Daily and Weekly Symptom Dynamics
1 Circadian Influences
ME/CFS symptoms show circadian variation, with most patients reporting worse symptoms in the morning (consistent with blunted cortisol awakening response) and a relative improvement in the late afternoon (Cambras et al. 2018). The model produces this pattern through the circadian terms in the HPA axis (Equation hpa axis) and sleep–wake models (Equation sleep wake). The flattened cortisol rhythm (\(a_c\) reduced) means that the morning cortisol peak is insufficient to suppress overnight inflammatory accumulation, producing morning symptom peaks. As the circadian alerting signal \(C(t)\) rises through the day, it partially compensates, producing the afternoon improvement.
2 Activity–Symptom Relationships
The relationship between activity and symptoms in ME/CFS is nonlinear and delayed, making it difficult for patients to identify safe activity levels. The model formalizes this relationship through the energy envelope framework (Section Post-Exertional Malaise Modeling). For a given activity profile \(\phi(t)\), the model predicts:
\[ \text{Symptom}(t + \tau_\text{PEM}) = f(\int_0^t J_\text{demand} (s) d s, E_\text{budget}, [\text{ATP}](t), \mathbf{C}_\text{pro} (t)) \tag{1}\]
where \(\tau_\text{PEM} \in [12, 72]\) hours is the PEM delay and \(f\) is a threshold function that produces minimal symptoms when cumulative demand stays below \(E_\text{budget}\) but escalates rapidly above it. This nonlinear threshold explains the common patient experience that small increases in activity beyond a critical level produce disproportionately large symptom responses.