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.