Safety and Cognitive Effects of Acute Intermittent Hypoxia-Induced Neuroplasticity in TBI

The purpose of this study is to determine whether Acute Intermittent Hypoxia (AIH) is safe to administer to medically stable chronic traumatic brain injury (TBI) patients. There is evidence indicating that AIH promotes central nervous system (CNS) neuroplasticity. AIH stimulates oxygen-sensitive serotonergic neurons in the

brainstem’s raphe nucleus leading to serotonin release into different regions of the CNS. This release leads to activation of serotonin receptors on or near cortical neurons and increased synthesis of multiple trophic factors including brain-derived neurotrophic factor, vascular endothelial growth factor, and erythropoietin. These actions

also influence the functioning of neurotransmitters such as GABA. Greater expression of growth factors in the brain facilitates neuroplasticity by increasing synaptic strength, cortical neuron and interneuron excitability, and intra- and inter-brain region connectivity. Of note is that hypoxia induced neuroplasticity only occurs with acute

intermittent exposure but is not evoked by continuous hypoxia of the same duration. Is AIH safe to administer to TBI patients? The preponderance of prior animal and human evidence suggests that daily episodes of mild AIH do not negatively impact important safety parameters such as resting blood pressure, arterial pressure, heart

rate, heart rate variability, cardiac output, or cognitive function. To date, AIH protocols that induce beneficial neuroplasticity without triggering pathological sequelaehave been restricted to brief episodes of modest hypoxia with a low cycle number, such as 15 x 90-second episodes of 10% inspired oxygen. Recent studies in humans

with chronic spinal cord injury and stroke demonstrates that these modest AIH episodes repeated for five consecutive days can be safely tolerated without pathological consequences. Another recent study showed that even a 4-week protocol of moderate daily AIH (cycling 9%/21% oxygen every 1.5 minutes, 15 cycles per day,

for 4 weeks) does not elicit adverse medical consequences or cognitive impairment. Thus, the cumulative evidence suggests that repetitive AIH may be safely used to study whether it can enhance neurobehavioral functioning in TBI patients without deleterious effects. In this study, we will administer mild AIH to 16 patients on

four different days spread over two weeks, starting with normal oxygen concentration (target SpO2 of 98%) and then progressively reducing the oxygen concentrations over the next three sessions (to 93%, 87%, & 82%). Our primary objective is to determine whether it is safe to administer mild AIH to chronic TBI patients with persistent

functional impairments, but who are clinically stable. As a secondary objective in this study, we will assess whether mild AIH administration had any post-session or cumulative effects post-studyon memory and cognition, cortical activation using paired-pulse inhibition, or whether pre-study brain architecture or functional connectivity

as detected by structural and resting-state functional magnetic resonance imaging predicts response to AIH. If there are no adverse effects of mild AIH in this study, clinical trials using mild AIH alone or in conjunction with neurobehavioral therapies could evaluate whether AIH facilitates improved functional performance after TBI.