Submaximal Exercise Provokes Increased Activation of the Anterior Default Mode Network During the Resting State as a Biomarker of Postexertional Malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by disabling fatigue and postexertional malaise. We developed a provocation paradigm with two submaximal bicycle exercise stress tests on consecutive days bracketed by magnetic resonance imaging, orthostatic intolerance, and symptom assessments before and after exercise in order to induce objective changes of exercise induced symptom exacerbation and cognitive dysfunction.Method: Blood oxygenation level dependent (BOLD) scans were performed while at rest on the preexercise and postexercise days in 34 ME/CFS and 24 control subjects. Seed regions from the FSL data library with significant BOLD signals were nodes that clustered into networks using independent component analysis. Differences in signal amplitudes between groups on pre- and post-exercise days were determined by general linear model and ANOVA.Results: The most striking exercise-induced effect in ME/CFS was the increased spontaneous activity in the medial prefrontal cortex that is the anterior node of the Default Mode Network (DMN). In contrast, this region had decreased activation for controls. Overall, controls had higher BOLD signals suggesting reduced global cerebral blood flow in ME/CFS.Conclusion: The dynamic increase in activation of the anterior DMN node after exercise may be a biomarker of postexertional malaise and symptom exacerbation in CFS. The specificity of this postexertional finding in ME/CFS can now be assessed by comparison to post-COVID fatigue, Gulf War Illness, fibromyalgia, chronic idiopathic fatigue, and fatigue in systemic medical and psychiatric diseases.

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 ).…”

“…This review contributes to clarification and hypothesis-generation by analyzing and interpreting literature pertaining to the pathogenesis of ME/CFS, with a focus on the possible role of glial cell populations. Glial dysfunction has frequently been postulated as a key feature of ME/CSF ( Barnden et al, 2011 ; Nakatomi et al, 2014 ; Glassford, 2017 ; Morris et al, 2018 , 2019 ; Staines et al, 2018 ; Shan et al, 2020 ; Nelson T. et al, 2021 ; Rayhan and Baraniuk, 2021 ), but a concise summary and in-depth discussion is still missing.…”

“…Metabolites altered in ME/CFS patients include a decrease of myo-inositol, a putative marker of glial dysfunction ( Noda et al, 2018 ), in the anterior cingulate cortex ( Godlewska et al, 2021 ), and an increase of choline – mainly found in glial cells and thought to indicate an increased cell membrane turnover notably due to reparative gliosis – in the left anterior cingulate ( Mueller et al, 2020 ) and basal ganglia ( Chaudhuri et al, 2003 ). More indirect indications of glial involvement in ME/CFS have been gleaned from the consistent findings of sluggish blood oxygenation level-dependent (BOLD) signal responses to cognitive tasks ( Tanaka et al, 2006 ; Shan et al, 2018 ) paradoxical activation of the default mode network (DMN) after physical exercise ( Rayhan and Baraniuk, 2021 ), and from reduced regional fluorodeoxyglucose (FDG) uptake in the right mediofrontal cortex, brain stem ( Tirelli et al, 1998 ) and orbitofrontal cortex ( Siessmeier et al, 2003 ), indicating hypometabolism ( Shan et al, 2020 ). Reduced white matter volume ( Barnden et al, 2011 , 2015 , 2016 ; Finkelmeyer et al, 2018 ) and impaired myelination ( Barnden et al, 2011 , 2016 , 2018 ; Thapaliya et al, 2020 , 2021 ), which may indicate oligodendrocyte involvement, have been inconsistent ( Shan et al, 2020 ).…”

Review of the Midbrain Ascending Arousal Network Nuclei and Implications for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Gulf War Illness (GWI) and Postexertional Malaise (PEM)

“…The DMN mediates self-referential thought, “mind-wandering”, systems planning, and abstraction of negative emotion when there are no tasks to be performed [ 50 , 116 ]. Exercise modifies the activity of the anterior node of the DMN in the medial prefrontal cortex with increased activation during a low cognitive load test in GWI compared to control [ 24 ], and during rest in ME/CFS [ 23 ]. Disruption of connections between the VTA-precuneus-posterior cingulate cortex circuit leads to disorders of consciousness [ 117 ].…”

“…Prior to exercise, ME/CFS had generally lower blood oxygenation level dependent (BOLD) signals than controls. However, after exercise, ME/CFS had elevated activation of the anterior node of the DMN in the medial prefrontal cortex compared to pre-exercise and to controls [ 23 ].…”