Neural substrates of inhibitory control deficits in 22q11.2 deletion syndrome

Abstract

22q11.2 deletion syndrome (22q11DS) is associated with elevated levels of impulsivity, inattention, and distractibility, which may be related to underlying neurobiological dysfunction due to haploinsufficiency for genes involved in dopaminergic neurotransmission (i.e. catechol-O-methyltransferase). The Stop-signal task has been employed to probe the neural circuitry involved in response inhibition (RI); findings in healthy individuals indicate that a fronto-basal ganglia network underlies successful inhibition of a prepotent motor response. However, little is known about the neurobiological substrates of RI difficulties in 22q11DS. Here, we investigated this using functional magnetic resonance imaging while 45 adult participants (15 22q11DS patients, 30 matched controls) performed the Stop-signal task. Healthy controls showed significantly greater activation than 22q11DS patients within frontal cortical and basal ganglia regions during successful RI, whereas 22q11DS patients did not show increased neural activity relative to controls in any regions. Using the Barratt Impulsivity Scale, we also investigated whether neural dysfunction during RI was associated with cognitive impulsivity in 22q11DS patients. RI-related activity within left middle frontal gyrus and basal ganglia was associated with severity of self-reported cognitive impulsivity. These results suggest reduced engagement of RI-related brain regions in 22q11DS patients, which may be relevant to characteristic behavioral manifestations of the disorder.

Keywords: fronto-basal ganglia; impulsivity; response inhibition; velocardiofacial syndrome.

Figure 1.

fMRI activity maps during performance of the Stop-signal task. Blue maps represent control activity, green maps represent 22q11DS patient activity, and red maps represent the between-group contrast of Controls > 22q11DS patients. Brain orientations are labeled such that S = superior, I = inferior, P = posterior, and A = anterior; R = right and L = left. (a) Activation maps represent the contrast of Stop Successful-Go, to investigate activity related to successful stopping. (b) Activation maps represent the contrast of Go-Null, to investigate activity related to response initiation. (c) Activation maps represent the contrast of Stop Unsuccessful-Stop Successful, to investigate activity related to inhibition failure.

Figure 2.

Relationship between response inhibition-related neural activity and cognitive impulsivity in 22q11DS. The X-axis values represent the residuals of the Cognitive Impulsivity subscore of the Barratt Impulsivity Scale and the Y-axis values represent the residuals for percent signal change during Stop Successful-Go within the following anatomically defined ROIs (after adjusting for age and years of education), which are displayed next to the corresponding plot: (a) left middle frontal gyrus, (b) right putamen, (c) right caudate, and (d) left thalamus. In the partial regression, the residuals (or errors of prediction) represent the parts of our variables of interest that are not predicted by age or gender. Brain orientations are labeled such that S = superior, I = inferior, P = posterior, and A = anterior; R = right, and L = left.