I. INTRODUCTION
4. Cognitive phenotype of 22q11DS
4.1. Focus on attention & executive functions
As often described in the context of neurodevelopmental disorders, attention and executive functions (EF) are points of weakness in 22q11DS. First of all, attention deficits are particularly frequent in 22q11DS, since 37-45% of individuals meet the criteria for ADHD and high rates of ADHD in adults (16-35%) suggest a persistence with age (Gothelf et al., 2013; Kates et al., 2019; Schneider, Debbané, et al., 2014; Young et al., 2011). The presentation of ADHD in 22q11DS is slightly different from idiopathic ADHD with higher rates of 22q11DS patients meeting the criteria for inattentive presentation (61-79% in 22q11DS vs. 38-57% in idiopathic ADHD) (Antshel et al., 2007; Niarchou, Martin, Thapar, Owen, & van den Bree, 2015;
Schneider, Debbané, et al., 2014; Willcutt, 2012). Moreover, because of the higher expression of the inattentive symptoms, deficits are more difficult to recognize or sometimes attributed to other origins such as low intellectual efficiency or learning disabilities, delaying diagnostic and proper care (Reilly, Senior, & Murtagh, 2015).
In terms of attentional cognitive processes, a study aimed at characterizing the neurocognitive profile of participants with 22q11DS demonstrated a deficit in sustained attention in 26 children and adolescents (Lewandowski, Shashi, Berry, & Kwapil, 2007). Similarly, de Sonneville et al.
(2018) found that 58 children and adolescents with 22q11DS scored below the norm on measures of alertness and sustained attention using a computerized battery (Amsterdam Neuropsychological Task). Finally, in a multicentric study of 236 participants diagnosed with 22q11DS aged 6 to 60 years, Morrison et al. (2020) demonstrated a deficit in sustained attention, observable from childhood to adulthood, remaining static over developmental stages.
Altogether, maintaining attention over long periods of time seem to be mostly affected in 22q11DS, matching the predominantly inattentive symptoms of ADHD described in the literature. Interestingly, impairment in sustained attention is demonstrated at the group level, independently of a diagnosis of ADHD.
Regarding EF, the profile of 22q11DS is less well defined, probably due to the complexity of this topic. Broadly defined, EF are considered to be a collection of related but distinct higher order abilities that allow us to formulate goals, plan how to achieve them, and carry them out successfully (Anderson & Reidy, 2012; Diamond, 2013; Miyake et al., 2000). When studying EF, two major challenges arise. First of all, although several models have been suggested in the literature, they generally agree on the fact that EF is not a unitary construct (Diamond, 2013;
Miyake et al., 2000). EF rather represents an “umbrella” term including multiple sub-domains such as inhibition, updating, shifting or planning. Secondly, EF depend partially on the frontal regions of the brain, whose maturation is protracted (compared to other cognitive function) and extends from childhood into early adulthood (Romine & Reynolds, 2005; Sousa, Amaro, Crego, Gonçalves, & Sampaio, 2018). Additionally, in the general population different sub-domains of EF have been demonstrated to mature at different pace (Akshoomoff et al., 2014; Anderson, 2002; Best & Miller, 2010).
According to this, in the literature on 22q11DS, previous studies have used a wide range of different methodologies and samples, yielding sometimes contradictory findings and an inconclusive overall profile. A recent meta-analysis including 43 papers confirmed a moderate to large EF deficit in 22q11DS (Moberg et al., 2018). More specifically, various isolated components of EFs have been examined in the literature. The authors highlighted deficits in inhibition (McCabe et al., 2014; Shapiro, Wong, & Simon, 2013), working memory (Azuma et al., 2009; Majerus, Van der Linden, Braissand, & Eliez, 2007; Montojo et al., 2014) and more sophisticated skills such as multitasking (Schneider et al., 2016). However, only a few studies have examined different components of EF using different tasks in the same population to refine the profile of deficit. L. E. Campbell et al. (2010) evaluated a broad spectrum of EF components in 50 participants aged 6 to 16 years old with 22q11DS. They highlighted difficulties in finding an alternative solution to a problem (cognitive flexibility), a longer time to initiate problem solving and poorer planning of steps to reach a goal, a shorter verbal span, and poor performance in spatial working memory. Moreover, apart from a slight tendency to premature responses (impulsivity), they did not show any difference in the inhibition tasks compared to the control group. Despite a considerable effort to better describe performance on different executive tasks, a main limitation of this study is that it examines a very wide age range (6 to 16 years). Indeed, because EF develop late and partially depend on the maturation of the frontal areas of the brain (Sousa et al., 2018), skills are at different stages of development when assessed. Although the authors ensured that the average age of the groups was comparable, the effect of age on the results was not taken into account. Shapiro, Tassone, Choudhary, & Simon (2014) describe the development of EF in children and adolescents with 22q11DS aged 7 to 14 years old. The authors evaluated 71 individuals with 22q11DS and 52 healthy controls using different tasks assessing the three components of EFs suggested by Miyake and colleagues:
inhibition, updating and flexibility (Miyake et al., 2000). They found lower performance in all
the domains assessed in individuals with 22q11DS, even when controlling for intellectual level.
In their study, they also observed atypical trajectories of development of inhibition and cognitive flexibility with age. Conversely, the development of working memory measures seemed to follow the same trajectory as that of the control participants. This study suggests that the development of EF in 22q11DS is relatively complex and not simply related to developmental delay. Indeed, the results indicate that different components of EF have different trajectories, as is also the case in the general population (e.g., Akshoomoff et al., 2014;
Anderson, 2002). However, the cross-sectional design of the study as well as the restricted age examined (7 to 14 years) limits the scope of possible conclusions on an actual developmental trajectory of these processes.
Taken together, previous results demonstrate the value of examining multiple components of attention and EF in the same sample to fully grasp the extent of impairment and further delineate the neuropsychological profile. The restricted age range and the cross-sectional design adopted also highlights the necessity for a longitudinal approach in the study of attention and EF in the context of neurodevelopmental disorders such as 22q11DS.