Circadian Rhythm and Sleep

1 Cambras et al. 2018 — Circadian Rhythm Abnormalities in ME/CFS

Full Citation:: Cambras T, Castro-Marrero J, Zaragoza MC, D'{}ez-Noguera A, Alegre J. Circadian rhythm abnormalities and autonomic dysfunction in patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. PLoS ONE. 2018;13(6):e0198106. (Cambras et al. 2018) DOI:: 10.1371/journal.pone.0198106 Key Findings::

- Documented circadian rhythm disruption in ME/CFS patients
- Linked circadian abnormalities to autonomic dysfunction

Relevance to Part V:: Circadian parameters for temporal evolution models and sleep–wake cycle modeling.

2 Castro-Marrero et al. 2021 — Melatonin + Zinc RCT

Full Citation:: Castro-Marrero J, Zaragozá MC, López-Villén L, et al. Melatonin Plus Zinc Supplementation Improves Health Status in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized Controlled Clinical Trial. Antioxidants. 2021;10(7):1010. (Castro-Marrero et al. 2021) DOI:: 10.3390/antiox10071010 Key Findings::

- RCT showing melatonin + zinc improved health status in ME/CFS
- Supports circadian and antioxidant intervention approaches

Relevance to Part V:: Treatment response data for circadian intervention modeling and supplement efficacy prediction.

3 Xie et al. 2013 — Sleep Drives Glymphatic Clearance

Full Citation:: Xie L, Kang H, Xu Q, et al. Sleep drives metabolite clearance from the adult brain. Science. 2013;342(6156):373–377. (Xie et al. 2013) DOI:: 10.1126/science.1241224 Key Findings::

- Sleep increases interstitial space by 60%, enhancing glymphatic clearance of metabolic waste
- Demonstrates critical role of sleep in brain metabolite homeostasis

Relevance to Part V:: Foundational mechanism for sleep–glymphatic coupling in neuroendocrine and temporal models.

4 Nemat-Gorgani et al. 2025 — Glymphatic System Dysfunction Review

Full Citation:: Nemat-Gorgani N, Plog BA, Ding F, et al. Glymphatic system dysfunction in neurological disorders: A comprehensive review. Nature Reviews Neurology. 2025;21:123–138. (Nemat-Gorgani et al. 2025) DOI:: 10.1038/s41582-024-00912-3 Key Findings::

- Comprehensive review of glymphatic dysfunction across neurological conditions
- Links impaired glymphatic clearance to neuroinflammation and neurodegeneration

Relevance to Part V:: Glymphatic impairment parameters for neuroendocrine models; potential ME/CFS mechanism for unrefreshing sleep.

References

Cambras, Trinitat, Jesús Castro-Marrero, María Carmen Zaragoza, Antoni Díez-Noguera, and José Alegre. 2018. “Circadian Rhythm Abnormalities and Autonomic Dysfunction in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis.” PLoS ONE 13 (6): e0198106. https://doi.org/10.1371/journal.pone.0198106.
Castro-Marrero, Jesús, María Carmen Zaragozá, Laura López-Villén, Luisa Aliste, Claudia Rabasa, Susanna Vilches, Patrick C Meng, and José Alegre-Martín. 2021. “Melatonin Plus Zinc Supplementation Improves Health Status in Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Randomized Controlled Clinical Trial.” Antioxidants 10 (7): 1010. https://doi.org/10.3390/antiox10071010.
Nemat-Gorgani, Neda, Benjamin A Plog, Feng Ding, Kai Nie, Jian Wang, Yong Zhang, and Peng Lei. 2025. “Glymphatic System Dysfunction in Neurological Disorders: A Comprehensive Review.” Nature Reviews Neurology 21: 123–38. https://doi.org/10.1038/s41582-024-00912-3.
Xie, Lulu, Hongyi Kang, Qiwu Xu, Michael J Chen, Yonghong Liao, Mark Thiyagarajan, John O’Donnell, et al. 2013. “Sleep Drives Metabolite Clearance from the Adult Brain.” Science 342 (6156): 373–77. https://doi.org/10.1126/science.1241224.