EXPRESS: Programmed Oscillatory Oxygen Therapy: Reframing Oxygen as a Dynamic Signal for Restoring Cerebrovascular Regulation After Ischemic Stroke.

Abstract

Successful recanalization after ischemic stroke does not always restore adequate microvascular perfusion within previously ischemic tissue, partly because persistent microcirculatory dysfunction, impaired neurovascular coupling, and perfusion-metabolism mismatch continue to disrupt cerebral blood flow regulation. Conventional continuous oxygen therapy primarily increases systemic oxygen availability, but may be insufficient to restore impaired cerebrovascular responsiveness, while excessive or prolonged oxygen exposure may increase oxidative stress and attenuate adaptive oxygen-sensitive pathways. In this Review, we propose programmed oscillatory oxygen therapy (POOT) as a treatment-design framework for dynamic oxygen modulation after ischemic stroke. Rather than treating oxygen solely as a metabolic substrate, POOT reframes oxygen as a dynamic biological signal that may engage hypoxia-inducible factor, reactive oxygen species, nitric oxide, and related oxygen-sensitive pathways to support cerebral blood flow regulation and neurovascular coupling. Unlike fixed intermittent hypoxia, intermittent hyperoxia, or hypoxia-hyperoxia training protocols, POOT is proposed as a parameter-explicit and potentially feedback-informed framework targeting post-recanalization microvascular dysfunction. This framework integrates response window, oxygen intensity, cycle structure, treatment frequency and duration, and physiological feedback, providing a conceptual basis for advancing oxygen therapy toward more individualized and precision-oriented modulation after ischemic stroke.