Open questions and thesis objectives

In the previous sections, we have established that 22q11DS has a broad but unique phenotype, clearly distinguishable from other genetic conditions or idiopathic intellectual disability. The singularity of the cognitive profile has also been demonstrated and similarities with cognitive impairments found in other neurodevelopmental disorders (such as schizophrenia or ADHD) are described. In this thesis we focus on two features of the cognitive profile (executive functions and memory) as well as the benefits of a stimulant medication in 22q11DS.

7.1. Extending knowledge on executive function and attention

The literature reviewed in the previous sections clearly point toward impairment of EF and attention in 22q11DS. However, due to the complex nature of EF, with evidence for fractionation (Miyake et al., 2000), one question remains: is 22q11DS associated with an overall EF impairment, or are some sub-domains of EF more impaired than others? To answer this question, it appears necessary to explore multiple sub-domains in one sample of participants to get a more accurate picture of the cognitive profile.

Altered brain maturational process of frontal regions during adolescence points toward an atypical developmental trajectory of EF and attention processes (Ramanathan et al., 2017;

Schaer et al., 2009). Previous evidence from the literature suggest that the cognitive impairment observed depends both on age and on the domain examined (Morrison et al., 2020; Shapiro et al., 2014). However, results are limited by a cross-sectional approach with either a small age range or using age as a categorical variable. Together, these results demonstrate the necessity to move past group comparisons (22q11DS vs. healthy controls) and instead consider trajectories of maturation of cognitive processes with age from childhood to early adulthood.

How does different sub-domains of EF develop with age? Do they follow similar developmental patterns? Will different tasks, targeting the same cognitive domain, yield different developmental patterns?

With Study 1, the first aim was to to delineate the developmental trajectories with age of multiple EF domains in a longitudinal sample using a broader age range than previous studies.

Given the high incidence of psychotic symptoms in 22q11DS, a second aim was to compare the development of EF in participants with/without comorbid psychotic symptoms. Finally, as third aim, association of EF deficits and adaptive functioning was explored. This work is however limited by a small number of cognitive sub-domains explored, yielding only a partial view of the overall developmental profile of EF and attention in 22q11DS.

With Study 2 the aims were not only to confirm but further extend previous findings on the developmental trajectories of EF and attention in 22q11DS. By exploring additional sub-domains using several tasks per domain in a broader age range, results provide a more reliable overview of patients’ cognitive profile. Additionally, the results of this second study also give us the opportunity to reflect on clinical implications for 22q11DS. Indeed, identifying developmental patterns in a specific domain (developmental deficit, lag, deterioration or

maturation) is crucial to set up age-appropriate guidelines and recommendations for evaluation, as well as select appropriate intervention strategies (such as compensation or remediation).

7.2. Extending knowledge on memory

As reviewed earlier, several studies have investigated memory functioning in 22q11DS showing overall a mild impairment of non-verbal memory (possibly influenced by sub-optimal memory acquisition) and relatively preserved verbal memory (L. E. Campbell et al., 2010;

Lajiness-O’Neill et al., 2005). However, reports from 22q11DS carriers and their families challenge the general assumption of spared verbal memory, pointing to forgetfulness and memory loss over time. This contrast leads to the following questions: are the available standardized tests really representative of “long-term” memory performance? Does 22q11DS patients have difficulties remembering after long delays (superior to 30 minutes)? Furthermore, previous literature specifically measuring forgetting suggests a difficulty suppressing irrelevant verbal information during retrieval, leading to memory dysfunction (Debbané et al., 2008).

Thus, open questions are: what kind of tools do we need to investigate patterns of forgetting over time? What does the trajectory of memory retention look like in 22q11DS? And what cognitive mechanisms sustain faster forgetting in this population?

With Study 3, we created a new memory assessment tools to suit our research question enabling us to investigate memory retention over an extended time span (thirty minutes, one day, one week and one month) and study rates of forgetting. The first aim was to investigate memory retention over time in 22q11DS and healthy controls. Due to the deficit reported in visuo-spatial processes, possibly influencing the encoding of visual information, we focused on the verbal modality. The second aim was to determine whether subgroups of patients could be identified based on their verbal memory retention profile. Finally, the third aim was to investigate neural correlates of the behavioral findings. While the results from this study demonstrated faster forgetting in 22q11DS participants (compared to healthy controls), the underlying cognitive

processes responsible for faster forgetting remained unclear. It was suggested that deficient memory consolidation and reconsolidation processes were involved. However, due to the design of the study including multiple retrieval opportunities (four recalls), higher rates of forgetting could result from impaired retrieval of memories or reflect increased sensitivity to interference through reconsolidation processes.

In Study 4, we created another version of the task previously used in Study 3, by removing intermediate delays in time, and only keeping retrieval after thirty minutes and one month. The first aim was to examine retrieval without interference of reconsolidation processes. The second aim was to examine the impact of reconsolidation on forgetting rates after a one-month delay by comparing performance in both designs (original design from Study 3 and new design from Study 4).

7.3. Intervention using medication

In the last part of this work, we explore one intervention possibility, namely using stimulant medication to improve EF, attention and memory. As previously mentioned, despite the high prevalence for psychopathology, patients with 22q11DS are rather undertreated for their psychiatric illnesses (Tang et al., 2014). Furthermore, only few studies have investigated the safety and effectiveness (short or long-term) of medication frequently prescribed in 22q11DS leaving clinicians with only limited knowledge. More specifically with regard to stimulant, despite the very high proportion of ADHD observed in 22q11DS and treatment recommendation including stimulants (NICE guidelines, 2018), only two studies have investigated the safety and effectiveness of methylphenidate in 22q11DS. Furthermore, samples were very small and limited cognitive domains were examined. Therefore, it remains to be investigated if MPH is a valuable medication to consider in 22q11DS? Does MPH improve all cognitive domains or is there a specificity in the effects?

With Study 5, we aimed to investigate the benefit of methylphenidate on core symptoms of ADHD, cognitive measures and daily-life functioning with questionnaires. Compared to previous studies, we explored the effects on a broader range of cognitive measures including attention, EF and memory.