The role of sleep in recovery following ischemic stroke: A review of human and animal data

Abstract

Despite advancements in understanding the pathophysiology of stroke and the state of the art in acute management of afflicted patients as well as in subsequent neurorehabilitation training, stroke remains the most common neurological cause of long-term disability in adulthood. To enhance stroke patients' independence and well-being it is necessary, therefore, to consider and develop new therapeutic strategies and approaches. We postulate that sleep might play a pivotal role in neurorehabilitation following stroke. Over the last two decades compelling evidence for a major function of sleep in neuroplasticity and neural network reorganization underlying learning and memory has evolved. Training and learning of new motor skills and knowledge can modulate the characteristics of subsequent sleep, which additionally can improve memory performance. While healthy sleep appears to support neuroplasticity resulting in improved learning and memory, disturbed sleep following stroke in animals and humans can impair stroke outcome. In addition, sleep disorders such as sleep disordered breathing, insomnia, and restless legs syndrome are frequent in stroke patients and associated with worse recovery outcomes. Studies investigating the evolution of post-stroke sleep changes suggest that these changes might also reflect neural network reorganization underlying functional recovery. Experimental and clinical studies provide evidence that pharmacological sleep promotion in rodents and treatment of sleep disorders in humans improves functional outcome following stroke. Taken together, there is accumulating evidence that sleep represents a "plasticity state" in the process of recovery following ischemic stroke. However, to test the key role of sleep and sleep disorders for stroke recovery and to better understand the underlying molecular mechanisms, experimental research and large-scale prospective studies in humans are necessary. The effects of hospital conditions, such as adjusting light conditions according to the patients' sleep-wake rhythms, or sleep promoting drugs and non-invasive brain stimulation to promote neuronal plasticity and recovery following stroke requires further investigation.

Keywords: EEG; Ischemic stroke; Neuroplasticity; Neurorehabilitation; Recovery; Sleep architecture; Sleep disorders.

Fig. 1

Schematic approach to classify temporal and spatial changes in post-stroke neuroplasticity covering changes from the micro- to macroscopic levels. Within the first days of stroke genes promoting growth and structural changes at the dendrites, synapses and axons of neurons are upregulated and inhibitory genes are reduced in the peri-infarct zone (Carmichael, 2006, Carmichael and Chesselet, 2002). The post-ischemic brain enters a state of hyperexcitability. Post-ischemic long-term potentiation (LTP) due to enhanced glutamergic transmission is postulated to occur and foster structural neuroplasticity (i.e. synaptic, dendritic and axonal growth) and reorganization of the disrupted neuronal network (Di Filippo et al., 2008, Krakauer et al., 2012). In the acute phase of stroke sleep may be neuroprotective as suggested from studies showing that fostering inhibitory GABA-ergic activity increases functional recovery (Gao et al., 2008, Hodor et al., 2014), whereas reducing excessive GABA-ergig activity, premature use-dependent neuronal activation and sleep disruption, have adverse effects on infarct size and post-stroke recovery (Clarkson et al., 2010, Dromerick et al., 2009, Gao et al., 2010). In the subchronic and chronic phases, sleep is assumed to promote use-dependent neuroplasticity and improve learning and stroke recovery (Siengsukon et al., 2015).

Fig. 2

Multiple facets of sleep intervention on recovery following ischemia. This diagram shows how sleep may differently modulate functional recovery after stroke depending on the time window when sleep alteration occurs (before or after ischemic stroke) and also by kinds of sleep alterations (deprived or enhanced). Particularly, sleep disturbances after stroke are detrimental in preclinical and clinical studies; enhancement of sleep following stroke is beneficial by increasing neuroplastic and neurogenic processes in preclinical studies; in humans post-stroke treatment of sleep disorders is suggested to improve stroke outcome (see Section 5). Sleep deprivation before stroke as a form of preconditioning treatment is neuroprotective, likely by increasing sleep homeostatically following ischemia. The neuroprotective effect of sleep deprivation pre-ischemia has been observed in preclinical studies.

Fig. 3

Sleep and sleep disturbances in stroke patients and prognosis of recovery. Good or bad prognosis of stroke recovery can depend on the presence or absence of sleep disturbances and on the severity and persistence of post-stroke changes in sleep's micro- and macrostructure.

Fig. 4

Improving stroke outcome by promoting healthy sleep. Treatment of post-stroke sleep disorders is associated with better stroke outcome and decreased risk for stroke reoccurrence. As suggested by animal studies promotion of sleep by drugs following a stroke is associated with increase neuroplasticity processes and better motor recovery. In stroke patients sleep might be promoted by increasing the homeostatic sleep drive, e.g. by environmental enrichment and optimized rehabilitative trainings or by non-invasive brain stimulation during training and during sleep.