Novel Actions of Acute Intermittent Hypoxia in Hemispheric Stroke

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PROJECT SUMMARY/ABSTRACT Stroke is the second leading cause of death and a leading cause of long-term disability worldwide. Despite the spontaneous recovery that occurs following a hemispheric stroke, more than half of stroke patients have substantial residual impairments, imposing a significant human and economic burden. The objective of this proposal is to investigate the potential of a novel therapeutic intervention — Acute Intermittent Hypoxia (AIH). This technique has shown significant promise in persons with spinal cord injury (SCI) and in our preliminary studies on stroke. AIH constitutes a brief, rapid reduction in oxygen concentration which stimulates the serotonergic pathways of the brainstem, and enhances activity of serotonin receptors in the brain and spinal cord. This results in increased synthesis of a key protein called brain-derived neurotrophic factor (BDNF), potentiating synaptic transmission and driving plasticity in the CNS. In persons with SCI, AIH has been demonstrated to be safe and cause broad-ranging changes in the CNS, including transient improvements in respiratory function, locomotor function, and hand dexterity. In this proposal we will extend our promising research on AIH-initiated plasticity in SCI patients to persons with stroke. Our specific aims are to (1) To assess the limb segmental distribution of AIH-induced increases in muscle activation in paretic limbs of stroke survivors, comparing strength measurements taken before and after an AIH sequence; (2) To determine whether AIH increases the severity of spasticity using reflex threshold measurements in spastic muscles. Here, we plan to use a linear motor (LinMot USA Inc.) to estimate reflex threshold in elbow flexors before and after AIH administration; (3) To evaluate the spatial distribution of motor unit activation in limb muscles using surface EMG grids and to implement motor unit decomposition protocols to determine which types of motor unit are activated following AIH administration. In the short-term, this study will help us gain a greater understanding of the efficacy and underlying mechanism of AIH-induced plasticity in stroke. In the long-term, this research will help establish AIH as both a novel therapeutic modality in and of itself for the treatment of stroke, and also as an adjunct technique to be combined with other intervention techniques. This translational proposal exemplifies the NIH Exploratory/Developmental Research Grant Program (R21) as it fosters developmental research for an emerging intervention that has the potential for several unique clinical applications.