Identifying predictive biomarkers for acute intermittent hypoxia induced motor recovery in persons with incomplete spinal cord injury

PROJECT SUMMARY Spinal cord injury (SCI) results in lifelong sensorimotor deficits, leading to chronic mobility impairments and loss of functional independence. The restoration of walking remains a highly valued goal for persons with chronic, incomplete SCI (iSCI) reducing sequalae due to immobility. Modest breathing modest bouts of low

oxygen (acute intermittent hypoxia; AIH), is shown to enhance motor recovery in both spinally injured rats and persons with SCI by inducing adaptive reorganization in spared neural circuitry. Detailed mechanistic studies of AIH-induced respiratory and non-respiratory motor plasticity in rats provide a fundamental basis to advance our

understanding and optimize the clinical benefits of AIH therapy. However, the underlying neural mechanisms that contribute to improvements in functional recovery in humans with SCI remain unclear. Importantly, we do not currently do not fully understand why AIH augments walking performance in humans with iSCI. In previous

studies, approximately 33% of study participants with chronic iSCI did not respond to the AIH intervention, not achieving clinically meaningful improvements in motor performance. In order to optimize the clinical translation of AIH as an adjuvant for walking rehabilitation, we will examine two critical knowledge gaps: (1) a lack of

understanding of the underlying mechanisms of AIH induced plasticity, (2) the identification of predictive biomarkers to determine who optimally responds to AIH. To address the first knowledge gap, we will validate the degree to which AIH engages the same cellular mechanisms in humans as observed in spinally injured rodents

by utilizing enzyme linked immunosorbent assays to quantify AIH induced synthesis of serotonin and brain derived neurotrophic factor. To address the second knowledge gap, we will use magnetic resonance imaging to measure descending tract connectivity as predictive biomarkers to identify responders in AIH. Responders will

be identified by quantifying gains in walking performance after the AIH intervention. To further support this approach, we will utilize transcranial magnetic stimulation to clarify the functional relevance of AIH induced changes in the excitability of descending tract connectivity. Together, these studies will not only advance the

detection of patients who will optimally respond but also identify patient specific factors that facilitate or inhibit AIH induced functional recovery. The insights gained from this study will enhance our understanding of how to harness AIH-induced plasticity to promote meaningful recovery and will profoundly impact the lives of persons

with chronic spinal injuries.