PROJECT SUMMARY / ABSTRACT Laryngeal dystonia (LD) is a neurological disorder that selectively affects speech production due to involuntary spasms in the laryngeal muscles. As speech communication is a vital part of our daily existence, LD symptoms have a pervasive effect on the quality of life of the affected individual, often extending beyond speech motor deficits and causing significant occupational disability, psychiatric comorbidities, long-lasting stress, and social isolation. Despite the chronic, debilitating impact of LD, its clinical management remains challenging. The current treatment of LD is mostly limited to the temporary relief of voice symptoms with repeated injections of botulinum toxin into the laryngeal muscles, which, however, are not effective in all patients. Thus, there is an urgent clinical need to develop next-generation therapeutic interventions that are informed by LD-specific pathophysiology for their most effective outcome in the majority of patients. Our long- term goal is to determine the causes and pathophysiology of LD and to establish enhanced diagnostics and treatment of this disorder. The overall objective of this study is to conduct a randomized, double-blind, sham- controlled, parallel design, phase 1 clinical trial to assess the feasibility and efficacy of a neurofeedback brain- computer interface (BCI) paradigm in LD patients that acts upon and modulates the disorder pathophysiology. Our central hypothesis is that the disorder-specific neural patterns, which are distinctly associated with symptomatic speech vs. asymptomatic whisper, maybe successfully targeted and modulated with neurofeedback BCI intervention for rehabilitation of speech production in LD patients. Our central hypothesis will be tested by pursuing two specific aims: (1) develop neural signatures of task-characteristic activity during symptomatic and asymptomatic speech motor behaviors in LD patients, and (2) assess the feasibility and efficacy of neurofeedback BCI therapeutic intervention in LD patients. The rationale for the proposed studies is that delineation of task-specific neural signatures in LD will establish a robust scientific foundation for their utilization as a feasible pathophysiological target of novel BCI therapeutic intervention. This research is significant because it is expected to have a meaningful translational impact by informing the conduct of the next phase of the clinical trial in LD patients and thus directly contribute to closing the critically existing gap in the clinical management of this disorder. The research proposed in this application is innovative because it uses a controlled experimental design and advanced methodologies to target disorder-specific central pathophysiology of LD for the development of new non-invasive treatment for these patients.

PROJECT NARRATIVE The proposed research aims to assess the feasibility and efficacy of adaptive brain-computer interface neurotechnology for a novel pathophysiologically based therapeutic intervention in patients with laryngeal dystonia. The proposed research is relevant to public health because non-invasive neuromodulation of brain abnormalities that are specifically linked to the pathophysiology of laryngeal dystonia is ultimately expected to lead to the establishment of a new direction for the treatment of this debilitating disorder. Thus, the proposed research is relevant to the part of NIH’s mission that pertains to developing and applying fundamental knowledge that will help reduce the burdens of human disability.