Brain Mechanisms of COVID-19-Sleep Disorders

Abstract

2020 and 2021 have been unprecedented years due to the rapid spread of the modified severe acute respiratory syndrome coronavirus around the world. The coronavirus disease 2019 (COVID-19) causes atypical infiltrated pneumonia with many neurological symptoms, and major sleep changes. The exposure of people to stress, such as social confinement and changes in daily routines, is accompanied by various sleep disturbances, known as 'coronasomnia' phenomenon. Sleep disorders induce neuroinflammation, which promotes the blood-brain barrier (BBB) disruption and entry of antigens and inflammatory factors into the brain. Here, we review findings and trends in sleep research in 2020-2021, demonstrating how COVID-19 and sleep disorders can induce BBB leakage via neuroinflammation, which might contribute to the 'coronasomnia' phenomenon. The new studies suggest that the control of sleep hygiene and quality should be incorporated into the rehabilitation of COVID-19 patients. We also discuss perspective strategies for the prevention of COVID-19-related BBB disorders. We demonstrate that sleep might be a novel biomarker of BBB leakage, and the analysis of sleep EEG patterns can be a breakthrough non-invasive technology for diagnosis of the COVID-19-caused BBB disruption.

Keywords: COVID-19-sleep disorders; brain mechanisms; the blood–brain barrier permeability.

Figure 1

The ‘coronasomnia’ phenomenon has been recently described as COVID-19-related sleep disorders, including insufficient sleep, poor sleep quality, insomnia, and disturbances of sleep-wake schedules associated with physical and emotional morbidity in the COVID-19 pandemic.

Figure 2

Illustration of the blood–brain barrier (BBB) disruption induced by sleep-related disorders. Middle upper figure demonstrates the various sleep disturbances, including insomnia, sleep deprivation, sleep apnea, associated with the BBB breakdown. The left figure shows that sleep loss causes low-grade inflammation of the brain, which facilitates the BBB disruption. Right (two-photon imaging of the brain capillaries filled by tetramethylrhodamine isothiocyanate–dextran 70 kDa) and the middle lower squares demonstrate the cerebral blood vessels damaged by cytokines leading to the BBB opening.

Figure 3

The biological clock of the blood–brain barrier permeability to cytokines (TNF-α, IL-6, IL-1α) and regulating their activity factors, such as hormones (NA and PGD2) and permeability-glycoprotein multidrug transporter (Pgp).

Figure 4

Brain mechanisms of COVID-19-sleep disorders: (A–C) The one hypothesis explains that the SARS-CoV-2 infiltrates the brain (A), possibly from the cribriform plate (B) and the olfactory epithelium (C). The cribriform plate (B) is a center of the lymphatic pathway of metabolic clearance and is a connective bridge between the cerebral spinal fluid and the cervical lymphatic system) [138,139,140,141,142,143,144,145]; (D,E) the virus can enter into the brain through the anatomical connection between the meningeal lymphatic vessels and the lymphatic vessels localized along the olfactory nerve [141]. The lymphatic window into the brain is considered in [146,147,148]; (F–H) The SARS-CoV-2 via the ACE2 receptor on the endothelial cells of the lymphatic vessels [149] can enter into the brain tissues inducing cytokine storm (F) and endothelial inflammation that alters the BBB integrity (G) facilitating COVID-19-related sleep disorders (H). SARS-CoV-2 also affects the olfactory centers (olfactory bulb and cortex), thereby reducing smell sensations [150,151,152,153,154,155,156].