The impedance mismatch theory: A non-equilibrium thermodynamic framework for a shared energetic stress pathway in...

Current neurobiological models of Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis (MS), and Huntington's Disease (HD) utilize multi-omic interactome analyses to map cascades of proteinopathy. While essential, these approaches often overlook the macroscopic thermodynamic limits of the neural substrate as an information processing system. We propose the Impedance Mismatch Theory, a theoretical biophysical model and quantitative framework for the thermodynamic limits of neural computation, positing that these distinct pathologies converge as a shared energetic stress pathway. We introduce the Neurophysiological Load Index (NLI)-a dimensionless parameter quantifying the mismatch between electrical computational drive, topological network impedance, and the local structural and microvascular dissipation capacity. Drawing on the Pennes Bioheat Transfer Equation and insights from multiplex network theory, we hypothesize that pathology initiates as localized thermal runaway, where resistive metabolic heat exceeds convective blood perfusion and thermal conduction, inducing acute decompensation. We outline cross-translational disease-network mechanisms, address the inverse cancer comorbidity paradox via speculative bioelectric attractor states, and propose falsifiable predictions involving high-resolution in vivo proton magnetic resonance spectroscopy thermometry (¹H-MRS-t) and phosphorus-31 magnetic resonance spectroscopy (³¹P-MRS).