title: Intermittent hypoxia and neurorehabilitation.
abstract: In recent years, it has become clear that brief, repeated presentations of hypoxia [i.e., acute intermittent hypoxia (AIH)] can boost the efficacy of more traditional therapeutic strategies in certain cases of neurologic dysfunction. This hypothesis derives from a series of studies in animal models and human subjects performed over the past 35 yr. In 1980, Millhorn et al. (Millhorn DE, Eldridge FL, Waldrop TG. Respir Physiol 41: 87-103, 1980) showed that electrical stimulation of carotid chemoafferent neurons produced a persistent, serotonin-dependent increase in phrenic motor output that outlasts the stimulus for more than 90 min (i.e., a "respiratory memory"). AIH elicits similar phrenic "long-term facilitation" (LTF) by a mechanism that requires cervical spinal serotonin receptor activation and de novo protein synthesis. From 2003 to present, a series of studies demonstrated that AIH can induce neuroplasticity in the injured spinal cord, causing functional recovery of breathing capacity after cervical spinal injury. Subsequently, it was demonstrated that repeated AIH (rAIH) can induce recovery of limb function, and the functional benefits of rAIH are greatest when paired with task-specific training. Since uncontrolled and/or prolonged intermittent hypoxia can elicit pathophysiology, a challenge of intermittent hypoxia research is to ensure that therapeutic protocols are well below the threshold for pathogenesis. This is possible since many low dose rAIH protocols have induced functional benefits without evidence of pathology. We propose that carefully controlled rAIH is a safe and noninvasive modality that can be paired with other neurorehabilitative strategies including traditional activity-based physical therapy or cell-based therapies such as intraspinal transplantation of neural progenitors.
authors.affiliation: Department of Physical Therapy College of Public Health and Health Professions, University of Florida, Gainesville, Florida;
authors.forename: Elisa J
authors.initials: EJ
authors.lastname: Gonzalez-Rothi
authors.affiliation: Department of Biological Sciences, College of Science, National Sun Yat-sen University, Kaohsiung City, Taiwan;
authors.forename: Kun-Ze
authors.initials: KZ
authors.lastname: Lee
authors.affiliation: Department of Integrative Biology and Physiology, University of California-Los Angeles, Los Angeles, California; and.
authors.forename: Erica A
authors.initials: EA
authors.lastname: Dale
authors.affiliation: Department of Neuroscience, College of Medicine, University of Florida, Gainesville, Florida.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Reier
authors.affiliation: Department of Physical Therapy College of Public Health and Health Professions, University of Florida, Gainesville, Florida;
authors.forename: Gordon S
authors.initials: GS
authors.lastname: Mitchell
authors.affiliation: Department of Physical Therapy College of Public Health and Health Professions, University of Florida, Gainesville, Florida; ddf@phhp.ufl.edu.
authors.forename: David D
authors.initials: DD
authors.lastname: Fuller
mesh_terms: D000818:Animals; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D009422:Nervous System Diseases / Q000503:physiopathology* / Q000534:rehabilitation*; D058953:Neural Stem Cells / Q000637:transplantation; D013119:Spinal Cord Injuries / Q000503:physiopathology / Q000534:rehabilitation
keywords: cellular transplantation; intermittent hypoxia; neurorehabilitation; spinal cord injury