Neurotransmitter Models
Neurotransmitter dynamics link energy metabolism, immune function, and neurological symptoms. The tryptophan–serotonin–kynurenine axis is particularly relevant to ME/CFS because it is modulated by both immune activation and energy status.
1 Tryptophan–Kynurenine Pathway
Tryptophan is metabolized through two competing pathways: serotonin synthesis (via tryptophan hydroxylase) and kynurenine production (via indoleamine 2,3-dioxygenase, IDO). Immune activation upregulates IDO, diverting tryptophan away from serotonin toward kynurenine and its downstream neurotoxic metabolites (quinolinic acid). The model tracks tryptophan (\(W\)), serotonin ($ 5 \(), and kynurenine (\)K$):
\[ \begin{aligned} \frac{d W}{d t} &= I_W - v_{\text{TPH}} \cdot \frac{W}{K_{\text{TPH}} + W} - v_{\text{IDO}} \cdot \frac{W}{K_{\text{IDO}} + W} - \delta_W W \\ \frac{d [5 \text{HT}]}{d t} &= v_{\text{TPH}} \cdot \frac{W}{K_{\text{TPH}} + W} - \delta_{5 \text{HT}} [5 \text{HT}] \\ \frac{d K}{d t} &= v_{\text{IDO}} \cdot \frac{W}{K_{\text{IDO}} + W} - \delta_K K \end{aligned} \tag{1}\]
where \(I_W\) is dietary tryptophan intake, and the IDO activity \(v_{\text{IDO}}\) is upregulated by IFN-\(\gamma\) from the immune model:
\[ v_{\text{IDO}} = v_{\text{IDO,basal}} + v_{\text{IDO,max}} \cdot \frac{[\text{IFN-} \gamma]^2}{K_{\text{IFN}}^2 + [\text{IFN-} \gamma]^2} \tag{2}\]
This coupling provides a mechanistic link between immune activation and neuropsychiatric symptoms: elevated IFN-\(\gamma\) \(->\) increased IDO activity \(->\) reduced serotonin and increased neurotoxic kynurenine metabolites. The IDO metabolic trap hypothesis (Phair, Davis, and Kashi 2019) extends this model by proposing bistability in IDO-2 kinetics, where a high-IDO state becomes self-sustaining even after the initial immune trigger resolves. Kynurenine pathway dysregulation has been documented in ME/CFS cohorts (Kavyani et al. 2022) (Dehhaghi et al. 2022).
2 Catecholamine Dynamics
The NIH deep phenotyping study documented altered catecholamine metabolites in ME/CFS cerebrospinal fluid (Walitt et al. 2024). Catecholamines (dopamine, norepinephrine, epinephrine) are synthesized from tyrosine through a sequential enzymatic pathway. The model tracks dopamine (\(\text{DA}\)) and norepinephrine (\(\text{NE}\)) in the CNS:
\[ \begin{aligned} \frac{d [\text{DA}]}{d t} &= v_{\text{TH}} \cdot \frac{[\text{Tyr}]}{K_{\text{TH}} + [\text{Tyr}]} \cdot \frac{[\text{BH}_4]}{K_{\text{BH}_4} + [\text{BH}_4]} - v_{\text{DBH}} \cdot \frac{[\text{DA}]}{K_{\text{DBH}} + [\text{DA}]} - \delta_{\text{DA}} [\text{DA}] \\ \frac{d [\text{NE}]}{d t} &= v_{\text{DBH}} \cdot \frac{[\text{DA}]}{K_{\text{DBH}} + [\text{DA}]} - \delta_{\text{NE}} [\text{NE}] \end{aligned} \tag{3}\]
where TH is tyrosine hydroxylase (rate-limiting), DBH is dopamine \(\beta\)-hydroxylase, and \([\text{BH}_4]\) is tetrahydrobiopterin—a cofactor shared with tryptophan hydroxylase and nitric oxide synthase. The shared BH₄ dependency creates competition: increased demand for BH₄ by one pathway (e.g., increased NO production during inflammation) reduces availability for catecholamine and serotonin synthesis. This provides a mechanistic explanation for the concurrent monoamine deficits observed in ME/CFS.