The development of cognitive control in children with chromosome 22q11.2 deletion syndrome

Abstract

Chromosome 22q11.2 Deletion Syndrome (22q11.2DS) is caused by the most common human microdeletion, and it is associated with cognitive impairments across many domains. While impairments in cognitive control have been described in children with 22q11.2DS, the nature and development of these impairments are not clear. Children with 22q11.2DS and typically developing children (TD) were tested on four well-validated tasks aimed at measuring specific foundational components of cognitive control: response inhibition, cognitive flexibility, and working memory. Molecular assays were also conducted in order to examine genotype of catechol-O-methyltransferase (COMT), a gene located within the deleted region in 22q11.2DS and hypothesized to play a role in cognitive control. Mixed model regression analyses were used to examine group differences, as well as age-related effects on cognitive control component processes in a cross-sectional analysis. Regression models with COMT genotype were also conducted in order to examine potential effects of the different variants of the gene. Response inhibition, cognitive flexibility, and working memory were impaired in children with 22q11.2DS relative to TD children, even after accounting for global intellectual functioning (as measured by full-scale IQ). When compared with TD individuals, children with 22q11.2DS demonstrated atypical age-related patterns of response inhibition and cognitive flexibility. Both groups demonstrated typical age-related associations with working memory. The results of this cross-sectional analysis suggest a specific aberration in the development of systems mediating response inhibition in a sub-set of children with 22q11.2DS. It will be important to follow up with longitudinal analyses to directly examine these developmental trajectories, and correlate neurocognitive variables with clinical and adaptive outcome measures.

Keywords: 22q11.2 deletion syndrome; catechol-O-methyltransferase (COMT); childhood cognitive development; cognitive control; developmental disorders; executive function.

Figure 1

Examples of the cognitive control battery. (A) For the Stroop task, participants had to respond by indicating the ink color on congruent (left) or incongruent (right) trials. (B) “Whack-a-mole” Go/No-Go task. Children were instructed to press a button as quickly as possible when a cartoon mole appeared (Go trial), but to avoid pressing the button when a vegetable appeared (No-Go trial). No-Go trials were preceded by 1, 3, or 5 Go trials (Adapted from Shapiro et al., 2013). (C) The two gray squares each represent a touch-screen display in the Visually-Cued Card Sort (VCCS). A sample of the target cards can be seen at the top of the screen, while the test card is below. The visual cue appears just below the test card, with a rainbow indicating to sort by color (left panel), and a star indicating to sort by shape (right panel). (D) The two gray squares each represent a touch-screen display in the for the verbal and non-verbal Self-Ordered Pointing Test (SOPT), respectively. Images represent a trial with 6 objects, the most difficult condition of the task.

Figure 2

Results of the response inhibition Stroop task. (A) Children with 22q11.2DS had lower accuracy relative to TD participants across all trial types: Congruent (C) or Incongruent (I) trials preceded by congruent (c) or incongruent (i) trials, respectively. (B) Response time (RT) was similar between groups. (C) Children with 22q11.2DS were more greatly affected by a preceding interfering stimulus, as measured by a larger RT difference on congruent trials preceded by incongruent trials (iC) relative to congruent trials following other congruents trial (cC), ^*p < 0.05.

Figure 3

Results of the response inhibition Go/No-Go task. (A) No-Go accuracy differed between groups ^*p < 0.05, while (B) response time on Go trials was similar between groups.

Figure 4

Results of Visually-Cued Card Sort (VCCS), a test of cognitive flexibility. (A) TD children had better accuracy when sorting by both dimensions (predominant and secondary, ^*p < 0.05). (B) Children with 22q11.2DS performed significantly worse when sorting by the secondary dimension relative to the predominant dimension, as indicated by this group difference in the ratio score of accuracy on Dimension 2 divided by that of Dimension 1 (^*p < 0.05).

Figure 5

Results of the working memory task, the self-ordered pointing test (SOPT). On the verbal version of the task, children with 22q11.2DS made more errors (A) and had a lower span (B) on the more difficult trials levels with 4 and 6 items to remember (^*p < 0.05). On the non-verbal version of the SOPT, children with 22q11.2DS made significantly more errors (C) and had a lower span (D) across all levels of the non-verbal SOPT, when compared to TD children (^*p < 0.05).

Figure 6

Age-related associations with cognitive control component processes. Age was not related to incongruent accuracy on the Stroop for either group (A). On the Go/No-Go task, TD children demonstrated a significant age-related association with No-Go accuracy (p < 0.05) while children with 22q11.2DS did not (B). Similarly, on the Visually-Cued Card Sort (VCCS), age was significantly associated with the ratio of Dimension 2 accuracy divided by that of Dimension 1 for TD children (p < 0.05) but not those with 22q11.2DS (C). Age significantly correlated with span on the Self-Ordered Pointing Test (SOPT) for both TD and 22q11.2DS children on the verbal (D) and nonverbal (E) versions of the task (p < 0.05).

Figure 7

COMT and cognitive control. The left panel depicts the primary outcome measures for each task graphed as a function of COMT variant for the individual children with 22q11.2DS. (A) Incongruent accuracy on the Stroop task. (B) Average No-Go accuracy on the response inhibition Go/No-Go task. (C) Accuracy ratio (Dimension 2/Dimension 1) on the VCCS. (D,E) Verbal and non-verbal span, respectively, on the most difficult level of the self-ordered pointing test (6 items to remember). The right panels of the figure depict the proportion of individuals within each performance quartile of the particular task that had the Met variant of the COMT gene.