Relationship of Impairments in Associative Learning With Intellectual Disability and Cerebellar Hypoplasia in Children With Autism

Background and objectives: The severity of autism spectrum disorder (ASD) varies widely and is associated with intellectual disability (ID) and brain dysmorphology. We tested the hypothesis that the heterogeneity of ASD can be accounted for, in part, by altered associative learning measured by eye-blink conditioning (EBC) paradigms, used to test for forebrain and cerebellar dysfunction across the full range of ASD severity and intellectual ability.

Methods: Children in this cohort study were diagnosed with ASD or typical development (TD); most children were recruited from a 10-year longitudinal study. Outcome measures were the percentage and timing of conditioned eye-blink responses (CRs) acquired to a tone, recorded photometrically and related to measures of ASD severity, IQ, and age-2 brain morphometry by MRI. A sequence of trace and delay EBC was used. Analysis of variance, t-test, and logistic regression (LR) were employed.

Results: Sixty-two children were studied at school-age. Nine ASD children with ID since age 2 (ASD+ID; IQ=49±6; 11.9±0.2 years-old [±SD]) learned more slowly than thirty TD children (IQ=120±16; 10.5±1.5 years-old [±SD]) during trace EBC and showed atypically early-onset CRs (1.4 SD pre-TD) related to hypoplasia of the cerebellum at age 2 but not of the amygdala, hippocampus, or cerebral cortex. Conversely, sixteen ASD children with robust intellectual development since age 2 (IQ=100±3; 12.0±0.4 years-old [±SD]) learned typically but showed early-onset CRs only during long-delay EBC (0.8 SD pre-TD) unrelated to hypoplasia of any measured brain area. Using sixteen EBC measures, binary LR classified ASD and TD with 80% accuracy (95%CI=72-88%), 81% sensitivity (95%CI=69-92%), and 79% specificity (95%CI=68-91%); multinomial LR more accurately classified children based on ID (94% accuracy, 95%CI=89-100%) than ASD severity (85% accuracy, 95%CI=77-93%). Separate analyses of thirty-nine children with MRI (2.1±0.3 years-old [±SD]) indicated that cerebellar hypoplasia did not predict ASD+ID over ages 2-4 (Cohen’s d=0.3), as compared to early-onset CRs during age-11 trace EBC (Cohen’s d=-1.3).

Conclusions: Trace EBC reveals the relationship between cerebellar hypoplasia and ASD+ID likely by engaging cerebro-cerebellar circuits involved in intellectual ability and implicit timing. Follow-up prospective studies using associative learning can determine whether ID can be predicted in children with early ASD diagnoses.