Extracellular matrix mechanics as an upstream organizing constraint in neurodivergent architectures: a hypothesis linking neural topology, volume transmission, and functional iron blockade

Current connectome-centered models do not fully account for the systemic pleiotropy and autonomic instability frequently observed across neurodivergent phenotypes. We propose the extracellular matrix (ECM) as an upstream mechanobiological constraint that may help organize part of this broader phenotype. Specifically, we hypothesize that a relatively hyporeticular, hyper-hydrated ECM could create a more mechanically permissive extracellular environment, altering local stiffness gradients and thereby influencing neuronal positioning, perineuronal net stabilization, extracellular signaling geometry, and the energetic cost of large-scale coordination. Within this framework, increased reliance on diffusion-permissive signaling dynamics is predicted to increase metabolic burden under high-demand conditions. We further propose that this energetic burden may recruit a distal containment physiology involving Functional Iron Blockade (FIB), a previously published and preliminarily operationalized construct describing adaptive intracellular iron sequestration under chronic stress and neurodivergence-related overload. In the present manuscript, the novel hypothesis is not the general FIB construct itself, but its placement within a broader ECM-to-network-to-containment cascade. Dysautonomia, executive fatigue, and shutdown-like states are therefore framed as predicted clinical correlates of this multiscale mechanobiological model. Direct in vivo evidence demonstrating altered ECM stiffness or hydration in neurodivergent human brains remains limited. Accordingly, this article does not claim that the full ECM-to-clinical cascade has already been demonstrated, but instead aims to organize a falsifiable hypothesis linking extracellular mechanics, signaling geometry, metabolic burden, and endothelial protection.