Altered Brain Structure-Function Relationships Underlie Executive Dysfunction in 22q11.2 Deletion Syndrome

Abstract

22q11.2 deletion syndrome (22q11DS) is a neurogenetic disorder associated with elevated rates of developmental neuropsychiatric disorders and impaired executive function (EF). Disrupted brain structure-function relationships may underlie EF deficits in 22q11DS. We administered the Behavior Rating Inventory of Executive Function (BRIEF) to assess real-world EF in patients with 22q11DS and matched controls (n = 86; age 6-17 years), along with cognitive measures that tap behavioral regulation and metacognition aspects of EF. Using FreeSurfer's whole-brain vertex cortical thickness pipeline, we investigated brain structure-EF relationships in patients with 22q11DS and controls. Behaviorally, patients with 22q11DS were impaired on multiple EF measures. Right orbitofrontal cortical thickness showed a differential relationship between real-world EF in patients with 22q11DS and controls. We also observed a group difference in the relationship between behavioral regulation and metacognition measures with thickness of ventral and dorsolateral prefrontal regions, respectively. Our findings suggest that executive dysfunction characteristic of 22q11DS is underscored by altered prefrontal cortical structure.

Keywords: Cognitive function; Copy number variation; Dopamine; Magnetic resonance imaging; Neurodevelopment; Neurogenetics; Prefrontal cortex.

Fig. 1

a BRIEF subscales. b Scores across BRIEF subscales in youth with 22q11DS and age-matched typically developing controls. Z scores were created based on normative data [38]; higher scores indicate greater pathology. Patients with 22q11DS show greater dysfunction on all subscales (p < 0.001, Bonferroni corrected).

Fig. 2

Relationship between BRIEF GEC score and cortical thickness in patients with 22q11DS vs. controls. Analysis was conducted using an unbiased, whole-brain approach. There was a significant interaction between group and BRIEF GEC score in the right OFC (cluster size 65,020.8 mm²; p < 0.05, corrected), indicating that increased cortical thickness in the right OFC was associated with more severe real-world executive dysfunction (higher BRIEF score) in patients with 22q11DS, whereas thicker OFC was associated with better EF (lower BRIEF score) in controls. The left panel shows the location of the cluster, and the right panel displays the relationship between mean thickness of the cluster and BRIEF scores in patients with 22q11DS and controls.

Fig. 3

a Relationship between performance on the CPT-IP and cortical thickness in patients with 22q11DS vs. controls. Whole-brain vertex-wise analysis revealed a significant group by task interaction in the right pars orbitalis region of the IFG (cluster size 919.46 mm², p < 0.05, corrected), indicating that the relationship between CPT-IP performance, as assessed by d-prime, and thickness in this region differs between patients with 22q11DS and controls. In patients with 22q11DS, increased cortical thickness in the IFG was associated with higher d-prime scores, whereas in controls, increased cortical thickness in this region was associated with lower d-prime scores. b Relationship between performance on the TRT and cortical thickness in patients with 22q11DS vs. controls. Whole-brain vertex-wise analyses revealed a significant group by task interaction in the right precentral gyrus (cluster size 1,434.62 mm², p < 0.05, corrected), indicating that the relationship between TRT and thickness in this region significantly differs between patients with 22q11DS and controls. In patients with 22q11DS, increased cortical thickness in the precentral gyrus was associated with higher accuracy scores, whereas in controls, increased cortical thickness in this region was associated with lower accuracy scores.