Tag: brain connectivity

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)

Evidence of clinical and brain recovery in post-COVID-19 condition: a three-year follow-up study

Abstract:

Fatigue and cognitive dysfunction linked to persistent brain changes have been reported for up to two years after COVID-19. In this study, we followed the clinical, neuroimaging and fluid biomarker trajectories over three years post SARS-CoV-2 infection to evaluate potential signs and underlying factors of brain recovery.

We conducted a monocentric, longitudinal study using resting-state functional and structural T1-weighted magnetic resonance imaging data from 51 patients with Post-COVID-19 Condition (mean age 50 years, 33 female) collected at a mean time of 6, 23 and 38 months after COVID-19 infection. The trajectory of brain changes was compared to 23 age- and sex-matched healthy controls (mean age 37 years, 13 female) with similar time intervals between brain scans and analysed in relation to clinical, neuropsychological and fluid biomarkers including interleukins and neurodestruction markers at all timepoints. In addition, hand grip strength to evaluate muscular fatigue, was assessed at the final follow-up visit.

Self-reported fatigue improved over time but was still moderate on average three years after COVID-19 infection, while measures of hand grip strength and cognitive performance were largely unaffected. We found a significant increase of both lateral ventricles (∼8%) and the third (∼6%) ventricle accompanied by a structural volume reduction in adjacent areas including the thalamus, pallidum, caudate nucleus and putamen. An increased neuronal activation pattern was widespread and pronounced in these areas. The brainstem no longer exhibited volume loss as reported in our pervious study, but enhanced functional connectivity. Laboratory markers including interleukins and neuronal injury markers remained within the normal reference ranges across all study timepoints.

Our study revealed an overall slow but evident clinical improvement, including improved fatigue, regular muscular strength and recovery as well as normal cognitive function without signs of systemic inflammation three years after COVID-19. Clinical improvement is reflected by a pattern of brain recovery along periventricular regions. This pattern is characterized by structural stabilization and increased connectivity starting in the brainstem as well as efficient neuronal recruitment and increased activation in the basal ganglia, with no evidence of neuronal injury. These results highlight the positive long-term recovery trajectory in post-COVID patients.

Source: Ravi Dadsena, Sophie Wetz, Anna Hofmann, Ana Sofia Costa, Sandro Romanzetti, Stella Andrea Lischewski, Christina Krockauer, Carolin Balloff, Ferdinand Binkofski, Jörg B Schulz, Kathrin Reetz, Julia Walders, Evidence of clinical and brain recovery in post-COVID-19 condition: a three-year follow-up study, Brain Communications, 2025;, fcaf366, https://doi.org/10.1093/braincomms/fcaf366 https://academic.oup.com/braincomms/advance-article/doi/10.1093/braincomms/fcaf366/8262587 (Full study available as PDF file)

Abnormal Brain Activation Patterns in Patients With Post-Acute Sequelae of COVID-19 (PASC) During Recovery: A fNIRS Study

Abstract:

COVID-19 has increased the likelihood of cognitive impairment in patients with post-acute sequelae of COVID-19 (PASC). There is a lack of direct evidence regarding the working memory performance of mild patients during the recovery period. This study employed functional near-infrared spectroscopy (fNIRS) to construct a mixed effects model for PASC patients performing the N-back task, assessing brain activation levels and brain connectivity.

PASC patients exhibited abnormally low activation in the parietal lobe (β = −0.21) and abnormally high activation in the occipital lobe (β = 0.40). There was a significant reduction in brain connectivity within the frontal–parietal and frontal–occipital networks.

These findings suggest that PASC patients experience impaired fronto-parietal network connectivity, rely more on the visual cortex to compensate for executive function deficits, and use this as a compensatory mechanism to reduce overall cerebral blood oxygenation. This study provides evidence of altered brain activation patterns in PASC patients during the recovery period due to cognitive impairment.

Source: Y. Ran, S. Wu, S. Liu, et al., “ Abnormal Brain Activation Patterns in Patients With Post-Acute Sequelae of COVID-19 (PASC) During Recovery: A fNIRS Study,” Journal of Biophotonics (2025): e202500206, https://doi.org/10.1002/jbio.202500206. https://onlinelibrary.wiley.com/doi/epdf/10.1002/jbio.202500206

Hypothalamus Connectivity in Adolescent Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Adolescent Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling illness of unknown etiology. Increasing evidence suggests hypothalamic involvement in ME/CFS pathophysiology, which has rarely been explored using magnetic resonance imaging (MRI) in the condition. This work aimed to use MRI to examine hypothalamus connectivity in adolescents with ME/CFS and explore how this relates to fatigue severity and illness duration.

25 adolescents with ME/CFS and 23 healthy controls completed a neuroimaging protocol consisting of structural and multishell diffusion-weighted imaging sequences, in addition to the PedsQL Multidimensional Fatigue Scale to assess fatigue severity. Information about illness duration was acquired at diagnosis. Preprocessing and streamlines tractography was performed using QSIPrep combined with a custom parcellation scheme to create structural networks. The number (degree) and weight (strength) of connections between lateralized hypothalamus regions and cortical and subcortical nodes were extracted, and relationships between connectivity measures, fatigue severity, and illness duration were performed using Bayesian regression models.

We observed weak-to-moderate evidence of increased degree, but not strength, of connections from the bilateral anterior-inferior (left: pd [%] = 99.18, median [95% CI] = -22.68[-40.96 to 4.45]; right: pd [%] = 99.86, median [95% CI] = -23.35[-38.47 to 8.20]), left anterior-superior (pd [%] = 99.33, median [95% CI] = -18.83[-33.45 to 4.07]) and total left hypothalamus (pd [%] = 99.44, median [95% CI] = -47.18[-83.74 to 11.03]) in the ME/CFS group compared with controls. Conversely, bilateral posterior hypothalamus degree decreased with increasing ME/CFS illness duration (left: pd [%] = 98.13, median [95% CI]: -0.47[-0.89 to 0.03]; right: pd [%] = 98.50, median [95% CI]:-0.43[-0.82 to 0.05]).

Finally, a weak relationship between right intermediate hypothalamus connectivity strength and fatigue severity was identified in the ME/CFS group (pd [%] = 99.35, median [95% CI] = -0.28[-0.51 to 0.06]), which was absent in controls. These findings suggest changes in hypothalamus connectivity may occur in adolescents with ME/CFS, warranting further investigation.

Source: Byrne H, Knight SJ, Josev EK, Scheinberg A, Beare R, Yang JYM, Oldham S, Rowe K, Seal ML. Hypothalamus Connectivity in Adolescent Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. J Neurosci Res. 2024 Oct;102(10):e25392. doi: 10.1002/jnr.25392. PMID: 39431934. https://onlinelibrary.wiley.com/doi/10.1002/jnr.25392 (Full text(

Brain and cognitive changes in patients with long COVID compared with infection-recovered control subjects

Abstract:

Between 2.5 and 28% of people infected with SARS-CoV-2 suffer Long COVID or persistence of symptoms for months after acute illness. Many symptoms are neurological, but the brain changes underlying the neuropsychological impairments remain unclear. This study aimed to provide a detailed description of the cognitive profile, the pattern of brain alterations in Long COVID and the potential association between them.

To address these objectives, 83 patients with persistent neurological symptoms after COVID-19 were recruited, and 22 now healthy controls chosen because they had suffered COVID-19 but did not experience persistent neurological symptoms. Patients and controls were matched for age, sex and educational level. All participants were assessed by clinical interview, comprehensive standardized neuropsychological tests and structural MRI. The mean global cognitive function of patients with Long COVID assessed by ACE III screening test (Overall Cognitive level – OCLz= -0.39± 0.12) was significantly below the infection recovered-controls (OCLz= +0.32± 0.16, p< 0.01).

We observed that 48% of patients with Long COVID had episodic memory deficit, with 27% also impaired overall cognitive function, especially attention, working memory, processing speed and verbal fluency. The MRI examination included grey matter morphometry and whole brain structural connectivity analysis. Compared to infection recovered controls, patients had thinner cortex in a specific cluster centred on the left posterior superior temporal gyrus.

In addition, lower fractional anisotropy (FA) and higher radial diffusivity (RD) were observed in widespread areas of the patients’ cerebral white matter relative to these controls. Correlations between cognitive status and brain abnormalities revealed a relationship between altered connectivity of white matter regions and impairments of episodic memory, overall cognitive function, attention and verbal fluency.

This study shows that patients with neurological Long COVID suffer brain changes, especially in several white matter areas, and these are associated with impairments of specific cognitive functions.

Source: Serrano Del Pueblo VM, Serrano-Heras G, Romero Sánchez CM, Piqueras Landete P, Rojas-Bartolome L, Feria I, Morris RGM, Strange B, Mansilla F, Zhang L, Castro-Robles B, Arias-Salazar L, López-López S, Payá M, Segura T, Muñoz-López M. Brain and cognitive changes in patients with long COVID compared with infection-recovered control subjects. Brain. 2024 Apr 2:awae101. doi: 10.1093/brain/awae101. Epub ahead of print. PMID: 38562097. https://pubmed.ncbi.nlm.nih.gov/38562097/

Neuroinflammatory imaging markers in white matter: insights into the cerebral consequences of post-acute sequelae of COVID-19 (PASC)

Abstract:

Symptoms of coronavirus disease 2019 (COVID-19) can persist for months or years after infection, a condition called Post-Acute Sequelae of COVID-19 (PASC). Whole-brain white matter and cortical gray matter health were assessed using multi-shell diffusion tensor imaging. Correlational tractography was utilized to dissect the nature and extent of white matter changes.

In this study of 42 male essential workers, the most common symptoms of Neurological PASC (n = 24) included fatigue (n = 19) and headache (n = 17). Participants with neurological PASC demonstrated alterations to whole-brain white matter health when compared to controls made up of uninfected, asymptomatic, or mildly infected controls (n = 18). Large differences were evident between PASC and controls in measures of fractional anisotropy (Cohen’s D=-0.54, P = 0.001) and cortical isotropic diffusion (Cohen’s D = 0.50, P = 0.002).

Symptoms were associated with white matter fractional anisotropy (fatigue: rho = -0.62, P < 0.001; headache: rho = -0.66, P < 0.001), as well as nine other measures of white and gray matter health. Brain fog was associated with improved cerebral functioning including improved white matter isotropic diffusion and quantitative anisotropy.

This study identified changes across measures of white and gray matter connectivity, neuroinflammation, and cerebral atrophy that were interrelated and associated with differences in symptoms of PASC. These results provide insights into the long-term cerebral implications of COVID-19.

Source: Sean Clouston, Chuan Huang, Jia Ying et al. Neuroinflammatory imaging markers in white matter: insights into the cerebral consequences of post-acute sequelae of COVID-19 (PASC), 19 January 2024, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-3760289/v1] https://www.researchsquare.com/article/rs-3760289/v1 (Full text)

Subcortical and Default Mode Network connectivity is impaired in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

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 (HC) 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.

Region-based comparison detected reduced FC between the pontine nucleus and cerebellum vermis IX (p=0.027) for ME/CFS patients compared to HC. Our ROI-to-voxel analysis found significant impairment of FC within ponto-cerebellar regions in ME/CFS. Correlation analyses of connectivity with clinical scores in ME/CFS patients detected associations of FC with ‘duration of illness’ and ‘memory scores’ in salience network hubs and cerebellum vermis, and with ‘respiratory rate’ within medulla and the default mode network FC.

This novel investigation is the first to report 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.

Source: Maira INDERYAS, Kiran Thapaliya, Sonya Marshall-Gradisnik, Markus Barth, Leighton Barnden. Subcortical and Default Mode Network connectivity is impaired in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Front. Neurosci. Sec. Brain Imaging Methods. Volume 17 – 2023 | doi: 10.3389/fnins.2023.1318094 https://www.frontiersin.org/articles/10.3389/fnins.2023.1318094/full (Full text)

Altered functional brain connectivity, efficiency, and information flow associated with brain fog after mild to moderate COVID-19 infection

Abstract:

COVID-19 is associated with increased risk for cognitive decline but very little is known regarding the neural mechanisms of this risk. We enrolled 49 adults (55% female, mean age = 30.7 +/- 8.7), 25 with and 24 without a history of COVID-19 infection. We administered standardized tests of cognitive function and acquired brain connectivity data using MRI.

The COVID-19 group demonstrated significantly lower cognitive function (W = 475, p < 0.001, effect size r = 0.58) and lower functional connectivity in multiple brain regions (mean t = 3.47 +/- 0.36, p = 0.03, corrected, effect size d = 0.92 to 1.5). Hypo-connectivity of these regions was inversely correlated with subjective cognitive function and directly correlated with fatigue (p < 0.05, corrected). These regions demonstrated significantly reduced local efficiency (p < 0.026, corrected) and altered effective connectivity (p < 0.001, corrected).

COVID-19 may have a widespread effect on the functional connectome characterized by lower functional connectivity and altered patterns of information processing efficiency and effective information flow. This may serve as an adaptation to the pathology of SARS-CoV-2 wherein the brain can continue functioning at near expected objective levels, but patients experience lowered efficiency as brain fog.

Source: Shelli R. Kesler, Oscar Y. Franco Rocha, Alexa De La Torre Schutz et al. Altered functional brain connectivity, efficiency, and information flow associated with brain fog after mild to moderate COVID-19 infection, 20 October 2023, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-3466991/v1] https://www.researchsquare.com/article/rs-3466991/v1 (Full text)

Altered brain connectivity in Long Covid during cognitive exertion: a pilot study

Abstract:

Introduction: Debilitating Long-Covid symptoms occur frequently after SARS-COVID-19 infection.

Methods: Functional MRI was acquired in 10 Long Covid (LCov) and 13 healthy controls (HC) with a 7 Tesla scanner during a cognitive (Stroop color-word) task. BOLD time series were computed for 7 salience and 4 default-mode network hubs, 2 hippocampus and 7 brainstem regions (ROIs). Connectivity was characterized by the correlation coefficient between each pair of ROI BOLD time series. We tested for HC versus LCov differences in connectivity between each pair of the 20 regions (ROI-to-ROI) and between each ROI and the rest of the brain (ROI-to-voxel). For LCov, we also performed regressions of ROI-to-ROI connectivity with clinical scores.

Results: Two ROI-to-ROI connectivities differed between HC and LCov. Both involved the brainstem rostral medulla, one connection to the midbrain, another to a DM network hub. Both were stronger in LCov than HC. ROI-to-voxel analysis detected multiple other regions where LCov connectivity differed from HC located in all major lobes. Most, but not all connections, were weaker in LCov than HC. LCov, but not HC connectivity, was correlated with clinical scores for disability and autonomic function and involved brainstem ROI.

Discussion: Multiple connectivity differences and clinical correlations involved brainstem ROIs. Stronger connectivity in LCov between the medulla and midbrain may reflect a compensatory response. This brainstem circuit regulates cortical arousal, autonomic function and the sleep-wake cycle. In contrast, this circuit exhibited weaker connectivity in ME/CFS. LCov connectivity regressions with disability and autonomic scores were consistent with altered brainstem connectivity in LCov.

Source: Barnden L, Thapaliya K, Eaton-Fitch N, Barth M, Marshall-Gradisnik S. Altered brain connectivity in Long Covid during cognitive exertion: a pilot study. Front Neurosci. 2023 Jun 22;17:1182607. doi: 10.3389/fnins.2023.1182607. PMID: 37425014; PMCID: PMC10323677. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10323677/ (Full text)

Altered Effective Connectivity of Resting-State Networks by Tai Chi Chuan in Chronic Fatigue Syndrome Patients: A Multivariate Granger Causality Study

Abstract:

Numerous evidence has shown that patients with chronic fatigue syndrome (CFS) have changes in resting brain functional connectivity, but there is no study on the brain network effect of Tai Chi Chuan intervention in CFS. To explore the influence of Tai Chi Chuan exercise on the causal relationship between brain functional networks in patients with CFS, 21 patients with CFS and 19 healthy controls were recruited for resting-state functional magnetic resonance imaging (rs-fMRI) scanning and 36-item Short-Form Health Survey (SF-36) scale assessment before and after 1month-long training in Tai Chi Chuan.

We extracted the resting brain networks using the independent component analysis (ICA) method, analyzed the changes of FC in these networks, conducted Granger causality analysis (GCA) on it, and analyzed the correlation between the difference causality value and the SF-36 scale. Compared to the healthy control group, the SF-36 scale scores of patients with CFS were lower at baseline. Meanwhile, the causal relationship between sensorimotor network (SMN) and default mode network (DMN) was weakened. ‘

The above abnormalities could be improved by Tai Chi Chuan training for 1 month. In addition, the correlation analyses showed that the causal relationship between SMN and DMN was positively correlated with the scores of Role Physical (RP) and Bodily Pain (BP) in CFS patients, and the change of causal relationship between SMN and DMN before and after training was positively correlated with the change of BP score.

The findings suggest that Tai Chi Chuan is helpful to improve the quality of life for patients with CFS. The change of Granger causality between SMN and DMN may be a readout parameter of CFS. Tai Chi Chuan may promote the functional plasticity of brain networks in patients with CFS by regulating the information transmission between them.

Source: Li Y, Wu K, Hu X, Xu T, Li Z, Zhang Y, Li K. Altered Effective Connectivity of Resting-State Networks by Tai Chi Chuan in Chronic Fatigue Syndrome Patients: A Multivariate Granger Causality Study. Front Neurol. 2022 Jun 3;13:858833. doi: 10.3389/fneur.2022.858833. PMID: 35720086; PMCID: PMC9203735. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9203735/ (Full text)