Danny R. Rose, Jr. MD
Sleep is a complex yet fundamental physiological state with wide-reaching implications for a variety of disease states that are still incompletely understood. The study of the various deleterious effects of sleep deprivation and benefits of physiologic sleep are ripe for application to the pathophysiology of stroke, which itself involves the study of the negative and positive effects of physiologic stressors and the importance of recovery and regeneration. Coauthors Pincherle and Pace et al. recently published a comprehensive review of current research in human and animal models about the effects of sleep as well as preconditioning in the context of acute ischemic stroke.
Sleep disorders are exceedingly prevalent; it is estimated that up to one third of adults do not get adequate sleep. Sleep deprivation (SD)/fragmentation induces autonomic nervous system dysfunction, increases inflammation and induces procoagulant factors and oxidative stress. In acute stroke, animal models show that sleep deprivation increases apoptosis and impairs neuroplasticity and neurogenesis. In human studies, sleep-disordered breathing (SDB) has been significantly associated with hypertension, atherosclerosis and cardiac arrhythmia. In addition, SDB was identified as an independent stroke predictor in one meta-analysis (OR 2.24, CI 1.57-3.19), and was shown to have a dose-response relationship in stroke/TIA survivors with respect to recurrent stroke/TIA and all-cause mortality in a separate review. Intermittent hypoxia, intrathoracic pressure changes, sympathetic activation, blood pressure lability, endothelial dysfunction and proinflammatory factors are all likely contributing factors associated with SDB.
Preconditioning or ischemic tolerance is the concept of applying a harmful stimulus near the threshold of cell damage to fortify tissue against subsequent ischemic injury. Animal models suggest a variety of mechanisms for this response, including downregulation of gene expression related to inflammation, energy metabolism, cell cycle regulation and ion channel activity, theoretically minimizing the extent of inflammatory damage while allowing adequate time for repair by arresting energy metabolism and the cell cycle. In addition, ischemic preconditioning (IP) also appears to promote neurogenesis, angiogenesis and inhibit excitatory pathways and cortical spreading depolarization (CSD), both of which are implicated as major pathogenic mechanisms in the ischemic cascade.
One key way this concept is studied in clinical trials is through remote ischemic conditioning (RIC), where short ischemic intervals are applied to a limb to protect target organs. Two phase I trials have shown safety of RIC in aneurysmal subarachnoid hemorrhage, a strategy intended to reduce the delayed ischemia that is a major factor in clinical deterioration and poor functional outcome. RIPAT (Remote Ischemic Preconditioning in the Prevention of Ischemic Brain Damage During Intracranial Aneurysm Treatment) and the PreLIMBS trial (Preconditioning With Limb Ischemia for Subarachnoid Hemorrhage) are currently ongoing trials that will shed light on this technique. These strategies are not applicable for acute stroke, given its unpredictable nature, but RIC during ischemia (termed remote ischemic perconditioning or RIPerC) showed increased tissue survival after 1 month in a voxel analysis. However, infarct size/progression by MRI and clinical outcome was unaffected in that study. Future studies are ongoing to clarify the applicability and efficacy of RIPerC in acute stroke.
Sleep deprivation as a form of preconditioning suggests that some of the pathogenic processes in SD can induce tissue fortification. In addition, there is strong support for the view that these benefits are also mediated by the rebound effect of increased sleep during the early phase after stroke. Pharmacologic studies looking at γ-hydroxybutyrate and Baclofen (which both promote slow-wave sleep in humans) show that they positively influence neuroplasticity and functional outcome, although their other benefits in inducing hypothermia and reducing spasticity confound these results.
Although many of these findings present significant challenges for translational researchers to apply them to the bedside, RIC and strategies to promote restorative sleep in the setting of acute stroke can readily be studied in the clinical setting. Population-based interventions aimed at identifying and treating sleep disorders may have significant benefits in the reduction of stroke and other cardiovascular events. The study of preconditioning and sleep with respect to stroke promises to continue to be a valuable resource in identifying mechanisms and factors related to brain protection and regeneration.