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also observed in patients with 22q11.2 DS, exacerbating their cognitive incapacity to represent others mental states by reading facial traits and respond accurately to social cues [55].
Although many studies of 22q11.2 DS describe impairments in higher-order cognitive processes, such as working memory and executive function [56, 57], there is evidence that, in this disorder, deficits manifest also at early stages of sensory processing during both visual and auditory tasks [9, 10]. Since the auditory sensory processing is a main topic of this thesis, a summary of auditory deficits observed in both 22q11.2 DS and schizophrenia will be presented in detail in Chapter 3.
1.3 The neuropsychiatric profile of individuals with 22q11.2 DS
The individuals with 22q11.2 DS express abnormal cognitive and social functioning, as well as neuroanatomical alterations, being one of the highest genetic risk factors for the development of neuropsychiatric disorders [19, 23, 28].
The 22q11.2 deletion carriers present disruptions across multiple symptom domains, and therefore the accurate characterization of the neuropsychiatric profile requires multi-dimensional assessment that contains various aspects of cognitive and emotional processing impairments. Notably, in a recent review of 15 studies and 1402 participants, Schneider and colleagues (2014), described the most common psychiatric conditions observed in this population and their prevalence across age [7]. The most prevalent paediatric neuropsychiatric disorders are attention deficits (37%), autism spectrum (12%), mood and anxiety disorders (38%). They observed that attention deficit disorder (ADHD) and oppositional defiant disorder (ODD) are overrepresented in males and are diagnosed more frequently during childhood, while autism spectrum disorder seems to be highly expressed both during late childhood and adolescence.
On the contrary, schizophrenia spectrum disorder was expressed mostly during adulthood being present in 25% of the emerging adults (18 to 25 years old), and 41% of the adults [7].
Furthermore, neuropsychiatric diagnoses, such as anxiety and ADHD, may serve as premorbid signs for later development of schizophrenia spectrum disorder [58, 59]. A summary is provided in Figure 2.
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Figure 2. The neuropsychiatric phenotypes in 22q11.2 deletion syndrome and the estimated comorbidity rates across disorders. The most common psychiatric conditions observed in this population and their prevalence across ages, including attention-deficit/hyperactivity disorder (ADHD), anxiety disorders, psychosis, schizophrenia, and autism spectrum disorder (ASD). Adapted from R.K. Jonas et al. 2014.
ADHD
The attention deficits characterize most of the individuals with 22q11.2 DS (37%).
Although, ADHD is the most common psychiatric disorder, the clinical presentation in 22q11.2 DS differ from the one measured in idiopathic ADHD. The 22q11.2 DS deletion carriers exhibit higher rates of ADHD inattentive subtype associated with higher rate of generalized anxiety disorder, and fewer hyperactive-impulsive symptoms compared to the clinical group [60].
Niarchou et al. (2018) examined longitudinally a large cohort of 22q11.2 deletion carriers to clarify the potential role of ADHD inattention symptoms in psychosis development in 22q11.2 DS. The authors observed a positive association between inattention symptoms and positive, negative and disorganized symptoms [59].
However, a recent longitudinal study [61] found a reduced persistence of ADHD symptoms from childhood to adolescence in 22q11.2 DS ( only 15%) predicted by increased rates of familial ADHD and history of childhood depression, suggesting that additional factors, like family history and psychiatric co-morbidities, may also play a role in the psychosis proneness alongside with inattention symptoms.
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Anxiety and depression
Anxiety disorders are often reported to be highly prevalent, both in schizophrenia (10 to 15 %) [62] and in individuals with 22q11.2 deletion syndrome (38%) [7], although the rates highly vary across studies. Symptoms of anxiety or depression are more frequently observed in the pediatric population with 22q11.2 DS and together with the COMT genotype are significant early childhood predictors for the later development of psychotic symptoms [46]. This may imply that genetic factors may predispose 22q11.2 deletion carriers to express a wide range of psychiatric phenotypes defined by anxiety or attention deficits early in development that may change into psychotic symptomatology during adolescence and youth.
Nevertheless, patients carrying the 22q11.2 deletion often express a mixed symptomatology from different disorders. Even with a clear diagnosis of depression, they often express comorbidities, such as anxiety or ADHD and thus, classifications into distinct categories defined as “anxiety”, “psychosis”’ or “depression” are unrealistic and to a large extent unhelpful for the development of future interventions [63].
Schizophrenia spectrum disorder and psychosis
Schizophrenia spectrum disorders are also highly prevalent in patients with 22q11.2 DS affecting approximately 10% of the adolescents, 25% of the emerging adults (18 to 25 years old), and 41% of the adults [7].
Figure3. The prevalence of schizophrenia spectrum disorders across ages in 22q11.2 deletion carriers. Adapted from Schneider et al., 2014 [7].
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Some studies suggest that up to 80% of the deletion carriers experience subthreshold positive and negative psychotic symptoms, with the positive symptoms being experienced by 30 to 60%
of adolescents, while the negative symptoms being present in 60 to 80% of adolescents and young adults with 22q11.2DS [7, 58]. Nevertheless, a recent multisite study part of the International 22q11.2 Deletion Syndrome Brain Behavior Consortium (IBBC) using the largest cohort (760 participants aged 6–55 years) investigated the development of subthreshold psychotic symptoms by age groups, and their association with cognitive deficits. The authors reported that 32.8% of participants met criteria for positive subthreshold psychotic symptoms, 21.7% of participants met criteria for negative subthreshold psychotic symptoms and 25.6%
met criteria for both positive and negative/disorganized subthreshold psychotic symptoms.
Further, the most prevalent subthreshold symptoms were the negative (poor ideational richness, avolition, and low occupational functioning) and disorganized (trouble with focus and attention) subthreshold symptoms [64].
There are evidence that positive and negative symptoms may underlie distinct physiological abnormalities.
The most characteristic positive symptoms are hallucinations or false perceptions, and delusions or persistent irrational beliefs. In schizophrenia, one common mechanism proposed to explain the positive symptoms involves the prediction error signal. This signal reflects processes like perception and inference, and thus abnormal mechanisms of prediction error may cause both false perceptions and irrational beliefs [65].
In 22q11.2 the prediction error mechanisms have not yet been investigated, and thus positive symptoms are explained mostly by neuroanatomical deficits, such as abnormal maturation of auditory thalamocortical connectivity [66] and hippocampal volume decrease during late adolescence [67].
The most characteristic negative symptoms are divided in two main domains: avolution/apathy and diminished expression of emotion and speech (alogia) [68]. In schizophrenia, the first domain has been proposed to underlie impairments in various dimensions of motivation [69], while the second domain has been proposed to underlie impairments in emotion perception (for blunted affect) [70] and reduced cognitive resources (for alogia) [71].
In 22q11.2 DS, the negative symptoms are also divided in two domains as shown by Schneider et al. (2012). Applying a factor analysis, the authors revealed two main domains related to negative symptomatology: the lack of motivation and impoverished emotional expression [72].
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Importantly, the negative symptoms in 22q11.2 DS might impact negatively daily-life functioning through reduced motivation towards goal-directed activities [72, 73] and verbal initiation impairment [74].
Predictors of transition to psychotic disorders and ages of onset in 22q11.2 deletion carriers have been reported to be similar with those from idiopathic psychosis populations [75, 76].
Additionally, impairments in various cognitive domains, as well as neuroanatomical abnormalities measured in 22q11.2 DS, are comparable with those measured in non-deleted clinical risk populations[77].
The 22q11.2 deletion carriers experience also a broad range of sensory processing impairments, like reduced mismatch response, a marker of prediction error, similar to those measured in schizophrenia which develop years before the full emergence of the disorder [4-6].
Consequently, the 22q11.2 DS provides the researchers the opportunity to investigate the neurobiological and functional changes preceding the onset of the schizophrenia and further, to identify markers that might guide early diagnosis and intervention in the near future.
1.4 Brain abnormalities of individuals with 22q11.2 DS