Searching for Neuronal Markers of Verbal Proficiency in Autism

Background:  Verbal proficiency at age 5 years is an important prognostic factor of long-term adjustment in autism spectrum disorders (ASD). Yet, the neuronal underpinnings of verbal proficiency in ASD are undetermined. Their characterization may lead to the identification of biomarkers applicable as early as the first identification of ASD, to guide treatment selection and track language outcomes. Our overarching aim is to obtain such a biomarker by means of resting-state (task-independent) fMRI (R-fMRI). R-fMRI is feasible in young populations, regardless of cognitive level, and it provides a wealth of information about intrinsic functional connectivity (iFC). 

Objectives:  We aimed to identify neuronal markers of verbal proficiency using R-fMRI measures of iFC applied to language-based circuits, first in a “training” sample of school-age children with ASD. Then, to explore the stability of the identified marker(s), we examined its relationship with verbal proficiency in an independent sample of preschoolers with ASD.

Methods:  Two independent samples of children with ASD were included: 34 school-age children (mean age 10.6±1.8years; 29 males) completing an awake R-fMRI scan; and 20 preschoolers (mean age: 60±10months; 18 males) completing a R-fMRI scan during natural sleep. To examine iFC of language circuits we focused on functional subregions of the left inferior frontal gyrus (IFG): the pars triangularis (pt), pars opercularis and the ventral premotor cortex, whose iFC was previously delineated by our group. Vineland Expressive Language (VEL) standard scores were used to index verbal proficiency. Two-step analyses were conducted. First, in the 34 school-age children with ASD, we examined the relationship between VEL scores and inter-individual differences in iFC patterns associated with each of the three IFG regions, at the voxel-wise, whole-brain level (Z>2.3, p<0.05, Gaussian random Field Theory corrected). Second, we examined the relationship between the iFC of circuit(s) identified in the first step with the VEL scores in the preschoolers with ASD. We also ran confirmatory analyses comparing iFC strength of the target circuit(s) between verbally and non-verbally proficient preschoolers identified based on the Autism Diagnostic Observation Schedule (ADOS) module level as proxy for expressive language use. 

Results: Voxel-wise analyses of the school-age sample revealed a significant positive relationship between VEL scores and the iFC of left IFGpt with a cluster in the posterior aspects of the right superior temporal sulcus (STS). Guided by this finding, we correlated the iFC within this circuit with VEL scores of the 20 preschoolers with ASD. The iFC of this circuit explained 16% of the variance in verbal proficiency (corresponding to r=0.40). Weaker iFC in the L-IFG R-STS related to poor verbal proficiency was also evident from comparisons of this circuit iFC between verbally and non-verbally proficient preschoolers per ADOS modules. 

Conclusions: Our findings underscore the role in ASD-related verbal proficiency of an interhemispheric circuit connecting the left IFG, typically involved in expressive language skills, with the right STS, classically implicated in broad aspects of social cognition. R-fMRI provides a feasible means for the identification of loci of disconnection in autism that may serve to identify prognostic markers of verbal proficiency.