Genetic Biomarkers of Intermittent Hypoxia-Induced Respiratory Motor Plasticity in Chronic SCI
Abstract
Breathing impairment greatly reduces quality of life and is a leading cause of illness, re-hospitalization and death in people with spinal cord injury (SCI). Thus, it is critical to devise new strategies that restore breathing function. One promising strategy to restore breathing capacity after SCI is to strengthen remaining neural pathways by inducing spinal neuroplasticity. Our research group has developed novel methods to induce spinal respiratory motor plasticity involving brief exposures to low oxygen, referred to as acute intermittent hypoxia or acute intermittent hypoxia (AIH). Exciting outcomes from nine completed SCI trials demonstrate that even a single day of AIH, or daily AIH for approximately 5 consecutive days, induces recovery of respiratory and non-respiratory functions, improving not only breathing, but walking and hand function after SCI. Unfortunately, approximately 40% of individuals exhibit minimal response to AIH. Therefore, the fundamental goal of this proposed research is to improve the therapeutic potential of AIH by (1) optimizing AIH protocols to maximize functional benefits, and (2) identify genetic biomarkers to distinguish those most/least likely to benefit from AIH-based treatments. A priority for AIH protocol optimization is to evaluate the impact of carbon dioxide (CO2) and its role in regulating AIH-induced plasticity. Preliminary data from our lab suggests that AIH combined with 5% inspired CO2 (hypercapnia, AIHH) robustly enhances respiratory neuroplasticity. In our first aim, we will test the hypothesis that a single AIHH session (consisting of 15, 1-min episodes of low oxygen combined with 5% CO2 with 1.5-min intervals breathing room air) elicits greater respiratory motor plasticity than AIH alone (without CO2) in individuals with chronic SCI. To assess respiratory motor plasticity, the primary outcome will be the amplitude of diaphragm motor responses when pathways from the brain to the diaphragm are stimulated with a brief, non-invasive magnetic pulse (transcranial magnetic stimulation). Further, emerging evidence indicates task-specific training enhances AIH-induced functional benefits suggesting even greater improvements when paired with AIHH. Thus, in our second aim, we will test the hypothesis that functional gains after 5 days of AIHH and respiratory strength training, a standard task-specific training approach, will be greater than five daily AIH sessions (without CO2) paired with respiratory strength training. Respiratory strength training will involve four sets of 6-12 forceful breaths through a small, hand-held device. Primary outcomes will be maximal inspiratory and expiratory pressure generation 1 day after the 5-day intervention. We selected these functional outcomes because these well-established measures are indicative of respiratory strength and associated with respiratory health and function after SCI. Before phase 3 clinical trials and potential clinical implementation, it is critical to distinguish those most and least likely to benefit from AIH-based treatments. In particular, common genetic variations in the human population may limit neuroplasticity and responses to AIH. Preliminary data from our lab indicates that certain dysfunctional genetic variants may characterize individuals who have a minimal response to AIH or AIHH. Therefore, in our third aim, we will test the hypothesis that individuals with dysfunctional genetic variants linked to molecules known to be necessary for AIH-induced respiratory motor plasticity will have limited responses to AIH or AIHH treatments. Saliva samples will be assessed for a panel of genes that are associated with impaired plasticity. Presence of these genetic biomarkers will be compared with outcomes following single AIH and AIHH sessions (Aim 1) and five daily sessions of combined AIH or AIHH plus respiratory strength training (Aim 2). Identifying how genes influence responses to AIH-based treatments will advance precision
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210478
Entities
People
- Emily J Fox
Organizations
- United States Army
- University of Florida