Differential Effects of Exercise on fMRI of the Midbrain Ascending Arousal Network Nuclei in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Gulf War Illness (GWI) in a Model of Postexertional Malaise (PEM)

Abstract

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Gulf War Illness (GWI) and control subjects underwent fMRI during difficult cognitive tests performed before and after submaximal exercise provocation (Washington 2020). Exercise caused increased activation in ME/CFS but decreased activation for GWI in the dorsal midbrain, left Rolandic operculum and right middle insula. Midbrain and isthmus nuclei participate in threat assessment, attention, cognition, mood, pain, sleep, and autonomic dysfunction. Methods: Activated midbrain nuclei were inferred by a re-analysis of data from 31 control, 36 ME/CFS and 78 GWI subjects using a seed region approach and the Harvard Ascending Arousal Network. Results: Before exercise, control and GWI subjects showed greater activation during cognition than ME/CFS in the left pedunculotegmental nucleus. Post exercise, ME/CFS subjects showed greater activation than GWI ones for midline periaqueductal gray, dorsal and median raphe, and right midbrain reticular formation, parabrachial complex and locus coeruleus. The change between days (delta) was positive for ME/CFS but negative for GWI, indicating reciprocal patterns of activation. The controls had no changes. Conclusions: Exercise caused the opposite effects with increased activation in ME/CFS but decreased activation in GWI, indicating different pathophysiological responses to exertion and mechanisms of disease. Midbrain and isthmus nuclei contribute to postexertional malaise in ME/CFS and GWI.

The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure

“…While the study record on exercise effects in ME/CFS using blood analyses is heterogenous, the brain imaging results are more consistent. Indeed, all neuroimaging studies that have compared ME/CFS patients with healthy controls demonstrated abnormalities in response to cognitive ( Barnden et al, 2015 , 2016 ; Shan et al, 2016 , 2017 ; Washington et al, 2020 ) or physical exertion ( Baraniuk et al, 2021 ; Rayhan and Baraniuk, 2021 ). Some of these abnormalities were interpreted to indicate dysfunction of the glia-controlled neurovascular unit ( Staines et al, 2018 ; Shan et al, 2020 ; Nelson T. et al, 2021 ).…”

Cerebral microstructural alterations in Post-COVID-condition are related to cognitive impairment, olfactory dysfunction and fatigue

“…Affection of vegetative hubs such as the hypothalamus and the hypothalamo-pituitary-adrenal axis is also frequently suggested to play a central role in the pathogenesis of fatigue 49 . With respect to the periaqueductal gray, increased activation has been measured after provocation of exercise in patients suffering from chronic fatigue syndrome 50 . In a cohort covering the late subacute phase (on average three months) after COVID-19 infection, an association between fatigue scores and lower fiber density within a widespread network of association, projection, and commissural tracts was detected 51 .…”

Central 5-HTergic hyperactivity induces myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)-like pathophysiology

“…A weak response by the HPA axis could explain at least hypocortisolism and PEM symptoms [ 17 ]. Recent fMRI studies of patients with ME/CFS have indicated impairment of reciprocal connectivity among several brain regions including the hypothalamus [ 52 ], and exercise-mediated overactivation in the whole RN and midbrain [ 53 ]. Consistent with reports of a reduced salivary cortisol awakening response and reduced serum ACTH levels [ 54 ], we also observed significantly reduced serum levels of cortisol in seventeen patients with ME/CFS (Fig.…”