Primary Research: NIH Deep Phenotyping Study

1 Walitt et al. 2024 β€” The Foundational Deep Phenotyping Study

Full Citation:: Walitt B, Singh K, LaMunion SR, et al. Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome. Nature Communications. 2024;15(1):907. DOI:: 10.1038/s41467-024-45107-3 PMID:: 38383456 PMCID:: PMC10881493 Published:: February 21, 2024 Study Design:: Cross-sectional deep phenotyping study Sample Size:: 17 PI-ME/CFS patients, 21 matched healthy controls Key Findings::

- Altered effort preference rather than physical or central fatigue (OR=1.65, $p$=0.04)
- Decreased brain activation in right temporal-parietal junction during motor tasks
- CSF catechol abnormalities: decreased DOPA ($p$=0.021), DOPAC ($p$=0.025), DHPG ($p$=0.006)
- Reduced peak VO~2~ on cardiopulmonary exercise testing ($p$=0.004)
- Chronotropic incompetence (5/8 PI-ME/CFS vs 1/9 controls, $p$=0.03)
- B-cell abnormalities: increased na\"ive B-cells ($p$=0.037), decreased switched memory B-cells ($p$=0.008)
- Sex-specific gene expression differences with $<$ 5% overlap between sexes

Conclusion:: ME/CFS appears to be a centrally mediated disorder characterized by altered effort preference, potentially associated with central catecholamine dysregulation. Limitations:: Small sample size (80% power only detects effects β‰₯0.94 SD); cross-sectional design; recruitment terminated due to COVID-19 pandemic.

2 Aregawi et al. 2026 β€” Central Noradrenergic Deficiency in PI-ME/CFS and PASC

Full Citation:: Aregawi M, Walitt B, Sullivan P, Norato G, Benjamin JD, Goldstein DS. Central noradrenergic deficiency in post-infectious chronic fatigue: neurobehavioral correlates. Brain Communications. 2026;8(3):fcag173. (Aregawi et al. 2026) DOI:: 10.1093/braincomms/fcag173 PMID:: 42205163 Study Design:: Cross-sectional CSF catecholamine study; composite pathway indices Sample Size:: n=16 PI-ME/CFS, n=34 PASC, n=32 Parkinson’s disease, n=40 healthy volunteers Key Findings::

- Novel composite NE Pathway index (NE+DHPG+MHPG) significantly lower in PI-ME/CFS and PASC vs HV
- DA Pathway (DA+DOPAC+HVA) normal across all groups β€” selective noradrenergic deficiency
- First report of CSF MHPG levels in PI-ME/CFS or PASC
- NE Pathway correlated with handgrip duration (rho=0.62) and MFI physical fatigue (rho=-0.43)
- PEM specifically associated with NE deficiency (PASC+PEM < PASC-noPEM)
- Parkinson's controls showed dual NE+DA deficiency confirming index validity

Conclusion:: Selective central noradrenergic deficiency is a neurochemical correlate of post-infectious ME/CFS and PASC with PEM, linked to motor output, fatigue severity, and overall health perception. Dopamine pathway preserved. Limitations:: Single NIH center; post-infectious only; small PI-ME/CFS subgroup (n=16); cross-sectional; no independent replication. Certainty Assessment::

- *Quality:* High (Brain Communications; novel composite index methodology)
- *Sample:* Medium (n=122 total, n=16 PI-ME/CFS subgroup)
- *Replication:* Partial (same NIH center as Walitt 2024, extended methodology)
- *Score:* 0.80

3 Institute of Medicine (IOM) 2015 Criteria

Full Citation:: Institute of Medicine (US) Committee on the Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, DC: National Academies Press; 2015. URL:: https://www.cdc.gov/me-cfs/hcp/diagnosis/iom-2015-diagnostic-criteria-1.html ISBN:: 978-0-309-31689-7 Key Requirements::

- Three required symptoms: (1) substantial reduction in functioning with fatigue β‰₯6 months, (2) post-exertional malaise, (3) unrefreshing sleep
- Plus at least one of: cognitive impairment OR orthostatic intolerance
- Symptoms must be present β‰₯50% of the time with moderate-to-severe intensity

Significance:: Proposed renaming to Systemic Exertion Intolerance Disease (SEID); currently used by CDC.

4 NICE 2021 Guidelines (NG206)

Full Citation:: National Institute for Health and Care Excellence. Myalgic encephalomyelitis (or encephalopathy)/chronic fatigue syndrome: diagnosis and management. NICE guideline [NG206]. London: NICE; 2021. URL:: https://www.nice.org.uk/guidance/ng206 Published:: October 29, 2021 Key Changes from 2007 Guideline::

- All four core symptoms required: debilitating fatiguability, PEM, unrefreshing sleep, cognitive difficulties
- Symptoms must persist β‰₯3 months (suspected from 6 weeks in adults, 4 weeks in children)
- Graded Exercise Therapy (GET) *no longer recommended*
- CBT not considered a treatment for ME/CFS itself
- Recognition of PEM as the cardinal symptom

Adoption:: Endorsed in Northern Ireland (2022); default guidance in Scotland (2025).

5 Canadian Consensus Criteria (2003)

Full Citation:: Carruthers BM, Jain AK, De Meirleir KL, et al. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols. Journal of Chronic Fatigue Syndrome. 2003;11(1):7–115. DOI:: 10.1300/J092v11n01_02 Significance:: First criteria to require PEM; more restrictive than Fukuda 1994; widely used in research.

6 Fukuda et al. 1994 (CDC Criteria)

Full Citation:: Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. The chronic fatigue syndrome: a comprehensive approach to its definition and study. Annals of Internal Medicine. 1994;121(12):953–959. DOI:: 10.7326/0003-4819-121-12-199412150-00009 PMID:: 7978722 Significance:: Most widely used research criteria historically; criticized for being too broad.

References

Aregawi, Mesfin, Brian Walitt, Peter Sullivan, Gustavo Norato, J. David Benjamin, and David Goldstein. 2026. β€œCentral Noradrenergic Deficiency in Post-Infectious Chronic Fatigue: Neurobehavioral Correlates.” Brain Communications. https://doi.org/10.1093/braincomms/fcag173.