Limbic Perfusion Is Reduced in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an illness characterized by a diverse range of debilitating symptoms including autonomic, immunologic, and cognitive dysfunction. Although neurological and cognitive aberrations have been consistently reported, relatively little is known regarding the regional cerebral blood flow (rCBF) in ME/CFS. In this study, we studied a cohort of 31 ME/CSF patients (average age: 42.8 ± 13.5 years) and 48 healthy controls (average age: 42.9 ± 12.0 years) using the pseudo-continuous arterial spin labeling (PCASL) technique on a whole-body clinical 3T MRI scanner. Besides routine clinical MRI, the protocol included a session of over 8 min-long rCBF measurement. The differences in the rCBF between the ME/CSF patients and healthy controls were statistically assessed with voxel-wise and AAL ROI-based two-sample t-tests. Linear regression analysis was also performed on the rCBF data by using the symptom severity score as the main regressor. In comparison with the healthy controls, the patient group showed significant hypoperfusion (uncorrected voxel wise p ≤ 0.001, FWE p ≤ 0.01) in several brain regions of the limbic system, including the anterior cingulate cortex, putamen, pallidum, and anterior ventral insular area. For the ME/CFS patients, the overall symptom severity score at rest was significantly associated with a reduced rCBF in the anterior cingulate cortex. The results of this study show that brain blood flow abnormalities in the limbic system may contribute to ME/CFS pathogenesis.

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

“…Eph/ephrin appears to also regulate oligodendrocyte precursor cells and oligodendrocytes, since they contribute to axonal insulation and may be involved in extracellular glutamate homeostasis and the regulation of excitotoxicity. Interestingly, Eph receptors are highly expressed in brain regions with morphological and physiological plasticity, including the amygdala and hippocampus, areas of particular interest in ME/CFS research ( Shan et al, 2020 ; Li et al, 2021 ). Proteomic analysis of CSF ( Schutzer et al, 2011 ) and circulating EVs ( Eguchi et al, 2020 ) also highlighted axonal guidance pathways linked to Eph/ephrin as possibly abnormal in ME/CFS.…”

“…One of the most consistent findings in ME/CFS is abnormal global and regional CBF in response to regulatory challenges including head tilt maneuvers as well as cognitive and physical exercise ( Ichise et al, 1992 ; Costa et al, 1995 ; Fischler et al, 1996 ; Tirelli et al, 1998 ; MacHale et al, 2000 ; Siessmeier et al, 2003 ; Yoshiuchi et al, 2006 ; Barnden et al, 2011 ; Biswal et al, 2011 ; Stewart et al, 2012 ; van Campen et al, 2020 ; Li et al, 2021 ; Rayhan and Baraniuk, 2021 ). The decrease in CBF on tilt table provocation can be independent of heart rate and blood pressure (BP) response ( van Campen et al, 2020 ), independent of normocapnia versus hypocapnia (van Campen et al, 2021 ), and has also been found in the subset of ME/CFS patients with joint hypermobility ( Campen et al, 2021 ).…”

“…In a recent MRI study of 31 ME/CSF patients using a pseudo-continuous arterial spin labeling (PCASL) technique, significant regional CBF abnormalities in several brain regions of the limbic system were noted at rest, i.e., without orthostatic or exercise challenge ( Li et al, 2021 ). The assumption of regional CBF abnormalities may be further supported by structural MRI findings of regional white matter loss in the left inferior fronto-occipital fasciculus ( Shan et al, 2016 ) and in the brain stem ( Barnden et al, 2011 , 2015 , 2016 , 2018 ; Finkelmeyer et al, 2018 ), sites that are particularly sensitive to hypoxia.…”

Orthostatic Challenge Causes Distinctive Symptomatic, Hemodynamic and Cognitive Responses in Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

“…Since then, several studies have found that many parts of the brain in people with ME/CFS have reduced blood flow (56)(57)(58)(59)(60). Furthermore, reduced regional cerebral blood flow is associated with increased symptom severity in people with ME/CFS (61). Recently, cerebral hypoperfusion also has been documented in most people with Long COVID (11,25).…”

Stress, Asthenia, and Cognitive Disorders

“…Thus, studies reported in 2018 showed that treatment with choline esterase inhibitors not only leads to improvements in cognitive performance, but also contributes to signifi cant reductions in the manifestations of cognitive exhaustion, one of the key symptoms of chronic fatigue, as compared with placebo [37]. The study was conducted on patients with often comes to the fore among patients' complaints as, in conditions of studying and performing intellectual activity, it is precisely the limitation to adequate cognitive functioning that can determine the greatest level of disability in patients [19].…”