Acute Sleep Modulation and Traumatic Brain Injury Study

Traumatic brain injury (TBI) is a major cause of death and disability worldwide. It produces diffuse axonal injury (DAI), which contributes to cognitive impairment, but effective disease-modifying treatment strategies are missing. We have recently developed a rat model of closed skull TBI that reproduces human TBI consequences, including DAI and clinical sequelae such as memory impairment. Here, we investigated whether sleep modulation after trauma has an impact on DAI and memory outcome. We assessed cognition with the novel object recognition test and stained for amyloid precursor protein, a DAI marker. We found that both sleep induction and restriction acutely after TBI enhanced encephalographic slow-wave activity, markedly reduced diffuse axonal damage in the cortex and hippocampus, and improved memory impairment 2 weeks after trauma. These results suggest that enhancing slow-wave sleep acutely after trauma may have a beneficial disease-modifying effect in subjects with acute TBI.

Traumatic Brain Injury Significance Statement

Traumatic brain injury (TBI) is a clinically important entity. Cognitive deficits belong to the most prevalent chronic posttraumatic symptoms, most likely due to diffuse axonal injury (DAI). A growing body of evidence suggests a role of sleep in the clearance of waste products in the brain, possibly including amyloid precursor protein (APP), a marker of DAI. In this study, we provide evidence that enhancement of slow-wave oscillatory activity in the delta-frequency range decreases the APP-immunoreactivity and preserves cognitive abilities after trauma, potentially offering novel, noninvasive treatment options for traumatic injury.

TBI Introduction

Traumatic brain injury (TBI) is a major public health concern affecting 12% of the general population worldwide and resulting in high rates of death and disability. The mostcommoncauses of TBI include violence, vehicle accidents, and falls (Styrke et al., 2007). TBI is currently interpreted as a disease process (Masel and DeWitt, 2010), presenting not only with acute manifestations, but also with long-lasting symptoms, potentially originated by progressive axonal injury (Bramlett and Dietrich, 2002, Inglese et al., 2005). Studies suggest that diffuse axonal injury (DAI) is an important contributor to posttraumatic cognitive impairment (Li et al., 2006, Kraus et al., 2007, Rostami et al., 2012), which is one of the most prevalent symptoms after TBI (Hall et al., 2005). Immunoreactivity to APP has been established as a gold standard for the detection of DAI. In addition to APP, pathological molecules that are linked to enhanced endoplasmic reticulum (ER) stress and to unfolded protein response, both of which are associated with neuronal death and with neurodegenerative disorders, have also been found to accumulate in the traumatized brain. Among these are activating transcription factor 4 (ATF-4), an ER stress marker, and ubiquitin (UB), a small regulatory protein playing a role in degradation of other proteins (Begum et al., 2014). Potentially noxious molecules are cleared via glymphatic pathways in the brain (Iliff et al., 2014, Plog et al., 2015), particularly during sleep and anesthesia, which are both characterized by predominant slow-wave activity (Xie et al., 2013). Indeed, there is an emerging discussion that sleep might serve as a potential treatment for a number of neurological conditions. Sleep restriction, resulting in increased slow-wave activity during subsequent rebound sleep (Borbe´ly et al., 1984, Franken et al., 1991), has been suggested to be beneficial for TBI (Martinez-Vargas et al., 2012) and stroke subjects (Cam et al., 2013). However, not only physiological sleep, but also pharmacological interventions aimed at increasing slow oscillatory encephalographic activity, were linked to APP clearance in an Alzheimer’s disease model (Klein et al., 2015) and similar interventions also improved outcome after stroke in rodents (Gao et al., 2008). Therefore, there is increasing evidence that interventions that enhance slow-wave activity could constitute novel, noninvasive treatment options for acute and chronic neurological conditions.