Autonomic Nervous System Models
1 Sympathetic–Parasympathetic Balance
The autonomic nervous system (ANS) regulates cardiovascular, respiratory, and gastrointestinal function through the opposing actions of the sympathetic (SNS) and parasympathetic (PNS) branches. Heart rate variability (HRV) analysis provides a non-invasive window into ANS function and is consistently abnormal in ME/CFS (Newton et al. 2007). The model tracks sympathetic tone (\(S\)) and parasympathetic (vagal) tone (\(V\)):
\[ \begin{aligned} \frac{d S}{d t} &= \sigma_S \cdot g_S (\text{BP}, \text{pain}, \text{stress}) - \delta_S S - k_{S V} V \\ \frac{d V}{d t} &= \sigma_V \cdot g_V (\text{BP}, \text{respiration}) - \delta_V V - k_{V S} S \end{aligned} \tag{1}\]
where \(g_S\) and \(g_V\) are input functions driven by baroreceptor signals (blood pressure, BP), pain, stress, and respiratory phase; \(k_{S V}\) and \(k_{V S}\) represent reciprocal inhibition between branches. Heart rate is determined by the balance:
\[ \text{HR}(t) = \text{HR}_{\text{intrinsic}} + \alpha_S \cdot S(t) - \alpha_V \cdot V(t) \tag{2}\]
where \(\text{HR}_{\text{intrinsic}} \approx 100\) bpm is the intrinsic sinoatrial node rate (without autonomic input), and \(\alpha_S\), \(\alpha_V\) are gain coefficients. In ME/CFS, the model represents autonomic dysfunction as elevated baseline \(S\) and reduced \(V\)—sympathetic predominance with vagal withdrawal—producing reduced HRV and elevated resting heart rate.
2 Orthostatic Intolerance Model
Orthostatic intolerance (OI) affects the majority of ME/CFS patients. Upon assuming an upright posture, gravitational pooling shifts 500–700 mL of blood to the lower extremities, requiring rapid compensatory responses. The model tracks mean arterial pressure (MAP) and heart rate during orthostatic challenge:
\[ \begin{aligned} \frac{d \text{MAP}}{d t} &= \frac{1}{\tau_{\text{MAP}}} [\text{MAP}_{\text{set}} + \alpha_{\text{SNS}} \cdot S - \text{MAP} - \Delta P_{\text{grav}} \cdot u(t)] \\ \frac{d \text{HR}}{d t} &= \frac{1}{\tau_{\text{HR}}} [\text{HR}_{\text{intrinsic}} + \alpha_S S - \alpha_V V - \text{HR}] \end{aligned} \tag{3}\]
where \(\Delta P_{\text{grav}} \cdot u(t)\) is the gravitational pressure drop upon standing (\(u(t)\) is a step function at the time of postural change), \(\tau_{\text{MAP}}\) and \(\tau_{\text{HR}}\) are response time constants, and \(\text{MAP}_{\text{set}}\) is the baroreflex set point. The baroreflex feedback adjusts sympathetic and vagal tone in response to MAP deviations:
\[ S_{\text{baro}} = S_0 + G_S \cdot (\text{MAP}_{\text{set}} - \text{MAP}), \quad V_{\text{baro}} = V_0 - G_V \cdot (\text{MAP}_{\text{set}} - \text{MAP}) \tag{4}\]
where \(G_S\) and \(G_V\) are baroreflex gains. In ME/CFS, the model represents OI through: (1) reduced blood volume (\(\Delta P_{\text{grav}}\) is amplified because the same gravitational redistribution removes a larger fraction of effective circulating volume), (2) impaired baroreflex gain (\(G_S\) and \(G_V\) reduced), and (3) excessive venous pooling (increased venous compliance in the lower extremities). The model reproduces the characteristic hemodynamic pattern of ME/CFS-associated OI: initial MAP drop, delayed or incomplete recovery, and compensatory tachycardia.
3 POTS Mechanism Model
Postural orthostatic tachycardia syndrome (POTS), defined as a sustained heart rate increase \(\geq 30\) bpm within 10 minutes of standing without orthostatic hypotension, is prevalent among ME/CFS patients. The orthostatic model (Equations orthostatic and baroreflex) reproduces POTS when the parameter combination produces adequate MAP maintenance (through excessive sympathetic activation) at the cost of sustained tachycardia. The model identifies three parameter regimes corresponding to distinct POTS subtypes:
- Neuropathic POTS: reduced \(G_V\) (impaired parasympathetic function) with compensatory sympathetic overdrive
- Hypovolemic POTS: reduced effective blood volume (increased \(\Delta P_{\text{grav}}\) effect) requiring greater compensatory response
- Hyperadrenergic POTS: elevated baseline \(S\) and increased \(\alpha_S\) gain, producing excessive heart rate response to normal orthostatic stress
This subtype classification has treatment implications: hypovolemic POTS responds to volume expansion (saline, fludrocortisone), neuropathic POTS to parasympathetic enhancement (pyridostigmine (Raj et al. 2005)), and hyperadrenergic POTS to sympatholytic agents (propranolol, clonidine).
