Patterns of Cortical Gyrification in Individuals with Idiopathic Autism Spectrum Disorder and 22q11.2 Deletion Syndrome

Background: 22q11.2 deletion syndrome (22q11.2DS) is a genetic condition accompanied by a range of physical symptoms, including cardiac defects, cleft palate, and immunodeficiency (McDonald-McGinn et al., 2015). Additionally, children with 22q11.2DS are at increased risk of developing behavioural symptoms similar to those observed in autism spectrum disorder (ASD) (Fine et al., 2005). To date, only a few structural neuroimaging studies have examined neuroanatomical differences in the brain of individuals with 22q11.2DS. Studies report significant differences in amygdala volume (Jalbrzikowski et al., 2017), cortical thickness, and surface area between 22q11.2DS individuals with and without ASD symptomatology (Gudbrandsen et al., 2018). Additionally, 22q11.2DS has been associated with decreases in cortical folding compared to healthy controls, in particular in frontal, parietal and midline structures (Schmitt et al., 2015; Srivastava et al., 2012; Bakker et al., 2016; Kunwar et al., 2012). However, no studies to date have examined cortical folding in 22q11.2DS individuals with ASD symptomatology. Thus, the neuroanatomical underpinnings of autistic symptoms in 22q11.2DS individuals remain poorly understood.

Objectives: The present study aimed to establish (1) whether similar behavioural symptoms across disorders are mediated by shared or distinct patterns of cortical folding, and (2) whether local gyrification in ASD is significantly modulated by the 22q11.2DS microdeletion.

Methods: Our sample consisted of four groups including 25 idiopathic ASD patients, 25 22q11.2DS patients with ASD symptomatology, 25 22q11.2DS patients without ASD symptomatology, and 51 neurotypical controls (6-25 years, FSIQ≥60, 66 males and 60 females; all groups were matched for age and gender). For all 126 participants, high-resolution structural T1-weighted images were acquired. Vertex-based estimates of the local gyrification index (lGI) were derived by regression of a general linear model with (1) a main effect of ASD, (2) a main effect of 22q11.2DS, (3) an ASD-by-22q11.2DS interaction effect, and (4) gender, site, age, IQ, and total brain volume as covariates. Pearson correlation coefficients between significant lGI measures across all individuals showing ASD symptoms, and measures of symptom severity (ADI-R and ADOS scores) were assessed.

Results: Following correction for multiple comparisons, we found significant differences in cortical folding between all individuals with 22q11.2DS compared to all individuals without the deletion in several large clusters distributed across the cortex. Moreover, based on the main effect of ASD, we established that individuals with ASD symptomatology showed distinct patterns of lGI from those without. Notably, we identified significant ASD-by-22q11.2DS interaction effects in two cortical regions: (1) the left precentral and postcentral gyrus, and (2) the right lateral orbitofrontal cortex and insula (see Figure 1). Across all individuals with ASD symptomatology, we observed a significant positive correlation between lGI of cluster 1 and symptom severity in the ADI-R subscale of restricted and repetitive behaviour (r = 0.4, p < .05) (see Figure 2).

Conclusions: Our findings imply that the patterns of cortical folding differ between individuals with the microdeletion and those without. Although sharing similar behavioural symptomatology, significant ASD-by-22q11.2DS interactions indicate that the neuroanatomical underpinnings of autistic symptoms could be separated from the neuroanatomical consequences resulting from the microdeletion.