Cerebellar Dysfunction in Autism Spectrum Disorders: Deriving Mechanistic Insights from an Internal Model Framework

Abstract

Autism spectrum disorders (ASD) are highly prevalent neurodevelopmental disorders; however, the neurobiological mechanisms underlying disordered behavior in ASD remain poorly understood. Notably, individuals with ASD have demonstrated difficulties generating implicitly derived behavioral predictions and adaptations. Although many brain regions are involved in these processes, the cerebellum contributes an outsized role to these behavioral functions. Consistent with this prominent role, cerebellar dysfunction has been increasingly implicated in ASD. In this review, we will utilize the foundational, theoretical contributions of the late neuroscientist Masao Ito to establish an internal model framework for the cerebellar contribution to ASD-relevant behavioral predictions and adaptations. Additionally, we will also explore and then apply his key experimental contributions towards an improved, mechanistic understanding of the contribution of cerebellar dysfunction to ASD.

Keywords: adaptation; autism spectrum disorders; cerebellum; implicit; internal models; prediction.

Fig. 1.

Block diagrams of internal model, including both cerebellar-mediated forward and inverse feedforward models. Diagram for sensorimotor (left) and for social behaviors (right) are shown. * ‘‘Social Model” represents the multiple effectors required for social behaviors. Sensory Feedback is represented by dashed lines. Error signals in the forward model are derived by comparison in the inferior olive (IO) of outputs from forward models and sensory feedback. Error is also derived by comparison of inverse model with all other input to the IO. These models are adapted from models presented by Masao Ito (See ‘‘Control of Mental Activities by Internal Models in the Cerebellum” Nat. Rev. Neuro. 2008).

Fig. 2.

Model of cerebellar and cerebral-cortical circuits composing internal models for discrete behaviors (A) Dysfunction present in autism spectrum disorders and the sequelae of dysfunction on internal model function (B) and resulting autism-related behavioral phenotypes (C). ASD: autism spectrum disorder; PC: Purkinje cell; DCN: deep cerebellar nuclei, LTD: long term depression, E/I: Excitatory/Inhibitory.