Leighton R. Barnden

Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients share similar symptoms including post-exertional malaise, neurocognitive impairment, and memory loss. The neurocognitive impairment in both conditions might be linked to alterations in the hippocampal subfields. Therefore, this study compared alterations in hippocampal subfields of 17 long COVID, 29 ME/CFS patients, and 15 healthy controls (HC). Structural MRI data was acquired with sub-millimeter isotropic resolution on a 7 Telsa MRI scanner and hippocampal subfield volumes were then estimated for each participant using FreeSurfer software. Our study found significantly larger volumes in the left hippocampal subfields of both long COVID and ME/CFS patients compared to HC. These included the left subiculum head (long COVID; p = 0.01, ME/CFS; p = 0.002,), presubiculum head (long COVID; p = 0.004, ME/CFS; p = 0.005), molecular layer hippocampus head (long COVID; p = 0.014, ME/CFS; p = 0.011), and whole hippocampal head (long COVID; p = 0.01, ME/CFS; p = 0.01). Notably, hippocampal subfield volumes were similar between long COVID and ME/CFS patients. Additionally, we found significant associations between hippocampal subfield volumes and severity measures of 'Pain', 'Duration of illness', 'Severity of fatigue', 'Impaired concentration', 'Unrefreshing sleep', and 'Physical function' in both conditions. These findings suggest that hippocampal alterations may contribute to the neurocognitive impairment experienced by long COVID and ME/CFS patients. Furthermore, our study highlights similarities between these two conditions.

The brain is the most complex organ in the human body, and is involved in memory, speech, and movement, as well as regulating the functions of many other organs within the body. Various imaging techniques have detected subtle brain changes in vivo in ME/CFS. This chapter explores different neuroimaging studies used to investigate structural, functional, neurochemical, and tissue microstructural alterations in ME/CFS. These include magnetic resonance imaging (MRI), positron emission tomography (PET), and single photon emission computed tomography (SPECT).

Background: The Stroop task was used to investigate differences in cognitive function between Long COVID (LC), Myalgic Encephalomyelitis / Chronic Fatigue Syndrome (ME/CFS) and healthy control subjects. Methods: Subjects viewed four color words or neutral (XXXX) stimuli with the same (congruent) or different color ink (incongruent). Cognitive conflict was inferred from response times for pairings of prestimuli and subsequent stimuli. Overall effects were assessed by univariate analysis with time courses determined for binned response times. Results: LC and ME/CFS had significantly longer response times than controls indicating cognitive dysfunction. Initial response times were ranked LC > ME > HC, and decreased according to power functions. At the end of the task (900s), times were ranked LC = ME > HC. Response times were significantly slower for stimuli following an incongruent prestimulus. Time series for Stroop effect, facilitation, interference, surprise index and practice power law parameters were generally similar in LC, ME/CFS and HC suggesting comparable patterns for recruitment of cognitive resources. The prestimulus data were analyzed and generated positive Stroop and interference effects that were distinct from stimulus effects. Conclusion: LC and ME/CFS have global slowing of response times that cannot be overcome by practice suggesting impaired communications between network nodes during problem solving. Analysis of matched prestimulus - stimulus effects adds a new dimension for understanding cognitive conflict. Brief summary: Cognitive dysfunction in Long COVID and ME/CFS was demonstrated using the Stroop task which found global slowing of response times and limitations of practice effects.

Objective: Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) patients experience multiple complex symptoms, potentially linked to imbalances in brain neurochemicals. This study aims to measure brain neurochemical levels in long COVID and ME/CFS patients as well as healthy controls to investigate associations with severity measures. Methods: Magnetic resonance spectroscopy data were acquired with a 3T Prisma magnetic resonance imaging scanner (Siemens Healthcare, Erlangen, Germany). We measured absolute levels of brain neurochemicals in the posterior cingulate cortex in long COVID (n = 17), ME/CFS (n = 17), and healthy controls (n = 10) using Osprey software. The statistical analyses were performed using SPSS version 29 (IBM, Armonk, NY). Age and sex were included as nuisance covariates. Results: Glutamate levels were significantly higher in patients with long COVID (P = .02) and ME/CFS (P = .017) than in healthy controls. No significant difference was found between the 2 patient cohorts. Additionally, N-acetyl-aspartate levels were significantly higher in long COVID patients (P = .012). Importantly, brain neurochemical levels were associated with self-reported severity measures in long COVID and ME/CFS. Conclusions: Our study identified significantly elevated glutamate and N-acetyl-aspartate levels in long COVID and ME/CFS patients compared with healthy controls. No significant differences in brain neurochemicals were observed between the 2 patient cohorts, suggesting a potential overlap in their underlying pathology. These findings suggest that imbalanced neurochemicals contribute to the complex symptoms experienced by long COVID and ME/CFS patients.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex chronic condition with core symptoms of fatigue and cognitive dysfunction, suggesting a key role for the central nervous system in the pathophysiology of this disease. Several studies have reported altered functional connectivity (FC) related to motor and cognitive deficits in ME/CFS patients. In this study, we compared functional connectivity differences between 31 ME/CFS and 15 healthy controls (HCs) using 7 Tesla MRI. Functional scans were acquired during a cognitive Stroop color-word task, and blood oxygen level-dependent (BOLD) time series were computed for 27 regions of interest (ROIs) in the cerebellum, brainstem, and salience and default mode networks. A region-based comparison detected reduced FC between the pontine nucleus and cerebellum vermis IX (p = 0.027) for ME/CFS patients compared to HCs. Our ROI-to-voxel analysis found significant impairment of FC within the ponto-cerebellar regions in ME/CFS. Correlation analyses of connectivity with clinical scores in ME/CFS patients detected associations between FC and 'duration of illness' and 'memory scores' in salience network hubs and cerebellum vermis and between FC and 'respiratory rate' within the medulla and the default mode network FC. This novel investigation is the first to report the extensive involvement of aberrant ponto-cerebellar connections consistent with ME/CFS symptomatology. This highlights the involvement of the brainstem and the cerebellum in the pathomechanism of ME/CFS.