Spinal Direct Current Stimulation to Enhance Breathing Following Cervical Spinal Cord Injury

PROJECT SUMMARY Candidate and Environment: Dr. Rana’s career objective is to establish an independent research program aimed to develop therapeutic strategies to enhance respiratory function following spinal cord injuries (SCIs). This proposal has been carefully designed to supplement the candidate’s strong background in SCI neurobiology and respiratory neurophysiology with the acquisition of additional technical skills to study neuromodulatory therapies in rodents and will make her ideally suited to succeed on her career path. The University of Florida is an ideal place for Dr. Rana to achieve these goals since it is home to the Breathing Research and Therapeutics Center which brings together basic and clinician scientists devoted to understanding and addressing physiological challenges of respiratory motor control in disease and injury conditions. The core mentoring team consists of Dr. David Fuller (scientist) and Dr. Emily Fox (clinician-scientist), who are leaders in the field of respiratory motor control and SCI rehabilitation, and have a track record of successful mentees. Research: Respiratory complications are a leading cause of morbidity and mortality in the SCI population. Thus, strategies to target respiratory motor recovery are urgently needed. Transcutaneous spinal direct current stimulation (tsDCS) is a non-invasive neuromodulatory therapy that involves the delivery of a constant low-intensity current to target neural tissue, resulting in increased activation of spinal pathways and motor neuron excitability. However, the feasibility and efficacy of tsDCS to restore breathing following SCI has never been investigated. We have recently demonstrated that ampakines (allosteric modulators of α-amino-3-hydroxy-5- methyl-4-isoxazolepropionic acid (AMPA) receptors) enhance diaphragm muscle activation at acute and chronic stages of SCI. Thus, we hypothesize that 1) tsDCS can safely stimulate diaphragm motor output after incomplete cervical SCI, and 2) pairing tsDCS with low-dose ampakine promotes neuroplasticity, and therefore, is an effective respiratory neurorehabilitation approach. We will use a multidisciplinary approach, including controlled neurophysiological phrenic nerve preparations (Aim 1 & 2) and a comprehensive system to quantify diaphragm activity and overall ventilation in awake/unrestrained rats (Aim 3 & 4) to accomplish the following aims: 1.) Develop an effective tsDCS protocol to increase phrenic activation after cervical SCI; 2.) Test whether pairing ampakine therapy with tsDCS will promote sustained increases in phrenic output; 3.) Test whether tsDCS paired with ampakines can safely enhance diaphragm EMG output in awake rats with cervical SCI; 4.) Test whether a rehabilitation paradigm, consisting of daily tsDCS + low-dose ampakine therapy, can promote sustained recovery of diaphragm activation after cervical SCI. This application encompasses both mentored and independent phases. For the mentored phase of this application, a strong scientific community and support structure has been set in place. Together the co-mentors will guide the candidate in developing the necessary skills to complete this work and transitioning into a career aimed at developing effective strategies to mitigate SCI-inducted motor dysfunction.