Exploring the mechanisms of acupuncture in improving cognitive function in post-COVID-19 myalgic encephalomyelitis/chronic fatigue syndrome: study protocol for a randomized controlled trial using multimodal MRI

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a common sequela following COVID-19. Although cognitive dysfunction is one of the most debilitating symptoms in ME/CFS, effective therapies are limited. Acupuncture is an important complementary and alternative therapy for ME/CFS and has been shown to have positive effects on cognitive dysfunction in other diseases. However, the effect and mechanism of acupuncture in treating cognitive dysfunction in post-COVID-19 ME/CFS(PCME/CFS) remain unclear. In this study, we designed a randomized controlled trial to evaluate the efficacy of acupuncture treatment in improving cognitive function in PCME/CFS and to investigate the neural mechanisms of acupuncture using multimodal magnetic resonance imaging (MRI) techniques.

Methods: A total of 129 patients and 30 healthy controls (HCs) will be enrolled. The 129 patients with PCME/CFS will be randomly assigned in a 1:1:1 ratio to a verum acupuncture (VA), sham acupuncture (SA), or a waitlist control group. Participants in the VA and SA groups will receive three sessions of treatment per week for 8 weeks, while patients in the waitlist control group will be treated after the 8-week waiting period. The primary outcome is the change in the Symbol Digit Modalities Test (SDMT) score from baseline to week 8. The secondary outcome measures include changes from baseline to endpoint (week 8) in cognitive performance as assessed by the Digit Span Test (DST), Trail Making Test (TMT), Rey Auditory Verbal Learning Test (RAVLT), Rey-Osterrieth complex figure test (RCFT), Stroop Color and Word Test (SCWT), phonemic fluency test, category fluency test, action fluency test, and 30-item Boston Naming Test (BNT-30). In addition, changes in hippocampal metabolites and resting-state functional connectivity(RSFC) will be examined using 1H-magnetic resonance spectroscopy(1H-MRS) and functional MRI (fMRI), respectively. Moreover, the Multidimensional Fatigue Inventory (MFI-20), Pittsburgh Sleep Quality Index (PSQI), Generalized Anxiety Disorder 7-item scale (GAD-7), 24-item Hamilton Depression Scale (HAMD-24), and 36-Item Short Form Survey (SF-36) will also be assessed at baseline and week 8.

Discussion: The results of this study will provide preliminary evidence regarding the efficacy of acupuncture therapy in improving cognitive function in PCME/CFS and will explore whether acupuncture improves cognitive function in this disease by modulating metabolism and RSFC in the hippocampus.

Clinical trial registration: www.clinicaltrials.gov, identifier: NCT07357688.

Source: Luo T, Luo Y, Huang L, Jin H, An Y, Huang J, Luo K, Guo Y, Wang D, Liu D, Wu X. Exploring the mechanisms of acupuncture in improving cognitive function in post-COVID-19 myalgic encephalomyelitis/chronic fatigue syndrome: study protocol for a randomized controlled trial using multimodal MRI. Front Neurol. 2026 Jun 3;17:1793397. doi: 10.3389/fneur.2026.1793397. PMID: 42383026; PMCID: PMC13318089. https://pmc.ncbi.nlm.nih.gov/articles/PMC13318089/ (Full text)

Validation of the Wood Mental Fatigue Inventory in adolescents with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Background: There is no consensus regarding the most reliable and valid measures of cognitive dysfunction in adolescents and adults with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The Wood Mental Fatigue Inventory (WMFI) is commonly used in adults while the Pediatric Quality of Life Multidimensional Fatigue Scale (PedsQL MFS) is commonly used in adolescents. This study examined whether the WMFI was valid in adolescents.

Methods: Over a two-year period, participants in a cohort study completed four questionnaires: PedsQL, PedsQL MFS, Functional Disability Inventory (FDI), and WMFI. We examined the validity of the WMFI in 55 healthy adolescents and 55 with ME/CFS, determined how well the WMFI and PedsQL MFS cognitive fatigue subscale correlated with one another and with general quality of life surveys, and examined each questionnaire’s responsiveness to change over time.

Results: The PedsQL MFS cognitive fatigue subscale and the WMFI had a strong negative correlation for both healthy controls and ME/CFS patients at baseline with R2 values of 0.3915 and 0.8049 respectively. There was a similar strong negative correlation (R2 = 0.7739) between the two questionnaires in ME/CFS participants at the 24 month point of follow-up after multi-modal treatment. Each questionnaire was found to be similarly responsive to change.

Conclusion: The WMFI had a high correlation with the PedsQL MFS cognitive fatigue subscale. The WMFI has the advantage of ease of scoring. Both measures were responsive to changes in mental fatigue among those with ME/CFS over time.

Source: Welch DC, Edwards CC, Broussard CA, Swope ME, Christoforou ME, Matson PA, Azola AM, Rowe PC. Validation of the Wood Mental Fatigue Inventory in adolescents with myalgic encephalomyelitis/chronic fatigue syndrome. Brain Behav Immun Health. 2026 Mar 25;53:101222. doi: 10.1016/j.bbih.2026.101222. PMID: 41953581; PMCID: PMC13053862. https://pmc.ncbi.nlm.nih.gov/articles/PMC13053862/ (Full text)

Functional olfactory impairment and fatigue in post-COVID-19 syndrome including ME/CFS – a longitudinal prospective observational study

Abstract:

Post-COVID-19 syndrome (PCS) affects a significant proportion of individuals, with olfactory impairment and fatigue as prominent long-term symptoms. A subset of PCS patients with pronounced fatigue meets the diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), here referred to as PCS-ME/CFS. This study explores the relationship between PCS, fatigue, and olfactory function, and investigates the potential of olfactory impairment as a diagnostic and prognostic marker.

We assessed olfactory function up to 28 months post-COVID-19 in 45 PCS patients (22 PCS, 23 PCS-ME/CFS) using the extended Sniffin’ Sticks test, which evaluates odor threshold, discrimination, and identification, providing a composite score. Fatigue severity and health-related quality of life were assessed using validated questionnaires, a standardized test measured cognitive function, and handgrip strength indicated physical fatiguability. Both PCS and PCS-ME/CFS patients showed significant improvement in olfactory function, with all patients returning to normosmia after 20 months, regardless of diagnosis.

While odor threshold was the most affected olfactory measure in Sniffin’ Sticks testing, odor identification was the only measure that remained impaired over time. Olfactory impairment correlated with cognitive, physical, and mental performance, with stronger correlations in the PCS group, particularly linking better odor discrimination at baseline to improved daily functioning and health-related quality of life after 20 months.

Our findings suggest that odor identification assessed in standardized testing may remain impaired the longest in patients with persisting symptoms after COVID-19, reflecting persisting central processing difficulties. Correlations between olfactory performance, cognitive function, and physical ability point to shared underlying mechanisms. Early olfactory improvements may be linked to better long-term cognitive outcomes, highlighting a possible prognostic role of olfactory function in these patients.

Source: Meyer-Arndt L, Pierchalla G, Mödl L, Wohlrab F, Legler F, Hoppmann U, Kedor C, Wittke K, Freitag H, Konietschke F, Olze H, Paul F, Scheibenbogen C, Bellmann-Strobl J, Förster-Ruhrmann U. Functional olfactory impairment and fatigue in post-COVID-19 syndrome including ME/CFS – a longitudinal prospective observational study. Brain Behav Immun Health. 2025 Oct 14;50:101124. doi: 10.1016/j.bbih.2025.101124. PMID: 41281896; PMCID: PMC12634829. https://pmc.ncbi.nlm.nih.gov/articles/PMC12634829/ (Full text)