Using transcranial alternating current stimulation to enhance working memory skills in youths with 22q11.2 deletion syndrome: A randomized double-blind sham-controlled study.

Abnormal cognitive development, particularly working memory (WM) deficits, is among the first apparent manifestations of psychosis. Yet, cognitive impairment only shows limited response to current pharmacological treatment. Alternative interventions to target cognition are highly needed in individuals at high risk for psychosis, like carriers of 22q11.2 deletion syndrome (22q11.2DS). Here we applied theta-tuned transcranial alternating current stimulation (tACS) between frontal and temporal regions during a visual WM task in 34 deletion carriers. We conducted a double-blind sham-controlled study over three consecutive days. The stimulation parameters were derived from individual structural MRI scan and HD-EEG data acquired at baseline (Day 1) to model current intensity and individual preferential theta peak. Participants were randomized to either sham or tACS (Days 2 and 3) and then completed a visual WM task and a control task. Our findings reveal that tACS was safe and well-tolerated among participants. We found a significantly increased accuracy in the visual WM but not the control task following tACS. Moreover, this enhancement in WM accuracy was greater after tACS than during tACS, indicating stronger offline effects than online effects. Our study therefore supports the application of repeated sessions of brain stimulation in 22q11.2DS.

Altered developmental trajectories of verbal learning skills in 22q11.2DS: associations with hippocampal development and psychosis.

BACKGROUND: The cognitive profile in 22q11.2 deletion syndrome (22q11.2DS) is often characterized by a discrepancy between nonverbal vs. verbal reasoning skills, in favor of the latter skills. This dissociation has also been observed in memory, with verbal learning skills described as a relative strength. Yet the development of these skills is still to be investigated. We thus aimed to explore verbal learning longitudinally. Furthermore, we explored verbal learning and its respective associations with hippocampal alterations and psychosis, which remain largely unknown despite their high prevalence in 22q11.2DS. METHODS: In total, 332 individuals (173 with 22q11.2DS) aged 5-30 years completed a verbal-paired associates task. Mixed-models regression analyses were conducted to explore developmental trajectories with threefold objectives. First, verbal learning and retention trajectories were compared between 22q11.2DS vs. HC. Second, we examined hippocampal volume development in 22q11.2DS participants with lower vs. higher verbal learning performance. Third, we explored verbal learning trajectories in 22q11.2DS participants with vs. without positive psychotic symptoms and with vs. without a psychotic spectrum disorder (PSD). RESULTS: Our findings first reveal lower verbal learning performance in 22q11.2DS, with a developmental plateau emerging from adolescence. Second, participants with lower verbal learning scores displayed a reduced left hippocampal tail volume. Third, participants with PSD showed a deterioration of verbal learning performance, independently of verbal reasoning skills. CONCLUSION: Our study challenges the current view of preserved verbal learning skills in 22q11.2DS and highlights associations with specific hippocampal alterations. We further identify verbal learning as a novel cognitive marker for psychosis in 22q11.2DS.

Effects of risperidone on psychotic symptoms and cognitive functions in 22q11.2 deletion syndrome: Results from a clinical trial.

Background: Carriers of the 22q11.2 deletion syndrome (22q11DS) have an enhanced risk of developing psychotic disorders. Full-blown psychosis is typically diagnosed by late adolescence/adulthood. However, cognitive decline is already apparent as early as childhood. Recent findings in mice show that antipsychotic medication administered during adolescence has a long-lasting neuroprotective effect. These findings offer promising evidence for implementing preventive treatment in humans at risk for psychosis. Methods: We conducted a 12-week double-blind randomized controlled clinical trial with individuals with 22q11DS. Recruitment difficulties resulted in a final sample size of 13 participants (n = 6 treated with antipsychotics and n = 7 receiving placebo). We examined the response to treatment and assessed its short- and long-term effects on psychotic symptomatology using the Structured Interview for Psychosis-Risk Syndromes (SIPS) and cognitive measures. Results: First, two treated participants discontinued treatment after experiencing adverse events. Second, treated participants showed a short-term improvement in 33.3% of the SIPS items, mainly those targeting negative symptoms. Third, reliable improvements in at least one measure of working memory and attention were respectively found in 83.3 and 66.7% of treated participants. Conclusion: This is the first double-blind study to investigate the potential neuroprotective effect of antipsychotics in humans at risk for psychosis. Our preliminary results suggest that antipsychotic treatment may prevent long-term deterioration in clinical symptoms and cognitive skills. Yet, given the limited sample size, our findings need to be replicated in larger samples. To do so, future studies may rather adopt open-label or retrospective designs to ensure sufficient power. Clinical trial registration: [www.ClinicalTrials.gov], identifier [NCT04639960].

Stimulant treatment effectiveness, safety and risk for psychosis in individuals with 22q11.2 deletion syndrome.

This study aimed to retrospectively evaluate an association between stimulant treatment for attention-deficit/hyperactivity disorder (ADHD) in individuals with 22q11.2DS and the development of psychotic disorders, to evaluate long-term effectiveness and safety of stimulant treatment in individuals with 22q11.2DS compared to individuals with idiopathic ADHD, and to explore effects of catechol-O-methyltransferase (COMT) genotype on 22q11.2DS response to stimulants and risk of side effects. Rates of stimulant use and methylphenidate equivalent exposure were compared among individuals with 22q11.2DS, between 51 with psychotic disorders and a control group of 57 22q11.2DS without psychotic disorders, from Tel Aviv and Geneva. In addition, 44 individuals with 22q11.2DS and ADHD from Tel Aviv who initiated stimulants before age 18 years were compared to a control group of 35 age- and sex-matched controls with idiopathic ADHD, for treatment effectiveness (Clinical Global Impression Scale-Improvement), and rates of side effects. Stimulant use history and methylphenidate equivalent exposure did not differ among individuals with 22q11.2DS, between those with and without psychotic disorders. The long-term retrospective follow-up (5.3 ± 4.1 years) of stimulant-treated individuals with 22q11.2DS showed a higher rate of significant clinical improvement of ADHD symptoms, compared to idiopathic ADHD individuals (p = 0.013), and similar side effect rates. There was no effect of the COMT genotype on response to stimulants or on any side effects. This preliminary long-term retrospective analysis suggests that stimulant treatment in 22q11.2DS is apparently safe in terms of psychosis conversion and rates of side effects, and that it is effective in alleviating ADHD symptoms.

Selective Effects of Methylphenidate on Attention and Inhibition in 22q11.2 Deletion Syndrome: Results From a Clinical Trial.

BACKGROUND: Attention deficit and/or hyperactivity disorder (ADHD) is the most prevalent psychiatric disorder in children with 22q11.2 deletion syndrome (22q11DS) and frequently persists into adulthood. Although medication with stimulant has been demonstrated to be highly effective in idiopathic ADHD, evidence in 22q11DS is still scarce. Previous studies have shown safety and effectiveness of methylphenidate (MPH) on core symptoms of ADHD as well as improvement of associated cognitive deficits. However, only a limited number of cognitive domains have been explored. METHODS: Twenty-three participants with 22q11DS and attention difficulties, aged 8-24 years, entered a clinical trial aiming to specify the effects of MPH on clinical symptoms, cognition, and daily-life behavior. The effects of treatment were compared with/without medication in a within-subject design. The trial included both participants naïve to the molecule and chronic users. RESULTS: Benefit from the treatment was demonstrated through a decrease in core ADHD symptoms, specifically inattention symptoms, and improvement of cognitive measures of attention and inhibition. Conversely, no significant change was found for other executive functions (such as cognitive flexibility, working memory, initiation), learning, or memory. Moreover, no significant improvement on ecological measures of daily-life executive functioning was found, possibly because of the short treatment period. We replicated safety, and although very frequent, side effects were of mild intensity and comparable with previous findings. CONCLUSIONS: This study extends the current knowledge on the effects of MPH in patients with 22q11DS. Treatment was found to be effective for core ADHD symptoms and cognitive measures of attention and inhibition.

Age-Related Improvements in Executive Functions and Focal Attention in 22q11.2 Deletion Syndrome Vary Across Domain and Task.

OBJECTIVE: Executive functions (EF) and focal attention have been identified as a weakness in the profile of 22q11.2 deletion syndrome (22q11DS). However, due to a high variety of tasks used across previous studies, it remains unclear whether impairments may be more pronounced for specific subdomains of EF and focal attention. Furthermore, age-related changes have only been examined in a few studies, so far only yielding a partial view of the overall developmental profile. METHOD: In a broad age range (8-35 years) composed of longitudinal data, 183 participants (103 diagnosed with 22q11DS) completed an extensive assessment of EF and attention. To get a more comprehensive overview of specific versus global impairments, several tasks were assessed within multiple domains. RESULTS: Results suggest differential impairments and trajectories in specific EF subdomains. Specifically, our findings suggest that individuals with 22q11DS not only showed lower overall inhibition skills, but also that initiation skills developed at a slower pace compared to healthy controls. Results are less clear regarding cognitive flexibility, updating and focal attention, for which performance strongly depended on the tasks that was selected to assess the domain. CONCLUSIONS: Findings confirm and extend knowledge on differential developmental patterns of EF and attention domains in 22q11DS. They further stress the necessity to administer extensive, multifaceted evaluations to gain a more reliable overview of patients' cognitive profile.

From Learning to Memory: A Comparison Between Verbal and Non-verbal Skills in 22q11.2 Deletion Syndrome.

Background: Previous studies on possible memory deficits in 22q11DS often focused on quantifying the information memorized, whereas learning processes have been mostly overlooked. Furthermore, methodological differences in task design have made verbal and non-verbal comparison challenging and mixed results have been observed depending on chosen stimuli. Method: 135 participants (78 with 22q11DS) completed a multi-trial memory task modeled after the Rey Auditory Verbal Learning Task, comparing verbal and non-verbal learning as well as retention over time. Performance in the 22q11DS group were compared to controls and learning curves were analyzed. Results: In 22q11DS, slower acquisition of non-verbal material and higher rates of errors in both verbal and non-verbal tasks was observed. After 30 min, free recall performance, when corrected for initial learning rate, was similar between 22q11DS and controls. Conversely, recognition performance was overall weaker for 22q11DS in both modalities (verbal and non-verbal). Conclusion: This study examined how information is acquired, retained in memory over time and how different recall modalities (free recall vs. recognition) could yield different performances. Clinical implications of the findings are discussed.

Long-term effects of early treatment with SSRIs on cognition and brain development in individuals with 22q11.2 deletion syndrome.

Cognitive deficits in individuals at risk of psychosis represent a significant challenge for research, as current strategies for symptomatic treatment are often ineffective. Recent studies showed that atypical cognitive development predicts the occurrence of psychotic symptoms. Additionally, abnormal brain development is known to predate clinical manifestations of psychosis. Therefore, critical developmental stages may be the best period for early interventions expected to prevent cognitive decline and protect brain maturation. However, it is challenging to identify and treat individuals at risk of psychosis in the general population before the onset of the first psychotic symptoms. 22q11.2 deletion syndrome (22q11DS), the neurogenetic disorder with the highest genetic risk for schizophrenia, provides the opportunity to prospectively study the development of subjects at risk for psychosis. In this retrospective cohort study, we aimed to establish if early treatment with SSRIs in children and adolescents with 22q11DS was associated with long-term effects on cognition and brain development. We included 98 participants with a confirmed diagnosis of 22q11DS followed up 2-4 times (age range: 10-32). Thirty subjects without psychiatric disorders never received psychotropic medications, thirty had psychotic symptoms but were not treated with SSRIs, and 38 received SSRIs treatment. An increase in IQ scores characterized the developmental trajectories of participants receiving treatment with SSRIs, even those with psychotic symptoms. The thickness of frontal regions and hippocampal volume were also relatively increased. The magnitude of the outcomes was inversely correlated to the age at the onset of the treatment. We provide preliminary evidence that early long-term treatment with SSRIs may attenuate the cognitive decline associated with psychosis in 22q11DS and developmental brain abnormalities.

Goal-Directed-Behavior in 22q11.2 Deletion Syndrome: Implication for Social Dysfunctions and the Emergence of Negative Symptoms.

BACKGROUND: Negative symptoms and social dysfunction are core features of the 22q11.2 deletion syndrome (22q11DS). Negative symptoms have been conceptualized as pathology of goal-directed-behaviors. Moreover, goal-directed-behaviors also appear to be a crucial step of social interactions. However, in 22q11DS, the extent to which goal-directed-behavior could be linked to social functioning difficulties and negative symptoms has never been examined. METHOD: Verbal and nonverbal initiation was measured using the verbal fluency and figural fluency tasks in 93 individuals with 22q11DS and 57 healthy controls aged between 8 and 30 years in order to assess goal-directed-behavior ability. The associations between initiation scores and social functioning/negative symptoms were investigated. In addition, the effect of COMT Val/Met polymorphism on initiation competences was examined. RESULTS: Results revealed diminished verbal and nonverbal initiation ability in 22q11DS individuals compared to controls. A positive correlation between verbal initiation and social functioning was found as well as between verbal initiation and negative symptoms, in particular social anhedonia. No differences in terms of initiation scores were found between individuals with 22q11DS carrying Met and Val polymorphism. CONCLUSION: Results indicate impaired goal-directed-behavior in the 22q11DS population. These deficits seem to support social functioning impairments frequently observed in the 22q11DS and to a lesser extent the expression of negative symptoms.

Favorable effects of omega-3 polyunsaturated fatty acids in attentional control and conversion rate to psychosis in 22q11.2 deletion syndrome.

Omega-3-polyunsaturated-fatty-acids were suggested against cognitive dysfunctions and conversion to psychosis. However, a recent multicenter trial found no effect in reducing conversion rates in individuals at risk of developing schizophrenia. Patients' genetic heterogeneity and the timing of treatment might influence omega-3 efficacy. Here, we addressed the impact of omega-3 early treatment in both mice and human subjects with a 22q11.2 genetic hemi-deletion (22q11DS), characterized by cognitive dysfunctions and high penetrance of schizophrenia. We first tested the behavioural and cognitive consequences of adolescent exposure to normal or omega-3-enriched diets in wild-type and 22q11DS (LgDel/+) mice. We then contrasted mouse data with those gathered from sixty-two patients with 22q11DS exposed to a normal diet or supplemented with omega-3 during pre-adolescence/adolescence. Adolescent omega-3 exposure had no effects in wild-type mice. However, this treatment ameliorated distractibility deficits revealed in LgDel/+ mice by the Five Choice Serial Reaction Time Task (5CSRTT). The omega-3 improvement in LgDel/+ mice was selective, as no other generalized cognitive and non-cognitive effects were evident. Similarly, omega-3-exposed 22q11DS patients showed long-lasting improvements on distractibility as revealed by the continuous performance test (CPT). Moreover, omega-3-exposed 22q11DS patients showed less risk of developing an Ultra High Risk status and lower conversion rate to psychosis. Our convergent mouse-human findings represent a first analysis on the effects of omega-3 early treatment in 22q11DS. The beneficial effects in attentional control and transition to psychosis could support the early use of omega-3 supplementation in the 22q11DS population.

[Formula: see text] Long-term verbal memory deficit and associated hippocampal alterations in 22q11.2 deletion syndrome.

Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a genetic disease associated with an increased risk for schizophrenia and a specific cognitive profile. In this paper, we challenge the current view of spared verbal memory in 22q11.2DS by investigating verbal memory consolidation processes over an extended time span to further qualify the neuropsychological profile. Our hypotheses are based on brain anomalies of the medial temporal lobes consistently reported in this syndrome.Eighty-four participants (45 with 22q11.2DS), aged 8-24 years old, completed a verbal episodic memory task to investigate long-term memory on four different time delays. We compared trajectories of forgetting between groups (22q11.2DS vs. controls) and analyzed performance inside the 22q11.2DS sample through cluster analyses. Potential links between memory performance and volume of the hippocampal subfields were examined.We showed accelerated long-term forgetting (ALF) in the 22q11.2DS group, visible after a delay of one day. Using mixed models, we showed significant differences in the shape of memory trajectories between subgroups of participants with 22q11.2DS. These sub-groups differed in terms of memory recognition, intellectual functioning, positive psychotic symptoms and grey matter volume of hippocampal subfields but not in terms of age.In conclusion, by investigating memory processes on longer delays than standardized memory tasks, we identified deficits in long-term memory consolidation leading to ALF in 22q11.2DS. Nevertheless, we showed that a subgroup of patients had larger memory consolidation deficit associated with lower intellectual functioning, higher rates of positive psychotic symptoms and hippocampal alterations.

Attention deficit hyperactivity disorder symptoms as antecedents of later psychotic outcomes in 22q11.2 deletion syndrome.

Individuals with 22q11.2 Deletion Syndrome (22q11.2DS) are at substantially heightened risk for psychosis. Thus, prevention and early intervention strategies that target the antecedents of psychosis in this high-risk group are a clinical priority. Attention Deficit Hyperactivity Disorder (ADHD) is one the most prevalent psychiatric disorders in children with 22q11.2DS, particularly the inattentive subtype. The aim of this study was to test the hypothesis that ADHD inattention symptoms predict later psychotic symptoms and/or psychotic disorder in those with 22q11.2DS. 250 children and adolescents with 22q11.2DS without psychotic symptoms at baseline took part in a longitudinal study. Assessments were performed using well-validated structured diagnostic instruments at two time points (T1 (mean age = 11.2, SD = 3.1) and T2 (mean age = 14.3, SD = 3.6)). Inattention symptoms at T1 were associated with development of psychotic symptoms at T2 (OR:1.2, p = 0.01) but weak associations were found with development of psychotic disorder (OR:1.2, p = 0.15). ADHD diagnosis at T1 was strongly associated with development of psychotic symptoms at T2 (OR:4.5, p < 0.001) and psychotic disorder (OR:5.9, p = 0.02). Our findings that inattention symptoms and the diagnosis of ADHD are associated with subsequent psychotic outcomes in 22q11.2DS have important clinical implications. Future studies examining the effects of stimulant and other ADHD treatments on individuals with 22q11.2DS are warranted.

Multimodal investigation of triple network connectivity in patients with 22q11DS and association with executive functions.

Large-scale brain networks play a prominent role in cognitive abilities and their activity is impaired in psychiatric disorders, such as schizophrenia. Patients with 22q11.2 deletion syndrome (22q11DS) are at high risk of developing schizophrenia and present similar cognitive impairments, including executive functions deficits. Thus, 22q11DS represents a model for the study of neural biomarkers associated with schizophrenia. In this study, we investigated structural and functional connectivity within and between the Default Mode (DMN), the Central Executive (CEN), and the Saliency network (SN) in 22q11DS using resting-state fMRI and DTI. Furthermore, we investigated if triple network impairments were related to executive dysfunctions or the presence of psychotic symptoms. Sixty-three patients with 22q11DS and sixty-eighty controls (age 6-33 years) were included in the study. Structural connectivity between main nodes of DMN, CEN, and SN was computed using probabilistic tractography. Functional connectivity was computed as the partial correlation between the time courses extracted from each node. Structural and functional connectivity measures were then correlated to executive functions and psychotic symptom scores. Our results showed mainly reduced structural connectivity within the CEN, DMN, and SN, in patients with 22q11DS compared with controls as well as reduced between-network connectivity. Functional connectivity appeared to be more preserved, with impairments being evident only within the DMN. Structural connectivity impairments were also related to executive dysfunctions. These findings show an association between triple network structural alterations and executive deficits in patients with the microdeletion, suggesting that 22q11DS and schizophrenia share common psychopathological mechanisms. Hum Brain Mapp 38:2177-2189, 2017. © 2017 Wiley Periodicals, Inc.

Visual memory profile in 22q11.2 microdeletion syndrome: are there differences in performance and neurobiological substrates between tasks linked to ventral and dorsal visual brain structures? A cross-sectional and longitudinal study.

BACKGROUND: Children affected by the 22q11.2 deletion syndrome (22q11.2DS) have a specific neuropsychological profile with strengths and weaknesses in several cognitive domains. Specifically, previous evidence has shown that patients with 22q11.2DS have more difficulties memorizing faces and visual-object characteristics of stimuli. In contrast, they have better performance in visuo-spatial memory tasks. The first focus of this study was to replicate these results in a larger sample of patients affected with 22q11.2DS and using a range of memory tasks. Moreover, we analyzed if the deficits were related to brain morphology in the structures typically underlying these abilities (ventral and dorsal visual streams). Finally, since the longitudinal development of visual memory is not clearly characterized in 22q11.2DS, we investigated its evolution from childhood to adolescence. METHODS: Seventy-one patients with 22q11.2DS and 49 control individuals aged between 9 and 16 years completed the Benton Visual Retention Test (BVRT) and specific subtests assessing visual memory from the Children's Memory Scale (CMS). The BVRT was used to compute spatial and object memory errors. For the CMS, specific subtests were classified into ventral, dorsal, and mixed subtests. Longitudinal data were obtained from a subset of 26 patients and 22 control individuals. RESULTS: Cross-sectional results showed that patients with 22q11.2DS were impaired in all visual memory measures, with stronger deficits in visual-object memory and memory of faces, compared to visuo-spatial memory. No correlations between morphological brain impairments and visual memory were found in patients with 22q11.2DS. Longitudinal findings revealed that participants with 22q11.2DS made more object memory errors than spatial memory errors at baseline. This difference was no longer significant at follow-up. CONCLUSIONS: Individuals with 22q11.2DS have impairments in visual memory abilities, with more pronounced difficulties in memorizing faces and visual-object characteristics. From childhood to adolescence, the visual cognitive profile of patients with 22q11.2DS seems globally stable even though some processes show an evolution with time. We hope that our results will help clinicians and caregivers to better understand the memory difficulties of young individuals with 22q11.2DS. This has a particular importance at school to facilitate recommendations concerning intervention strategies for these young patients.

Developmental trajectories of executive functions in 22q11.2 deletion syndrome.

BACKGROUND: 22q11.2 deletion syndrome (22q11.2DS) is a genetic disorder associated with a specific cognitive profile. Higher-order cognitive skills like executive functions (EF) are reported as a relative weakness in this population. The present study aimed to delineate the developmental trajectories of multiple EF domains in a longitudinal sample using a broader age range than previous studies. Given the high incidence of psychotic symptoms in 22q11.2DS, we also compared the development of EF in participants with/without comorbid psychotic symptoms. Given the importance of EF in daily life, the third aim of the study was to characterize the link between EF and adaptive functioning. METHODS: The sample consisted of 95 individuals with 22q11.2DS and 100 typically developing controls aged 6-26 years. A large proportion of the sample (55.38 %) had multiple time points available. Between-group differences in the developmental trajectories of three subdomains of EF (verbal fluency, working memory, and inhibition) were examined using mixed models regression analyses. Analyses were repeated comparing only the 22q11.2DS group based on the presence/absence of psychotic symptoms to investigate the influence of executive dysfunction on the emergence of psychotic symptoms. Hierarchical stepwise regression analyses were also conducted to investigate the predictive value of EF on adaptive functioning. RESULTS: We observed lower performance on EF domains, as well as atypical development of working memory and verbal fluency. Participants who presented with negative symptoms exhibited different developmental trajectories of inhibition and working memory. Adaptive functioning level was not significantly predicted by EF scores. CONCLUSIONS: The present study highlighted domain-specific atypical trajectories of EF in individuals with 22q11.DS and explored the link with psychotic symptoms. However, no relation between EF and adaptive functioning was observed.

Altruism costs-the cheap signal from amygdala.

When people state their willingness to pay for something, the amount usually differs from the behavior in a real purchase situation. The discrepancy between a hypothetical answer and the real act is called hypothetical bias. We investigated neural processes of hypothetical bias regarding monetary donations to public goods using fMRI with the hypothesis that amygdala codes for real costs. Real decisions activated amygdala more than hypothetical decisions. This was observed for both accepted and rejected proposals. The more the subjects accepted real donation proposals the greater was the activity in rostral anterior cingulate cortex-a region known to control amygdala but also neural processing of the cost-benefit difference. The presentation of a charitable donation goal evoked an insula activity that predicted the later decision to donate. In conclusion, we have identified the neural mechanisms underlying real donation behavior, compatible with theories on hypothetical bias. Our findings imply that the emotional system has an important role in real decision making as it signals what kind of immediate cost and reward an outcome is associated with.