Fig. 10. Pathophysiology of PI-ME/CFS.

Diagram illustrates potential mechanisms and a cascade of events that lead to the development of ME/CFS after an infection. Exposure to an infection leads to concomitant and persistent immune dysfunction and changes in gut microbiome. Immune dysfunction affects both innate and adaptive immune systems that are sex dependent. We hypothesize that these changes are driven by antigen persistence of the infectious pathogen. These immune and microbial alterations impact the brain, leading to decreased concentrations of metabolites which impacts brain function. The catecholamine nuclei release lower levels of catechols, which impacts the autonomic nervous system and manifests with decreased heart rate variability and decreased baroreflex cardiovascular function, with downstream effects on cardiopulmonary capacity. Altered hypothalamic function leads to decreased activation of the temporoparietal junction during motor tasks, suggesting a failure of the integrative brain regions necessary to drive the motor cortex. This decreased brain activity is experienced as physical and psychological symptoms and impacts effort preferences, leading to decreased engagement of the motor system and decreases in maintaining force output during motor tasks. Both the autonomic and central motor dysfunction result in a reduction in physical activity. With time, the reduction in physical activity leads to muscular and cardiovascular deconditioning, and functional disability. All these features make up the PI-ME/CFS phenotype.