proposed study will deliver new insights into the pathophysiologic mechanisms of unsafe and inefficient swallowing in ALS to drive the development of future intervention strategies and lead to earlier and more accurate identification of swallowing impairment. Earlier identification and better treatment strategies for swallowing dysfunction in ALS will lead to improvements in oral intake, nutrition, pulmonary health and quality of life and ultimately reduce aspiration pneumonia associated mortality in this challenging population.