A Two-Hit Model of Autism: Adolescence as the Second Hit

Abstract

Adolescence brings dramatic changes in behavior and neural organization. Unfortunately, for some 30% of individuals with autism, there is marked decline in adaptive functioning during adolescence. We propose a two-hit model of autism. First, early perturbations in neural development function as a "first hit" that sets up a neural system that is "built to fail" in the face of a second hit. Second, the confluence of pubertal hormones, neural reorganization, and increasing social demands during adolescence provides the "second hit" that interferes with the ability to transition into adult social roles and levels of adaptive functioning. In support of this model, we review evidence about adolescent-specific neural and behavioral development in autism. We conclude with predictions and recommendations for empirical investigation about several domains in which developmental trajectories for individuals with autism may be uniquely deterred in adolescence.

Keywords: adolescent peer relations; autism; brain; risk taking; social behavior.

Fig. 1

Schematic illustration of a two-hit model of schizophrenia. The model proposes that there is a first hit via prenatal genetic or environmental disruptions in the developmental central nervous system. As a result, the system is primed with vulnerable neuronal circuitry that is subsequently exacerbated by a second hit to the system via potential environmental factors that lead to the onset of schizophrenia systems, specifically during adolescence. Adapted from Maynard, Sikich, Lieberman, and LaMantia (2001).

Fig. 2

Schematic illustration of a developmentally sensitive two-hit model of autism. We propose that the first hit (i.e., genetic and neurodevelopmental disruptions) calibrates the system to be fundamentally vulnerable, which leads to poor childhood outcomes. A subsequent second hit (adolescent-specific developmental tasks and pubertal hormones) compounds previous neural vulnerabilities in addition to creating new and importantly different vulnerabilities, which lead to impediments in attaining adult levels of adaptive functioning. Colored lines within the diagram are numbered by area of research. The blue line predicts links between vulnerable neural circuits and poor childhood outcomes, which has been minimally characterized in the literature. The green lines are symbolic of two predictions that have yet to be addressed: how poor childhood outcomes cascade into poor adolescent outcomes and how poor adolescent outcomes (as a result of a second hit) lead to a failure to transition into adult social roles and levels of adaptive functioning.