The effects of external and internal perturbations on the robustness of modeled sensitization loops: implications for neuropsychiatric disorders

Robustness, i.e. the ability of a system to maintain stability despite perturbations, is an important issue considering normal function but also pathophysiological mechanisms. With respect to the latter, such robustness might even be a pitfall when it prevents the effects of treatments. In particular, this can be relevant in the case of sensitization and kindling effects (e.g. due to drugs, seizures or disease episodes) which lead to unbeneficial longterm changes in (neuro)biological systems. We recently investigated neuronal and clinically disease-related sensitization mechanisms (Huber et al. J Psychiatr Res 2001;35: 49–57 and Neuropsychopharmacology 2003;28: S13-S20). In the present study we use this computational approach and investigate the robustness of the sensitzation model with respect to external perturbations and internal system parameter changes. We show, that the potentially unstable mechanism of sensitization–modeled as recurrent excitation (recurrent positive feedback)–can behave surprisingly stable over large parametric ranges. We explain on hand of simulations which principal biological and biophysical plausible mechanisms underlie this behavior and which implications arise for neuropsychiatric disorders.

Supported by the EU 6th framework program: Network of Excellence BioSim (RA5WP10).