Slow stress-load accumulation dominates BDNF-dependent gain in a ten-state computational model of stress biochemistry

BackgroundAcute stress responses are often reversible, whereas sustained stress can produce coordinated disruption across endocrine, metabolic, inflammatory, antioxidant, and neuroplastic pathways. The Tiered Stress Biochemistry Model (TSBM) is a hypothesis-generating ten-state ordinary differential-equation framework linking a stylized cortisol signal to noradrenergic drive, vitamin C, a phenomenological aldosterone/renin-angiotensin drive, magnesium, normalized BDNF-related and Nrf2-related states, inflammation, and tryptophan-kynurenine metabolism. MethodsFive prespecified scenarios (normal, acute, chronic, depression-like, and low-cortisol PTSD-like) were simulated for 168 hours. Analyses included local stability, output-specific sensitivity screening, structural ablation, a 400-draw Latin-hypercube scan over independent {+/-} 20% parameter ranges, uncertainty distributions for threshold-crossing times, a success-conditioned parameter-trade-off screen, and a wider scan in which hypothesized BDNF-feedback gain magnitudes varied log-uniformly from 0.1 to 10 times nominal. Parameters were classified as literature-derived, literature-constrained/model-defined, calibrated, or hypothesized. ResultsUnder the specified forcing assumptions, sustained stress produced coordinated changes across several pathways. In the depression-like scenario, removing slow stress-load accumulation increased day-7 BDNF-related activity from 47.2% to 82.6%, reduced inflammation from 14.63 to 2.15 arbitrary units, and lowered KYN/TRP from 0.173 to 0.057. Removing BDNF-dependent gain increased BDNF only to 49.1% and delayed KYN/TRP crossing by 2.5 hours. The stricter multi-output conclusion was retained in 91% of uncertainty draws. Median crossing times retained the nominal sequence, but the complete four-event order occurred in only 43% of all draws. ConclusionsWithin this reduced model, a shared slow stress-load process coordinates the high-exposure state, whereas BDNF-dependent feedback acts mainly as an amplifier. The model generates an experimentally testable staging hypothesis: under sustained high-exposure forcing, magnesium changes may precede later BDNF-related and KYN/TRP changes. Longitudinal studies are required to determine whether this sequence occurs biologically, whether it is reversible, and whether it has clinical relevance. The simulations are not diagnostic or treatment recommendations.