Sleep–Wake Cycle Models
Unrefreshing sleep is a core symptom of ME/CFS. The two-process model of sleep regulation, originally developed by Borbély, provides a quantitative framework. Sleep propensity is determined by the interaction of a homeostatic process (\(S\), sleep pressure) and a circadian process (\(C\)):
\[ \begin{aligned} \frac{d S}{d t} &= cases(r_{\text{build}} \cdot (S_{max} - S) & \text{during waking}, -r_{\text{decay}} \cdot (S - S_{min}) & \text{during sleep}) \\ C(t) &= C_0 + C_1 sin(\frac{2 \pi t}{24} - \phi_s) \end{aligned} \tag{1}\]
Sleep onset occurs when \(S > C + \theta_{\text{on}}\) (sleep pressure exceeds circadian alerting plus threshold), and waking occurs when \(S < C - \theta_{\text{off}}\). In ME/CFS, the model predicts unrefreshing sleep through:
- Impaired sleep pressure dissipation: reduced \(r_{\text{decay}}\), meaning sleep pressure does not fully clear during sleep (consistent with reduced slow-wave sleep in polysomnographic studies)
- Elevated waking sleep pressure build rate: increased \(r_{\text{build}}\), reflecting the higher metabolic cost of waking activities in an energy-deficient state (adenosine accumulation is linked to ATP consumption)
- Blunted circadian amplitude: reduced \(C_1\), flattening the circadian alerting signal (consistent with the HPA axis circadian reduction in HPA Axis Models and with melatonin studies (Castro-Marrero et al. 2021))
The combination produces a sleep phenotype where patients fall asleep easily (elevated \(S\)) but wake unrefreshed (residual \(S\) remains high) and experience daytime somnolence (chronically elevated \(S\) during waking hours). The model further predicts that circadian disruption (irregular sleep schedules) worsens the phenotype by desynchronizing the \(S\) and \(C\) processes, providing formal support for sleep hygiene recommendations in ME/CFS management.
The homeostatic sleep drive is mediated by extracellular adenosine, which accumulates as a byproduct of ATP hydrolysis during waking. In ME/CFS, impaired ATP production (Chapter Energy Metabolism Models) may paradoxically accelerate adenosine accumulation through increased AMP \(->\) adenosine conversion, while simultaneously impairing the glymphatic clearance of adenosine during sleep (Xie et al. 2013) (Nemat-Gorgani et al. 2025). This dual mechanism—accelerated build-up and impaired clearance—predicts that: (1) sleep pressure builds faster in ME/CFS patients than in healthy controls for equivalent activity levels; (2) improving mitochondrial function should improve sleep quality independent of sleep-targeted interventions; and (3) glymphatic function markers should correlate with unrefreshing sleep severity.
Certainty: 0.35. The adenosine–ATP link is biochemically sound, but direct measurement of brain adenosine dynamics in ME/CFS patients has not been performed, and the glymphatic connection remains extrapolated from neurodegenerative disease research.