The Generalized Adaptation Account of Autism.

The heterogeneous phenomenology of autism together with diverse patterns of comorbidities led in the past to formulation of manifold theories and hypotheses on different explanatory levels. We scrutinize most recent findings from genetics, neurobiology and physiology and derive testable hypotheses about possible physiological links between domains. With focus on altered sensory perception and neuronal processing in ASD, we assume two intertwined regulatory feedback circuits under the umbrella of genetics and environmental factors. Both regulatory circuits are highly variable between individuals in line with the heterogeneous spectrum of ASD. The circuits set off from altered pathways and connectivity in ASD, fueling HPA-axis activity and distress. In the first circuit altered tryptophan metabolism leads to higher neurotoxic substances and reinforces the excitation:inhibition imbalance in the brain. The second circuit focuses on the impact and interaction with the environment and its rhythms in ASD. With lower melatonin levels, as the pacemaker molecule of the circadian system, we assume misalignment to outer and inner states corroborated from the known comorbidities in ASD. Alterations of the microbiome composition in ASD are supposed to act as a regulatory linking factor for both circuits. Overall, we assume that altered internal balance on cellular and neurophysiological levels is one of the main reasons leading to a lower ability in ASD to adapt to the environment and own internal changing states, leading to the conceptualization of autism as a condition of generalized imbalance in adaptation. This comprehensive framework opens up new perspectives on possible intervention and prevention strategies.