Response to Specific Stimuli
1 Physical Exertion
Physical exertion produces the most well-characterized stimulus–response relationship in ME/CFS via the two-day CPET protocol (Keller et al. 2024). The model simulates a standardized exercise test as a ramping \(J_\text{demand} (t)\) function.
Healthy temporal profile. In healthy individuals, the model (Section Healthy Exercise Response Dynamics) predicts a multi-timescale response that serves as the baseline against which ME/CFS deviations are measured. (1) Immediate recovery (0–2 hours): ATP and lactate return to baseline as metabolic demand normalizes; this is the fast timescale of metabolic kinetics. (2) Delayed-onset muscle soreness (24–72 hours): local inflammatory repair of mechanical micro-damage peaks at 24–48 hours (Equation doms inflammation); this is self-limiting and confined to the exercised tissue, producing soreness without systemic symptoms. (3) Supercompensation (48–96 hours): AMPK-driven mitochondrial biogenesis produces a net increase in healthy mitochondrial mass (\(\Delta M_h^\text{net} > 0\), Equation supercompensation), leaving the system stronger than before the exertion. The fact that the model reproduces these well-established healthy timescales—without parameter fitting, purely from the interaction of its fast (metabolic), intermediate (inflammatory), and slow (biogenesis) ODE components—constitutes a face validation of the model framework before it is applied to ME/CFS.
ME/CFS temporal profile. In ME/CFS, each of the three healthy timescales is pathologically altered. Key model predictions, validated against CPET data:
- Reduced peak VO₂: Limited by both cardiovascular (reduced CO) and metabolic (reduced ETC capacity) constraints
- Early anaerobic threshold: Transition to glycolytic dominance at lower workloads because oxidative capacity ceiling is reduced
- Day-2 decrement: The model predicts that ROS-mediated damage from day-1 exertion reduces ETC capacity by 5–15% on day 2, lowering peak VO₂ and anaerobic threshold. This is the pathological counterpart of healthy DOMS: where healthy individuals experience local, self-limiting inflammation, ME/CFS patients experience systemic ROS-mediated ETC damage that worsens capacity rather than repairing tissue
- Prolonged recovery: The model predicts that post-exercise ATP and cytokine levels require 48–96 hours to return to pre-exercise baseline, versus \(<24\) hours for metabolic normalization in healthy controls. The 48–96 hour window that produces supercompensation in health (Section Healthy Exercise Response Dynamics) instead produces net mitochondrial loss (\(\Delta M_h^\text{net} < 0\))—the anti-supercompensation phenomenon that is the hallmark of the disease (Section DOMS Model Scope)
2 Cognitive Exertion
Cognitive exertion increases brain ATP demand by 10–20% above baseline (versus 5–10-fold increases for intense physical exercise in skeletal muscle). Despite the smaller absolute demand, the brain is particularly vulnerable because it has minimal energy reserves and depends on continuous aerobic metabolism. The model predicts that cognitive PEM is mediated by the same energy depletion mechanism as physical PEM but manifests at lower total energy expenditure because brain tissue is operating closer to its metabolic ceiling.
3 Infections
Intercurrent infections are the most common trigger for ME/CFS relapses. The model simulates infection as a combined perturbation: increased \(V(t)\), increased immune activation (\(N_a\), \(T_e\), cytokines), and increased energy demand (\(J_\text{immune}\)). In the ME/CFS model, the immune response is both delayed (slower NK cell and T cell activation due to exhaustion and energy limitation) and prolonged (impaired viral clearance extends the infectious period), resulting in greater cumulative damage. The model predicts that the severity of relapse depends on the product of infection intensity and duration, suggesting that early antiviral intervention could reduce relapse severity.
4 Environmental Factors
Temperature extremes, chemical exposures, and sensory overload are reported ME/CFS triggers. The model represents these as perturbations to specific subsystems: temperature extremes alter metabolic rate and autonomic demand; chemical exposures (volatile organic compounds, fragrances) can trigger mast cell activation and neuroinflammation (Frioni et al. 2024); sensory overload increases CNS energy demand and sympathetic activation. The common pathway is an increase in total energy demand \(J_\text{demand}\) above the reduced energy envelope, triggering the PEM cascade.