Improving Human Cerebrovascular Function Using Acute Intermittent Hypoxia

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PROJECT SUMMARY Vascular dysfunction contributes to the pathology of numerous neurological conditions, however current treatment options to address these factors are insufficient. The overall objective of this project is to test the potential of a novel intervention to improve the brain’s blood supply, thereby mitigating the vascular contributions to neurodegeneration and functional impairment. Acute Intermittent Hypoxia (AIH) is emerging as a powerful therapy to improve overall cardiovascular health and facilitate neural plasticity, however its impact on human cerebrovascular function is unclear. Hypoxia is known to generally influence angiogenesis and blood flow, and exposures to brief hypoxic stimuli can “precondition” the vasculature of other organs to be more resilient to severe hypoxic threat. This study tests the hypothesis that a 3-week daily AIH intervention will drive beneficial vascular plasticity in the human brain. Healthy participants will be recruited to complete a randomized sham- controlled crossover trial to assess the impact of daily AIH versus a sham intervention. This study employs a highly innovative magnetic resonance imaging (MRI) protocol to assess the beneficial effects of AIH on regional human cerebrovascular physiology, using advanced perfusion imaging and prospectively-targeted gas challenges to evoke vasodilatory responses. The impact of AIH on brain physiology will be determined through comparison of pre- and post-intervention MRI scans in two specific aims. 1) Phase-contrast MRI and multi-post- label-delay pseudo-continuous Arterial Spin Labeling MRI will be performed to quantify both whole-brain and regional tissue perfusion and vascular transit times at rest. 2) Inhaled hypoxia and hypercapnia gas challenges will be administered during MRI scanning to measure cerebrovascular reactivity (CVR), the responsiveness of blood vessels to a dilatory stimulus. Unlike previous studies that use gross metrics (e.g., transcranial Doppler ultrasonography), the regional insight provided by Arterial Spin Labeling MRI will be important for tracking the effectiveness and safety of AIH in future patient studies. The imaging protocol also provides a quantitative framework to optimize the AIH “dose” for a given cohort or individual. Finally, the proposed research is significant because our results may demonstrate that AIH is a powerful and practical tool for improving the health of the brain’s vasculature. This is of particular importance in patients where other approaches for modifying vascular risk factors (e.g., aerobic exercise) may be challenging to apply due to cognitive or motor impairment. If this proof-of concept study is successful, AIH will become an exciting new intervention for facilitating cerebrovascular plasticity and opening up new therapeutic treatment opportunities in the numerous neurological disorders where vascular dysfunction is implicated, including Multiple Sclerosis, Parkinson’s Disease, and several forms of dementia. By beneficially modifying cerebrovascular physiology in these patients, AIH has the potential to address the vascular and neurovascular pathologies that contribute to the progression of neurologic impairment.