Mechanisms of Sleep Disturbance in ME/CFS

Dr. Claudia Schilling talked about mechanisms of sleep disturbance in ME/CFS. To start with, pre-existing sleep disturbance has been identified as a risk factor for developing a post-acute infection syndrome (PAIS). At the same time, it is one the central diagnostic criteria for ME/CFS and affects around 50% of post-COVID syndrome patients. It also exerts influence on other symptoms, including fatigue and cognitive dysfunction. Lastly, sleep disturbance also serves as a window to impaired brain function. There is a strong bidirectional relationship between sleep, on the one hand, and inflammation and immune activation, on the other hand. Sleep disturbance leads to adrenergic stimulation, for example, affecting leukocytes and cortisol release thereby leading to a suppression of proinflammatory pathways. In turn, inflammation can have a strong effect on sleep, depending on the magnitude of the inflammatory process. Even within a mild inflammatory context there is an increased propensity to non-rapid eye movement (REM) sleep. One of the central mechanisms behind sleep disturbances in PAIS may be blood-brain-barrier dysfunction, as revealed by a magnetic resonance imaging (MRI) study. Neural mechanisms, too, may be causative factors, wherein certain brain networks may be dysfunctional, including the thalamic cortical network. One study measured blood oxygenation in a cohort of Long COVID patients and found slightly but significantly lower oxygenation starting about 5 to 10 minutes after sleep onset. This oxygenation decrease may be a marker for Long COVID-associated organ dysfunction. Another study looked at how insomnia in the context of post-COVID syndrome may differ from general insomnia by use of polysomnography. There appeared to be central nervous system differences in post-COVID insomnia compared to other insomnia patients. Other research has also shown that the normal coupling between sleep spindles and slow oscillations—two important brain rhythms involved in sleep—is disrupted in both Long COVID and ME/CFS. This finding suggests abnormalities in the microstructure of sleep and may serve as an electrophysiological biomarker of sleep dysfunction in post-COVID conditions. Another proposed mechanism involves alterations in the balance between cortical excitation and inhibition, a process that is crucial for sleep regulation and is linked to hyperarousal. This balance depends largely on the neuro-transmitters glutamate and gamma-aminobutyric acid (GABA). Studies of chronic insomnia have previously found evidence of altered GABAergic transmission, and preliminary findings in post-COVID patients suggest reduced cortical GABA levels. These changes may contribute to insomnia by disrupting the normal regulation of neural activity. Overall, evidence suggests that sleep disturbances in PAIS may arise from a combination of immune-related effects on the brain, particularly in the context of blood–brain barrier dysfunction, abnormalities in sleep-regulating neural networks, and an altered balance between excitatory and inhibitory brain activity. These mechanisms may contribute to neuropsychiatric symptoms, including insomnia. Finally, the investigation of sleep disturbances can generate important insights into the clinical heterogeneity of PAIS and may provide indications for the differential effectiveness of treatment strategies.