Neuroinflammation Models
1 Microglial Activation
Microglia are the resident immune cells of the central nervous system. PET imaging studies have shown increased neuroinflammatory markers in ME/CFS patients (Raijmakers et al. 2021). Microglia exist in a continuum of activation states, simplified here to resting (\(\mu_r\)), activated pro-inflammatory (\(\mu_1\)), and activated anti-inflammatory/reparative (\(\mu_2\)):
\[ \begin{aligned} \frac{d \mu_r}{d t} &= -k_1(\mathbf{S}) \mu_r - k_2(\mathbf{S}) \mu_r + k_{\text{deact},1} \mu_1 + k_{\text{deact},2} \mu_2 \\ \frac{d \mu_1}{d t} &= k_1(\mathbf{S}) \mu_r - k_{\text{deact},1} \mu_1 - k_{12} \mu_1 \\ \frac{d \mu_2}{d t} &= k_2(\mathbf{S}) \mu_r + k_{12} \mu_1 - k_{\text{deact},2} \mu_2 \end{aligned} \tag{1}\]
where \(\mathbf{S}\) is the vector of activation signals (including peripheral cytokines crossing the blood–brain barrier, neuronal damage signals, and ATP released from stressed cells), \(k_1\) promotes pro-inflammatory activation (driven by TNF-\(\alpha\), IFN-\(\gamma\)), \(k_2\) promotes anti-inflammatory activation (driven by IL-4, IL-10), and \(k_{12}\) is the rate of polarization from \(\mu_1\) to \(\mu_2\). In ME/CFS, the model predicts a shift toward sustained \(\mu_1\) dominance due to persistent peripheral inflammatory signals crossing the blood–brain barrier.
2 Blood–Brain Barrier Model
The blood–brain barrier (BBB) regulates the transport of cytokines, immune cells, and metabolites between the peripheral circulation and the CNS. BBB permeability is modeled as a function of inflammatory state:
\[ P_{\text{BBB}}(t) = P_0 + \Delta P \cdot \frac{[\text{TNF-}\alpha]^2 + [\text{IL-1}\beta]^2}{K_{\text{BBB}}^2 + [\text{TNF-}\alpha]^2 + [\text{IL-1}\beta]^2} \tag{2}\]
where \(P_0\) is the baseline permeability and \(\Delta P\) is the maximum inflammation-induced increase. The squared terms reflect the cooperative nature of tight junction disruption: moderate cytokine levels have minimal effect, but sustained elevation above \(K_{\text{BBB}}\) is predicted to cause progressive barrier breakdown. Cytokine transport across the BBB follows:
\[ J_{\text{BBB},i} = P_{\text{BBB}} \cdot (C_i^{\text{plasma}} - C_i^{\text{CNS}}) + T_{\text{active},i} \tag{3}\]
where \(T_{\text{active},i}\) represents active (saturable) transport mechanisms for specific cytokines. This coupling ensures that peripheral immune activation in ME/CFS produces CNS effects with a delay and attenuation determined by BBB integrity—potentially explaining why neurological symptoms worsen during immune flares and improve during periods of immune quiescence.