Fig. 3.

Proposed model by which PASC-associated increases in TGFB may disrupt circadian rhythms, uncouple central and peripheral circadian rhythms and cause progression to ME/CFS. A) Healthy rhythms in the central nervous system (CNS) and peripheral organs are coordinated by multiple mechanisms that coincide with daily activity and routines to reinforce rhythms through multiple overlapping mechanisms. With optimal synchronization rhythmic processes in brain function (red) and physiology (purple) are timed and mutually reinforced. B) Post-inflammatory cytokine changes may increase levels of TGFB to disrupt the alignment of circadian rhythms, especially in peripheral organ systems. Other factors such as hypoxia and poor light exposure may further contribute to misalignment, and/or cause a negative feedback loop and further weakening central rhythms. Misalignment of CNS and peripheral physiology may lead to symptoms of ME/CFS including fatigue, inattention, depression, autonomic instability, cold intolerance and orthostatic hypotension. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)