Combinatorial respiratory rehabilitation approaches to enhance breathing recovery after cervical spinal cord injury

University Of Florida, Gainesville FL

Investigators

Abstract

ABSTRACT Cervical spinal cord injury (SCI) disrupts neural pathways to spinal respiratory motor neurons, causing impaired breathing and even death. New treatment strategies are desperately needed to improve breathing ability after cervical SCI. Since most SCIs are incomplete, meaningful functional recovery can be induced by harnessing the intrinsic capacity for neuroplasticity, strengthening spared neural pathways to respiratory motor neurons. Therapeutic acute intermittent hypoxia (tAIH) is a simple, safe and effective means to induce respiratory motor plasticity and improve breathing ability in rodent models of acute cervical SCI but is considerably less effective with chronic injury. However, tAIH is highly effective in non-respiratory motor systems in chronic SCI, but only when paired with task-specific training. The impact of combined tAIH and task-specific respiratory training is not known. Thus, our fundamental goal is to maximize breathing recovery after chronic, incomplete cervical SCI using a combinatorial approach that pairs tAIH with respiratory training. We propose to study two distinct respiratory training paradigms: physical exercise and exposure to elevated levels of carbon dioxide (CO2; e.g., hypercapnia). Physical exercise increases breathing via a well-known and reproducible phenomenon known as “exercise hyperpnea”, whereby breathing is increased in proportion to metabolic rate and blood gas levels are regulated by a mechanism independent of chemoreceptor feedback. On the other hand, we can elicit robust, automatic increases in breathing via hypercapnia, which may provide an opportunity for task specific training in cases where vigorous exercise is not possible (e.g., those with limited mobility). This unique form of respiratory training involves activation of carotid CO2 chemoreceptors and is well tolerated and easily administered to individuals with impaired mobility. Although the mechanisms differ, both exercise hyperpnea and hypercapnia engage neural pathways involved in automatic (vs. volitional) breathing control, thus represent forms of automatic respiratory training. We will test the hypotheses that maximal therapeutic benefits will be achieved when tAIH is paired with either treadmill- or hypercapnia-based respiratory training. We will test our working cellular model concerning mechanisms of synergy between tAIH and task- specific training, which we hypothesize converges on spinal BDNF/TrkB signaling in phrenic motor neurons. Lastly, we predict lasting changes in the neural circuits innervating phrenic motor neurons, shifting the balance of excitatory vs inhibitory inputs, and ultimately increasing their excitability and overall motor output. These are the first studies to pair tAIH with respiratory training that targets automatic respiratory control, which is critical for restoring independent breathing ability. This research will inform future clinical trials as we seek potent and enduring recovery of breathing ability after chronic SCI. Indeed, our team has a documented history of translation, and we are actively translating highly novel discoveries from preclinical models to persons with SCI. Thus, in a very real sense, our work will help accelerate translation of promising ideas into clinical practice.