Tag: neurocognitive functioning

Distinct functional connectivity patterns in myalgic encephalomyelitis and long COVID patients during cognitive fatigue: a 7 Tesla task-fMRI study

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and long COVID are chronic debilitating illnesses featuring fatigue, post-exertional malaise (PEM) and neurocognitive deficits. Temporal correlation of neural activity between distinct brain regions, also referred to as functional connectivity (FC), can provide insights into how brain networks coordinate, at rest or during task. Therefore, we explored intrinsic FC correlates of cognitive fatigue in ME/CFS and long COVID patients during two Stroop-colour-word paradigms on 7 Tesla fMRI.

Methods: 450 sagittal volumes were acquired from seventy-eight participants: 32 patients with MECFS (pwME/CFS); 19 long COVID (pwLC) and 27 healthy controls (HC) during performance of baseline or Pre (before/during fatigue build-up) and repeat Post (fatigue set-in) Stroop tasks. Structural and functional data were analysed using the CONN toolbox.

Results: Regions of interest (ROI-to-ROI) analysis revealed significantly increased FC in subcortical regions in HC for Pre vs Post. Relative to HC, pwLC showed significantly reduced FC between nucleus accumbens and vermis 3 (p = 0.02) in Pre and increased FC in the prefrontal cortex and hippocampus (p = 0.02) in Post. pwME/CFS showed a significantly increased FC between the left cuneiform nucleus and right medulla (p = 0.03). Compared to HC, reduced FC was significant in pwLC during Pre, and between medulla and hippocampus (p = 0.04) and between nucleus accumbens and vermis (p = 0.001) during Post. Aberrant FC was significant for pwME/CFS in core networks during Pre. Core network FC to the cerebellum, amygdala, caudate and red nucleus correlated with symptom scores for cognition in both pwME/CFS and pwLC. Hippocampus and cerebellar FC correlated with duration of illness in pwME/CFS.

Conclusions: Our findings of reduced dopaminergic hippocampal-nucleus-accumbens connectivity imply blunted motivation and cognition. Extensive FC differences in subcortical and core networks in patient cohorts were detected relative to an increased FC in HC. High regional communication indicative of greater task engagement by HC was distinctive while FC differences in ME/CFS and long COVID patients indicated reduced and dysregulated regional coordination that may serve as candidate biomarkers of symptomatology in long COVID and ME/CFS.

Source: Inderyas M, Thapaliya K, Marshall-Gradisnik S, Barnden L. Distinct functional connectivity patterns in myalgic encephalomyelitis and long COVID patients during cognitive fatigue: a 7 Tesla task-fMRI study. J Transl Med. 2026 Jan 20. doi: 10.1186/s12967-026-07708-y. Epub ahead of print. PMID: 41559785. https://link.springer.com/article/10.1186/s12967-026-07708-y (Full text)

Gut Microbiome and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Insights into Disease Mechanisms

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling clinical condition, whose hallmark characteristic is post-exertional malaise (PEM). It can affect many organs and systems, leading to severe impairment of patients’ quality of life. Although numerous post-infectious, immunological, neurological, metabolic, and endocrine alterations have been documented, neither a definitive diagnostic marker nor approved treatments are available. The etiology and pathophysiology remain incompletely understood; however, emerging evidence suggests that the gut microbiome plays a role in immune responses and the development of ME/CFS.

It is hypothesized that specific disturbances in gut microbiome composition, known as dysbiosis, may compromise the integrity of the intestinal barrier. This consequently leads to translocation of microbial components, which further triggers an immune response and systemic inflammation complicating the clinical presentation of ME/CFS. Furthermore, in terms of the so-called gut-brain axis, microbiome changes may lead to distinct neurocognitive impairments observed in ME/CFS patients.

This review offers the readers a broad perspective on the topic on ME/CFS, with a particular emphasis on the interplay between the gut microbiome and disease mechanisms. Last but not least, recent data on potential treatment strategies for intestinal dysbiosis in ME/CFS patients have been included.

Source: Nikolova R, Donchev D, Vaseva K, Ivanov IN. Gut Microbiome and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Insights into Disease Mechanisms. Int J Mol Sci. 2025 Dec 31;27(1):425. doi: 10.3390/ijms27010425. PMID: 41516296; PMCID: PMC12785659. https://pmc.ncbi.nlm.nih.gov/articles/PMC12785659/ (Full text)

Two Neurocognitive Domains Identified for Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post-Acute Sequelae of COVID-19

Abstract:

Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Post-Acute Sequelae of COVID-19 (PASC) often have neurocognitive complaints that involve memory and concentration problems and difficulties paying attention. Other neurocognitive domains such as hypersensitivity to noise and light have rarely been included as aspects of neurocognitive impairment for these post-viral conditions.

The current study evaluated a more extensive list of neurocognitive items for a group of 2,313 patients with ME/CFS and 299 patients with PASC. Exploratory factor analyses found two factors for each patient group, one involving classic memory and concentration symptoms and the other involving sensory overload phenomena. The findings suggest that researchers might consider expanding the types of self-report neurocognitive symptoms among patients with these post-viral illnesses.

Source: Ariadna E Sandoval, Mingqi Li, Leonard A. Jason. Two Neurocognitive Domains Identified for Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Post-Acute Sequelae of COVID-19. Front. Neurol., Sec. Cognitive and Behavioral Neurology, Volume 16 – 2025 | doi: 10.3389/fneur.2025.1612548 https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2025.1612548/abstract

Hippocampal subfield volume alterations and associations with severity measures in long COVID and ME/CFS: A 7T MRI study

Abstract:

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.

Source: Thapaliya K, Marshall-Gradisnik S, Eaton-Fitch N, Barth M, Inderyas M, Barnden L. Hippocampal subfield volume alterations and associations with severity measures in long COVID and ME/CFS: A 7T MRI study. PLoS One. 2025 Jan 13;20(1):e0316625. doi: 10.1371/journal.pone.0316625. PMID: 39804864; PMCID: PMC11729965. https://pmc.ncbi.nlm.nih.gov/articles/PMC11729965/ (Full text)

A causal link between autoantibodies and neurological symptoms in long COVID

Summary:

Acute SARS-CoV-2 infection triggers the generation of diverse and functional autoantibodies (AABs), even after mild cases. Persistently elevated autoantibodies have been found in some individuals with long COVID (LC). Using a >21,000 human protein array, we identified diverse AAB targets in LC patients that correlated with their symptoms.

Elevated AABs to proteins in the nervous system were found in LC patients with neurocognitive and neurological symptoms. Purified Immunoglobulin G (IgG) samples from these individuals reacted with human pons tissue and were cross-reactive with mouse sciatic nerves, spinal cord, and meninges. Antibody reactivity to sciatic nerves and meninges correlated with patient-reported headache and disorientation. Passive transfer of IgG from patients to mice led to increased sensitivity and pain, mirroring patient-reported symptoms. Similarly, mice injected with IgG showed loss of balance and coordination, reflecting donor-reported dizziness. Our findings suggest that targeting AABs could benefit some LC patients.

Source: Keyla Santos Guedes de Sa, Julio Silva, Rafael Bayarri-Olmos, Ryan Brinda, Robert Alec Rath Constable, Patricia A. Colom Diaz, Dong il Kwon, Gisele Rodrigues, Li Wenxue, Christopher Baker, Bornali Bhattacharjee, Jamie Wood, Laura Tabacof, Yansheng Liu, David Putrino, Tamas L. Horvath, Akiko Iwasaki. A causal link between autoantibodies and neurological symptoms in long COVID. medRxiv 2024.06.18.24309100; doi: https://doi.org/10.1101/2024.06.18.24309100 https://www.medrxiv.org/content/10.1101/2024.06.18.24309100v1.full-text (Full text)

Examining well-being and cognitive function in people with long Covid and ME/CFS, and age-matched healthy controls: A Case-Case-Control Study

Abstract:

Purpose: Well-being and cognitive function had not previously been compared between people with long COVID and people with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Therefore, this study examined well-being and cognitive function in people with long COVID (∼16 months illness duration; n= 17) and ME/CFS (∼16 years illness duration; n=24), versus age-matched healthy controls (n=16).

Methods: Well-being was examined using several questionnaires, namely the Health Visual Analogue Scale (VAS), Fatigue Severity Scale (FSS), Post-exertional malaise (PEM), Pittsburgh Sleep Quality Index (PSQI), European Quality of Life-5 Domains (EQ-5D), MRC Dyspnoea, Self-Efficacy (SELTC), The Edinburgh Neurosymptoms Questionnaire (ENS), General Anxiety Disorder 7 (GAD-7), and Patient Health Questionnaire 9 (PHQ-9). Cognitive function was examined using Single Digit Modalities Test (SDMT), Stroop test, and Trails A and B. These were delivered via a mobile application (app) built specifically for this remote data collection.

Results: The main findings of the present investigation were that people with ME/CFS and people with long COVID were generally comparable on all well-being and cognitive function measures, but self-reported worse values for pain, fatigue, Post-exertional malaise, sleep quality, general well-being in relation to mobility, usual activities, self-care, breathlessness, neurological symptoms, self-efficacy, and other well-being such as anxiety and depression, compared to controls. There was no effect of group for cognitive function measures.

Conclusions: These data suggest that both people with long COVID and people with ME/CFS have similar impairment on well-being measures examined herein. Therefore, interventions that target well-being of people with ME/CFS and long COVID are required.

Source: Sanal-Hayes NEM, Mclaughlin M, Hayes LD, Berry ECJ, Sculthorpe NF. Examining well-being and cognitive function in people with long Covid and ME/CFS, and age-matched healthy controls: A Case-Case-Control Study. Am J Med. 2024 May 13:S0002-9343(24)00273-0. doi: 10.1016/j.amjmed.2024.04.041. Epub ahead of print. PMID: 38750713. https://www.amjmed.com/article/S0002-9343(24)00273-0/fulltext (Full text)

Phenylephrine Alters Phase Synchronization between Cerebral Blood Velocity and Blood Pressure in Chronic Fatigue Syndrome with Orthostatic Intolerance

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) with orthostatic intolerance (OI) is characterized by neuro-cognitive deficits perhaps related to upright hypocapnia and loss of cerebral autoregulation (CA). We performed N-back neurocognition testing and calculated the phase synchronization index (PhSI) between Arterial Pressure (AP) and cerebral blood velocity (CBV) as a time-dependent measurement of cerebral autoregulation in 11 control (mean age=24.1 years) and 15 ME/CFS patients (mean age=21.8 years). All ME/CFS patients had postural tachycardia syndrome (POTS).

A 10-minute 60⁰ head-up tilt (HUT) significantly increased heart rate (109.4 ± 3.9 vs. 77.2 ± 1.6 beats/min, P <0.05) and respiratory rate (20.9 ± 1.7 vs. 14.2 ± 1.2 breaths/min, P < 0.05) and decreased end-tidal CO2 (ETCO2; 33.9 ± 1.1 vs. 42.8 ± 1.2 Torr, P < 0.05) in ME/CFS vs. control. In ME/CFS, HUT significantly decreased CBV compared to control (-22.5% vs -8.7%, p<0.005).

To mitigate the orthostatic CBV reduction, we administered supplemental CO2, phenylephrine and acetazolamide and performed N-back testing supine and during HUT. Only phenylephrine corrected the orthostatic decrease in neurocognition by reverting % correct n=4 N-back during HUT in ME/CFS similar to control (ME/CFS=38.5±5.5 vs. ME/CFS+PE= 65.6±5.7 vs. Control 56.9±7.5). HUT in ME/CFS resulted in increased PhSI values indicating decreased CA. While CO2 and Acetazolamide had no effect on PhSI in ME/CFS, PE caused a significant reduction in PhSI (ME/CFS=0.80±0.03 vs ME/CFS+PE= 0.69±0.04, p< 0.05) and improved cerebral autoregulation. Thus, PE improved neurocognitive function in ME/CFS patients, perhaps related to improved neurovascular coupling, cerebral autoregulation and maintenance of CBV.

Source: Medow MS, Stewart JM. Phenylephrine Alters Phase Synchronization between Cerebral Blood Velocity and Blood Pressure in Chronic Fatigue Syndrome with Orthostatic Intolerance. Am J Physiol Regul Integr Comp Physiol. 2024 Apr 29. doi: 10.1152/ajpregu.00071.2024. Epub ahead of print. PMID: 38682242. https://journals.physiology.org/doi/abs/10.1152/ajpregu.00071.2024 (Full text available as PDF file)

Exploring the neurocognitive consequences of post-exertional malaise in myalgic encephalomyelitis

Background and aims:

Myalgic encephalomyelitis (ME) is a complex, debilitating and heterogeneous disorder. It affects over 500,000 people in Canada but remains poorly understood. People are affected with multi-systemic symptoms such as fatigue that is not alleviated by rest, pain, cognitive impairment and post-exertional malaise (PEM), which is considered as the hallmark symptom of ME. PEM is triggered by minimal mental or physical effort and exacerbates other symptoms. Our aim was to measure how individuals’ cognition can be impacted by the induction of PEM, and investigate the difference in cognitive response.

Section snippets:

Methods
A prospective cohort of people with ME (n = 42) and matched healthy controls (n = 15) was recruited and subjected to PEM induction through a 90-minutes mechanical arm stimulation. BrainCheck test (BrainCheck, Inc., TX, USA) was used at baseline (T0) and after 90 minutes of stimulation to evaluate six cognitive domains for which each participant received a score and a population percentile based on their performance.

Results
Comparison between both groups was significant (p < 0.05) at T90, but not at T0, in four out of six cognitive domains. We then classified our ME cohort in three clusters by k-means method based on the Δ percentile (T90-T0) for each cognitive task. This stratification allowed us to notice how some cognitive domains seem more affected depending on the cluster, namely memory and attention.

Conclusions
These results showed the impact of PEM on the disturbance of cognition in the context of ME as well as the variability of cognitive domains affected in people with ME.

Source: Corinne Leveau, Iurie Caraus, Anita Franco, Alain Moreau. Exploring the neurocognitive consequences of post-exertional malaise in myalgic encephalomyelitis. Journal of the Neurological Sciences, Volume 455, Supplement, December 2023, 122590. https://www.sciencedirect.com/science/article/abs/pii/S0022510X23020518

 

Characterization of neurocognitive deficits in patients with post-COVID-19 syndrome: persistence, patients’ complaints, and clinical predictors.

Abstract:

Introduction: Cognitive symptoms persisting beyond 3 months following COVID-19 present a considerable disease burden. We aimed to establish a domain-specific cognitive profile of post-COVID-19 syndrome (PCS). We examined the deficits’ persistence, relationships with subjective cognitive complaints, and clinical variables, to identify the most relevant cognitive deficits and their predictors.

Methods: This cross-sectional study examined cognitive performance and patient-reported and clinical predictors of cognitive deficits in PCS patients (n = 282) and socio-demographically comparable healthy controls (n = 52).

Results: On the Oxford Cognitive Screen-Plus, the patient group scored significantly lower in delayed verbal memory, attention, and executive functioning than the healthy group. In each affected domain, 10 to 20% of patients performed more than 1.5 SD below the control mean. Delayed memory was particularly affected, with a small effect of hospitalization and age. Attention scores were predicted by hospitalization and fatigue.

Discussion: Thus, PCS is associated with long-term cognitive dysfunction, particularly in delayed memory, attention, and executive functioning. Memory deficits seem to be of particular relevance to patients’ experience of subjective impairment. Hospitalization, fatigue, and age seem to predict cognitive deficits, while time since infection, depression, and pre-existing conditions do not.

Source: Kozik V, Reuken P, Utech I, Gramlich J, Stallmach Z, Demeyere N, Rakers F, Schwab M, Stallmach A, Finke K. Characterization of neurocognitive deficits in patients with post-COVID-19 syndrome: persistence, patients’ complaints, and clinical predictors. Front Psychol. 2023 Oct 17;14:1233144. doi: 10.3389/fpsyg.2023.1233144. PMID: 37915528; PMCID: PMC10616256. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10616256/ (Full text)

Fatigue in post COVID-19 patients: the P4O2 COVID-19 study

Abstract:

Background: Some patients do not fully recover after COVID-19 and have symptoms occurring 3 months after acute illness, lasting for >2 months, defined as post COVID-19. Fatigue seems most present in post COVID-19 and part of the patients might develop symptoms similar to chronic fatigue syndrome.

Aim: To determine the occurrence of fatigue and other symptoms in post COVID-19 patients.

Methods: In the prospective P4O2 COVID-19 cohort, post COVID-19 patients aged 40-65 years were recruited from outpatient post-COVID clinics in 5 Dutch hospitals between May 2021-September 2022. At 3-6 months post-COVID, patients completed the Fatigue Severity Scale (FSS). If the FSS score was ≥4 (the cut-off for severe fatigue), patients also completed the DePaul Symptom Questionnaire version 2 (DSQ-2). The FSS ranges from 1-7 and a higher score means more fatigued. The DSQ-2 rates frequency and severity of 79 symptoms on a 5-point Likert scale. Binary thresholds (if scored ≥2 on both severity and frequency, the threshold is met and the symptom is present) were calculated.

Results: The mean age of the 78 included patients was 53.9±6.2 and 51.7% were male. Median (IQR) FSS score was 5.6 (4.2-6.3) and 66 patients (84.6%) had a score ≥4. According to the DSQ-2 (n=61), patients reported a median (IQR) of 16 (8-23) symptoms. The majority of the patients experienced fatigue (85%). Furthermore, post-exertional malaise (PEM) (40%), sleep-related problems (37%), pain (21%) and neurocognitive problems (23%) were frequently reported.

Conclusion: The occurrence of severe fatigue 3-6 months after COVID-19 was 84.6% in our cohort. Patients with severe fatigue also frequently reported PEM, sleep related problems, pain and neurocognitive problems.

Source: Merel E.B. Cornelissen, Lizan D. Bloemsma, Nadia Baalbaki, Somayeh Bazdar, Jelle M. Blankestijn, Inés Beekers, Rosanne J.H.C.G. Beijers, Joop P. Van Den Bergh, Debbie Gach, J.J. Miranda Geelhoed, Sebastiaan Holverda, Laura Houweling, John J. Jacobs, Renée Jonker, Ivo Van Der Lee, Paulien M.A. Linders, Lieke C.E. Noij, Esther J. Nossent, Marianne A. Van De Pol, Daphne W. Schaminee, Annemie M.W.J. Schols, Lisanne T. Schuurman, Brigitte Sondermeijer, Anouk W. Vaes, Els J.M. Weersink, Yolanda De Wit-Van Wijck, Martijn A. Spruit, Anke H. Maitland-Van Der Zee. Fatigue in post COVID-19 patients: the P4O2 COVID-19 study. European Respiratory Journal 2023 62: PA4574; DOI: 10.1183/13993003.congress-2023.PA4574 https://erj.ersjournals.com/content/62/suppl_67/PA4574.abstract