The main goals of the present study were to describe executive dysfunction in 22q11.2DS, to examine developmental patterns in the syndrome compared to controls as well as the influence of psychotic symptoms on these patterns, and to identify the predictive value of EF on adaptive functioning. To achieve these goals, we used multiple measures of EF to describe the development of working memory, inhibition, and verbal fluency in a longitudinal study of 22q11.2DS individuals and healthy controls ages 6 to 26.
Atypical developmental trajectories of specific EF domains
Lower performance was observed on all EF variables for participants with 22q11.2DS compared to controls. In the 22q11.2DS group, atypical developmental trajectories were observed for working memory and verbal fluency, whereas the shape of the inhibition measures’ trajectories did not differ between the two populations. These EF impairments are commensurate with previous studies examining working memory and inhibition [20, 22]; however, to our knowledge, this is the first study reporting verbal fluency alterations in the syndrome.
Development of verbal fluency
In typically developing children, verbal fluency, measured by the number of words produced during a specific time lap, improves with age  until 13 to 15 years old [1, 48]. Similarly, in our control sample, we observed a gradual increase in performance on the verbal fluency task, though we did not observe a peak around mid-adolescence (13–15 years). One possible explanation for this difference could be that a group of older controls with very high scores influenced the trajectory of our control group. By contrast, improvement with age in the 22q11.2DS group was minimal, suggesting that as affected individuals get older, their strategies to successfully initiate and produce words from a semantic category do not progress as quickly as for controls. Interestingly, our sample groups performed similarly on the verbal fluency task during childhood (6–8 years old) before between-group differences became greater with age, a seemingly banal observation that deserves careful consideration given that non-executive aspects (verbal memory disorders or lowered psychomotor speed) can affect verbal fluency (e.g., ). To ensure that the results reported here are mostly due to executive dysfunction, and not due to a lower lexical level in participants with 22q11.2DS, we conducted a secondary analysis on vocabulary performances. We observed different patterns of development for the word fluency task and the vocabulary task. This indicates that even though the lexical level of the 22q11.2DS group is significantly lower than controls, the developmental path is similar between both groups (see Table 3 and Fig. 1). Trajectories for both groups displayed a gradual increase in raw scores until the age of 20, indicating that the lexical stock in the 22q11.2DS group increases at the same pace as in the control group. The results observed for the vocabulary task are in contrast with the developmental trajectories obtained for the verbal fluency task, which exhibited a significant difference in shape. As displayed in Fig. 1, there was only a minimal improvement with age in the 22q11.2DS group. This implies that even though their lexical stock increases with age, the number of words correctly produced during the verbal fluency test remains (approximately) identical. Altogether, this analysis suggests that the atypical trajectory observed for the verbal fluency task reflects, at least partially, an executive dysfunction even though it is not a pure executive measure. A qualitative analysis of the productions (i.e., clustering of words, switch between clusters) would be an informative addition to future studies [48, 50].
Development of working memory
Verbal working memory, measured by a number repetition task (backward digit span), is another EF domain explored longitudinally in the present study. Our participant groups differed in the shape of their development on verbal working memory measures, indicating that this domain develops atypically in 22q11.2DS compared to controls. However, similar to the verbal fluency results, while the younger children (6–8 years old) were not especially different from the controls, participants with 22q11.2DS tended to reach a developmental plateau much faster than controls. These results contrast with previous findings suggesting that working memory develops typically within the syndrome (i.e., weaker performance but same progression as in the control group) . This difference may be related to two important methodological discrepancies with Shapiro et al.’s study. First, the limited age range in the previous study (7 to 14 years old) may have made it difficult to observe changes occurring later in life. This is in accordance with our result that younger children with 22q11.2DS performed similarly to their typically developing peers on working memory tasks. Without the inclusion of older adolescents and adults in our sample, we would not have observed a developmental plateau in working memory. Second, Shapiro et al. adopted a cross-sectional design, which may have prevented the detection of atypical developmental trajectories in the 22q11.2DS group.
Development of inhibition
The final EF domain investigated in the present study was inhibition, which was evaluated using measures of the cognitive cost of inhibition (Stroop ratio) and impulse control (CPT commission errors and hit reaction time). The performance of 22q11.2DS participants on the inhibition measures exhibited a shape resembling that of controls, despite the fact that the 22q11.2DS group’s scores were significantly lower than those of the controls (i.e., significant intercept difference). Specifically, the pattern emerging from our analyses depicted an increase in inhibition capacities with age in 22q11.2DS, echoing what is observed in the control group. These results are in contradiction with previous findings reporting atypical developmental of inhibition in 22q11.2DS . However, the methodological differences between the two studies (age range, task differences, longitudinal design) may, once again, account for these discrepancies. The same group of authors published a previous study examining the development of inhibition using a task that differentiated between the processes underlying response inhibition (proactive, reactive) . The authors reported significant differences between these processes suggesting that the mechanisms underlying inhibition might be affected unevenly in the syndrome. In light of these previous findings, it may be that our tasks tap different underlying constructs than the tasks used by Shapiro et al. Future studies examining the different components of inhibition longitudinally would help explain these discrepancies.
In summary, our first hypothesis was only partially supported. 22q11.2DS individuals were impaired on all three EF domains compared to controls but exhibited atypical development on only two of those domains (working memory and verbal fluency).
Role of intellectual disability on EF measures
Post hoc analyses allowed us to disentangle the influence of intellectual disability on EF tasks in the present study. Even when individuals meeting the criterion for intellectual disability (full-scale IQ lower than 70 points) were removed from the 22q11.2DS sample, the trajectories of working memory, verbal fluency, and cognitive inhibition remained unchanged. This indicates that the different developmental trajectories (differences in shape) of working memory and verbal fluency between 22q11.2DS and controls are not only a by-product of intellectual disability. Furthermore, the intercept difference for the cognitive inhibition measure indicates a specific deficit rather than a consequence of intellectual disability. On the other hand, the developmental trajectory of motor inhibition (CPT commission errors and hit reaction time) no longer differed between the two groups, after the exclusion of individuals with intellectual disability. This lack of difference indicates that individuals affected by 22q11.2DS with an IQ higher than 70 have comparable motor inhibition than controls and that the subgroup with an IQ below 70 was probably driving the observation of poor impulse control.
Interestingly, when compared against each other, the 22q11.2DS subgroups did not significantly differ on EF measures, except for verbal fluency. A possible explanation for this result is that, as already mentioned before, verbal fluency is greatly influenced by non-executive functions that are also measured in IQ scales (e.g., vocabulary). Nevertheless, the fact that the higher than 70 subgroup performed differently than controls indicates that verbal fluency is impaired in 22q11.2DS.
Relationship between executive dysfunctions and psychotic symptomatology
By comparing trajectories of individuals who displayed psychotic symptoms at any time point to those who did not, we found a link between certain executive domains and negative symptoms. Specifically, both for inhibition and working memory, performance of individuals with or without psychotic symptoms were very similar in childhood. However, improvement of these two processes with age was minimal for individuals with negative symptoms, whereas the group without symptoms improved significantly and regularly. These results seem to indicate that EF dysfunction exists prior to the onset of negative symptoms. On the opposite, no association was found with positive symptoms.
Hereby, we replicated that EF dysfunctions are specifically associated with the emergence of negative symptoms, whereas they are independent of positive symptoms in patients with schizophrenia [26, 28]. Also, these results are in line with a previous study by our group in 22q11.2DS, showing that negative symptoms were associated with deficits in multitasking skills . In the present study, specific associations were found with the inhibition and working memory domains, which are involved in maintaining goals in memory and purposely implementing them at the right moment (e.g., in resisting dominant action scheme). It suggests that these processes could underlie the development of negative symptoms and is in accordance with previous conceptualizations of negative symptoms as a “pathology” of goal-directed behavior . However, this hypothesis should be further examined, and these results need to be interpreted with caution since only a few aspects of EF were examined in the present study. In fact, positive symptoms could be influenced by an atypical development of other executive domains not considered in the scope of this article.
EF and adaptive functioning
Contrary to our second hypothesis, we found no relationship between EF measures and adaptive functioning scores. It is possible that the absence of significant relationship is at least partially explained by our choice of EF tasks. Indeed, difficulties experienced in a test situation are not directly related to difficulties observed in the real world, such as those assessed in the VABS inventory . Furthermore, examining only one process at the time, in a controlled experimental setting, free from distraction, may not be representative of day-to-day tasks that require the simultaneous use of several EF domains. For this reason, questionnaires targeting behavioral aspects of EF in a naturalistic context (i.e., Behavior Rating Inventory of Executive Functions (BRIEF) ) are usually poorly related to cognitive measures of EF in different clinical populations (i.e., ). In the field of 22q11.2DS, our group previously showed that poor multitasking abilities, as measured during a naturalistic experimental paradigm, were significantly associated with the VABS daily living skills domain . Indeed, failure to multitask effectively may be a bigger hindrance to functional impairment than intellectual disability. These results indicate that to fully understand EF deficits in 22q11.2DS and to develop targeted interventions, it is necessary to use multiple measures with ecological validity to target core aspects of EF (i.e., inhibition, updating, cognitive flexibility).
Limits, future directions, and clinical implications
Our work is not without critical limitations. First of all, the EF tasks used in the present study were selected retrospectively from a large longitudinal dataset. The chosen EF tasks involve other aspects of cognition and are not “pure” measures of EF. For example, working memory was only evaluated on its verbal component, whereas the visuospatial component is also very important. Furthermore, data on significant aspects of EF, such as cognitive flexibility or planning skills, were not available longitudinally, despite the fact that they are reported as weaknesses in this syndrome [16, 22]. Given that two out of the three investigated domains showed atypical development, other domains could be affected too. Future research should focus on collecting longitudinal data on a larger sample of tasks that specifically target and isolate EF domains. Furthermore, it would be important to integrate measures or questionnaires with ecological validity to truly capture the executive profile of this specific population. Finally, as illustrated in the current study, a great variability between individuals with 22q11.2DS was observed on the executive tasks. This heterogeneity begs the question of how to identify and characterize subgroups within the 22q11.2DS population. Future research should investigate this aspect in order to create more specific interventions.
Clinical implications of the results presented here are various. First of all, the data reported in this paper suggest that young children with 22q11.2DS (6–8 years old) have comparable performance to controls in some executive domains, but the gap between both groups widens progressively during adolescence. Furthermore, different executive domains do not display similar developmental patterns. Therefore, regular comprehensive neuropsychological assessments of EF should be conducted with individuals affected by 22q11.2DS to identify specific impairments. Secondly, if executive dysfunction is highlighted, specific interventions as well as environmental improvements could be implemented (e.g., planning and organization flowcharts, minimizing environmental interferences, break down information in small chunks). Finally, it remains to be examined whether cognitive remediation programs performed during childhood and focusing on EF have a beneficial impact on the development of EF later in life.