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.

Social skills in neurodevelopmental disorders: a study using role-plays to assess adolescents and young adults with 22q11.2 deletion syndrome and autism spectrum disorders.

BACKGROUNDS: Social skills are frequently impaired in neurodevelopmental disorders and genetic conditions, including 22q11.2 deletion syndrome (22q11DS) and autism spectrum disorders (ASD). Although often assessed with questionnaires, direct assessment provides a more valid estimate of the constructs. Role-plays (i.e., simulates situational settings) therefore appear to be an appropriate indicator of social skills in daily life. METHODS: This co-registered study involved 53 individuals with 22q11DS, 34 individuals with ASD, and 64 typically developing (TD) peers aged 12-30 years. All participants were assessed with role-plays as well as parent-reported questionnaires and clinical interviews focusing on social skills, functioning and anxiety. RESULTS: Both clinical groups showed impaired social skills compared to TD, but distinct social profiles emerged between the groups. Individuals with 22q11DS displayed higher social appropriateness and clarity of speech but weaker general argumentation and negotiation skills, with the opposite pattern observed in participants with ASD. No association was found between social skills measured by direct observation and caregiver reports. Social anxiety, although higher in clinical groups than in TD, was not associated with role-plays. CONCLUSIONS: This study highlights the need to train social skills through tailored interventions to target the specific difficulties of each clinical population. It also highlights the importance of combining measures as they do not necessarily provide the same outcome.

Thalamic contributions to psychosis susceptibility: Evidence from co-activation patterns accounting for intra-seed spatial variability (µCAPs).

The temporal variability of the thalamus in functional networks may provide valuable insights into the pathophysiology of schizophrenia. To address the complexity of the role of the thalamic nuclei in psychosis, we introduced micro-co-activation patterns (µCAPs) and employed this method on the human genetic model of schizophrenia 22q11.2 deletion syndrome (22q11.2DS). Participants underwent resting-state functional MRI and a data-driven iterative process resulting in the identification of six whole-brain µCAPs with specific activity patterns within the thalamus. Unlike conventional methods, µCAPs extract dynamic spatial patterns that reveal partially overlapping and non-mutually exclusive functional subparts. Thus, the µCAPs method detects finer foci of activity within the initial seed region, retaining valuable and clinically relevant temporal and spatial information. We found that a µCAP showing co-activation of the mediodorsal thalamus with brain-wide cortical regions was expressed significantly less frequently in patients with 22q11.2DS, and its occurrence negatively correlated with the severity of positive psychotic symptoms. Additionally, activity within the auditory-visual cortex and their respective geniculate nuclei was expressed in two different µCAPs. One of these auditory-visual µCAPs co-activated with salience areas, while the other co-activated with the default mode network (DMN). A significant shift of occurrence from the salience+visuo-auditory-thalamus to the DMN + visuo-auditory-thalamus µCAP was observed in patients with 22q11.2DS. Thus, our findings support existing research on the gatekeeping role of the thalamus for sensory information in the pathophysiology of psychosis and revisit the evidence of geniculate nuclei hyperconnectivity with the audio-visual cortex in 22q11.2DS in the context of dynamic functional connectivity, seen here as the specific hyper-occurrence of these circuits with the task-negative brain networks.

The role of mentalizing in the relationship between schizotypal personality traits and state signs of psychosis risk captured by cognitive and perceptive basic symptoms.

Objective: Schizotypal traits and disturbances in mentalizing (the capacity to understand the mental states driving one's own and others' behaviors) have been implicated in increased vulnerability for psychosis. Therefore, we explored the associations linking schizotypal traits, mentalizing difficulties and their interactions to clinical high-risk for psychosis (CHR-P), as captured by the Basic Symptoms (BS) approach, during adolescence and young adulthood. Methods: Eighty-seven adolescents and young adults from the general population (46% male, 44% female; age: 14-23 years) were assessed with the Schizophrenia Proneness Interview (SPI-CY/A) for 11 perceptive and cognitive BS, with the Schizotypal Personality Questionnaire (SPQ) for schizotypal traits, and with the Reflective Functioning Questionnaire (RFQ) for self-reported mentalizing abilities. The RFQ evaluates the level of certainty (RFQc scale) and uncertainty (RFQu scale) with which individuals use mental state information to explain their own and others' behaviors. Results: Logistic regression models showed significant positive effects of the SPQ disorganization scale on perceptive BS and of the SPQ interpersonal scale on cognitive BS. Post-hoc analyses revealed that schizotypal features pertaining to odd speech and social anxiety, respectively, were associated with perceptive and cognitive BS. Furthermore, higher scores on the RFQu scale and lower scores on the RFQc scale independently explained the presence of cognitive BS. Finally, significant interaction effects between RFQc and SPQ odd speech on perceptive BS, and between RFQc and SPQ social anxiety on cognitive BS were found. Conclusion: Our findings suggest that schizotypal traits and mentalizing significantly relate both independently and through their interactions to the presence of cognitive and perceptive BS included in CHR-P criteria. Furthermore, mentalizing dysfunction may contribute in the relation between schizotypal traits and early state signs of CHR-P. Mentalizing may support both detection and early treatment of CHR-P among adolescents and young adults who present with trait risk for psychosis.

The coupling between the spatial and temporal scales of neural processes revealed by a joint time-vertex connectome spectral analysis.

Brain oscillations are produced by the coordinated activity of large groups of neurons and different rhythms are thought to reflect different modes of information processing. These modes, in turn, are known to occur at different spatial scales. Nevertheless, how these rhythms support different spatial modes of information processing at the brain scale is not yet fully understood. Here we use "Joint Time-Vertex Spectral Analysis" to characterize the joint spectral content of brain activity both in time (temporal frequencies) and in space over the connectivity graph (spatial connectome harmonics). This method allows us to characterize the relationship between spatially localized or distributed neural processes on one side and their respective temporal frequency bands in source-reconstructed M/EEG signals. We explore this approach on two different datasets, an auditory steady-state response (ASSR) and a visual grating task. Our results suggest that different information processing mechanisms are carried out at different frequency bands: while spatially distributed activity (which may also be interpreted as integration) specifically occurs at low temporal frequencies (alpha and theta) and low graph spatial frequencies, localized electrical activity (i.e., segregation) is observed at high temporal frequencies (high and low gamma) over restricted high spatial graph frequencies. Crucially, the estimated contribution of the distributed and localized neural activity predicts performance in a behavioral task, demonstrating the neurophysiological relevance of the joint time-vertex spectral representation.

Chromatin regulators in the TBX1 network confer risk for conotruncal heart defects in 22q11.2DS.

Congenital heart disease (CHD) affecting the conotruncal region of the heart, occurs in 40-50% of patients with 22q11.2 deletion syndrome (22q11.2DS). This syndrome is a rare disorder with relative genetic homogeneity that can facilitate identification of genetic modifiers. Haploinsufficiency of TBX1, encoding a T-box transcription factor, is one of the main genes responsible for the etiology of the syndrome. We suggest that genetic modifiers of conotruncal defects in patients with 22q11.2DS may be in the TBX1 gene network. To identify genetic modifiers, we analyzed rare, predicted damaging variants in whole genome sequence of 456 cases with conotruncal defects and 537 controls, with 22q11.2DS. We then performed gene set approaches and identified chromatin regulatory genes as modifiers. Chromatin genes with recurrent damaging variants include EP400, KAT6A, KMT2C, KMT2D, NSD1, CHD7 and PHF21A. In total, we identified 37 chromatin regulatory genes, that may increase risk for conotruncal heart defects in 8.5% of 22q11.2DS cases. Many of these genes were identified as risk factors for sporadic CHD in the general population. These genes are co-expressed in cardiac progenitor cells with TBX1, suggesting that they may be in the same genetic network. The genes KAT6A, KMT2C, CHD7 and EZH2, have been previously shown to genetically interact with TBX1 in mouse models. Our findings indicate that disturbance of chromatin regulatory genes impact the TBX1 gene network serving as genetic modifiers of 22q11.2DS and sporadic CHD, suggesting that there are some shared mechanisms involving the TBX1 gene network in the etiology of CHD.

Multivariate patterns of disrupted sleep longitudinally predict affective vulnerability to psychosis in 22q11.2 Deletion Syndrome.

22q11.2 deletion syndrome (22q11DS) contributes dramatically to increased genetic risk for psychopathology, and in particular schizophrenia. Sleep disorders, including obstructive sleep apnea (OSA), are also highly prevalent, making 22q11DS a unique model to explore their impact on psychosis vulnerability. Still, the contribution of sleep disturbances to psychosis vulnerability remains unclear. We characterized the sleep phenotype of 69 individuals with 22q11DS and 38 healthy controls with actigraphy and sleep questionnaires. Psychiatric symptoms were measured concomitantly with the baseline sleep assessment and at longitudinal follow-up, 3.58±0.85 years later. We used a novel multivariate partial-least-square-correlation (PLSC) approach to identify sleep patterns combining objective and subjective variables, which correlated with psychiatric symptoms. We dissected longitudinal pathways linking sleep disturbances to psychosis, using multi-layer-network-analysis. 22q11DS was characterized by a non-restorative sleep pattern, combining increased daytime fatigue despite longer sleep duration. Non-restorative sleep combined with OSA symptoms correlated with both emotional and psychotic symptoms. Moreover, a sleep pattern evocative of OSA predicted longitudinal worsening of positive and negative symptoms, by accentuating the effects of emotional dysregulation. These results suggest that sleep disturbances could significantly increase psychosis risk, along an affective pathway. If confirmed, this suggests that systematic screening of sleep quality could mitigate psychosis vulnerability in 22q11DS.

Amygdala subdivisions exhibit aberrant whole-brain functional connectivity in relation to stress intolerance and psychotic symptoms in 22q11.2DS.

The amygdala is a key region in emotional regulation, which is often impaired in psychosis. However, it is unclear if amygdala dysfunction directly contributes to psychosis, or whether it contributes to psychosis through symptoms of emotional dysregulation. We studied the functional connectivity of amygdala subdivisions in patients with 22q11.2DS, a known genetic model for psychosis susceptibility. We investigated how dysmaturation of each subdivision's connectivity contributes to positive psychotic symptoms and impaired tolerance to stress in deletion carriers. Longitudinally-repeated MRI scans from 105 patients with 22q11.2DS (64 at high-risk for psychosis and 37 with impaired tolerance to stress) and 120 healthy controls between the ages of 5 to 30 years were included. We calculated seed-based whole-brain functional connectivity for amygdalar subdivisions and employed a longitudinal multivariate approach to evaluate the developmental trajectory of functional connectivity across groups. Patients with 22q11.2DS presented a multivariate pattern of decreased basolateral amygdala (BLA)-frontal connectivity alongside increased BLA-hippocampal connectivity. Moreover, associations between developmental drops in centro-medial amygdala (CMA)-frontal connectivity to both impaired tolerance to stress and positive psychotic symptoms in deletion carriers were detected. Superficial amygdala hyperconnectivity to the striatum was revealed as a specific pattern arising in patients who develop mild to moderate positive psychotic symptoms. Overall, CMA-frontal dysconnectivity was found as a mutual neurobiological substrate in both impaired tolerance to stress and psychosis, suggesting a role in prodromal dysregulation of emotions in psychosis. While BLA dysconnectivity was found to be an early finding in patients with 22q11.2DS, which contributes to impaired tolerance to stress.

Excitatory/Inhibitory Imbalance Underlies Hippocampal Atrophy in Individuals With 22q11.2 Deletion Syndrome With Psychotic Symptoms.

BACKGROUND: Abnormal neurotransmitter levels have been reported in individuals at high risk for schizophrenia, leading to a shift in the excitatory/inhibitory balance. However, it is unclear whether these alterations predate the onset of clinically relevant symptoms. Our aim was to explore in vivo measures of excitatory/inhibitory balance in 22q11.2 deletion carriers, a population at genetic risk for psychosis. METHODS: Glx (glutamate+glutamine) and GABA+ (gamma-aminobutyric acid with macromolecules and homocarnosine) concentrations were estimated in the anterior cingulate cortex, superior temporal cortex, and hippocampus using the Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS) sequence and the Gannet toolbox in 52 deletion carriers and 42 control participants. T1-weighted images were acquired longitudinally and processed with FreeSurfer version 6 to extract hippocampal volume. Subgroup analyses were conducted in deletion carriers with psychotic symptoms. RESULTS: While no differences were found in the anterior cingulate cortex, deletion carriers had higher levels of Glx in the hippocampus and superior temporal cortex and lower levels of GABA+ in the hippocampus than control participants. We additionally found a higher Glx concentration in the hippocampus of deletion carriers with psychotic symptoms. Finally, more pronounced hippocampal atrophy was significantly associated with increased Glx levels in deletion carriers. CONCLUSIONS: We provide evidence for an excitatory/inhibitory imbalance in temporal brain structures of deletion carriers, with a further hippocampal Glx increase in individuals with psychotic symptoms that was associated with hippocampal atrophy. These results are in line with theories proposing abnormally enhanced glutamate levels as a mechanistic explanation for hippocampal atrophy via excitotoxicity. Our results highlight a central role of glutamate in the hippocampus of individuals at genetic risk for schizophrenia.

Increased affective reactivity to daily social stressors is associated with more severe psychotic symptoms in youths with 22q11.2 deletion syndrome.

BACKGROUND: Increased reactivity to minor stressors is considered a risk factor for psychosis, especially in vulnerable individuals. In the present study, we investigated affective and psychotic stress reactivity as well as its link with psychotic symptoms and psychopathology in youths with 22q11.2 deletion syndrome (22q11DS), a neurogenetic condition associated with a high risk for psychosis. METHODS: A 6-day ecological momentary assessment protocol was used to assess perceived daily-life stress as well as affective and psychotic reactivity to stress in participants with 22q11DS (n = 38, age = 18.4) and healthy controls (HC; n = 53, age = 19.1). Psychotic symptoms, general psychopathology, and coping strategies were also assessed through clinical interviews and questionnaires. RESULTS: Participants with 22q11DS reported higher levels of perceived social stress (b = 0.21, p = 0.036) but lower levels of activity-related stress (b = -0.31, p = 0.003) in their daily lives compared to HC. The groups did not differ in affective or psychotic reactivity to stress, but individuals with 22q11DS who reported increased affective reactivity to social stressors showed more severe positive psychotic symptoms (rs = 0.505, p = 0.008). Finally, avoidance coping strategies moderated the association between stress and negative affects. CONCLUSIONS: Our results suggest an increased vulnerability for daily social stress in youths with 22q11DS, and link elevated social stress reactivity to heightened psychotic symptom severity. Given the high risk for psychosis in 22q11DS, interventions should focus on reducing social stress and developing adaptive coping strategies.

Updated clinical practice recommendations for managing children with 22q11.2 deletion syndrome.

This review aimed to update the clinical practice guidelines for managing children and adolescents with 22q11.2 deletion syndrome (22q11.2DS). The 22q11.2 Society, the international scientific organization studying chromosome 22q11.2 differences and related conditions, recruited expert clinicians worldwide to revise the original 2011 pediatric clinical practice guidelines in a stepwise process: (1) a systematic literature search (1992-2021), (2) study selection and data extraction by clinical experts from 9 different countries, covering 24 subspecialties, and (3) creation of a draft consensus document based on the literature and expert opinion, which was further shaped by survey results from family support organizations regarding perceived needs. Of 2441 22q11.2DS-relevant publications initially identified, 2344 received full-text reviews, including 1545 meeting criteria for potential relevance to clinical care of children and adolescents. Informed by the available literature, recommendations were formulated. Given evidence base limitations, multidisciplinary recommendations represent consensus statements of good practice for this evolving field. These recommendations provide contemporary guidance for evaluation, surveillance, and management of the many 22q11.2DS-associated physical, cognitive, behavioral, and psychiatric morbidities while addressing important genetic counseling and psychosocial issues.

Visual processing of complex social scenes in 22q11.2 deletion syndrome: Relevance for negative symptoms.

Current explanatory models of negative symptoms in schizophrenia have suggested the role of social cognition in symptom formation and maintenance. This study examined a core aspect of social cognition, namely social perception, and its association with clinical manifestations in 22q11.2 deletion syndrome (22q11DS), a genetic model of schizophrenia. We used an eye-tracking device to analyze developmental trajectories of complex and dynamic social scenes exploration in 58 participants with 22q11DS compared to 79 typically developing controls. Participants with 22q11DS showed divergent patterns of social scene exploration compared to healthy individuals from childhood to adulthood. We evidenced a more scattered gaze pattern and a lower number of shared gaze foci compared to healthy controls. Associations with negative symptoms, anxiety level, and face recognition were observed. Findings reveal abnormal visual exploration of complex social information from childhood to adulthood in 22q11DS. Atypical gaze patterns appear related to clinical manifestations in this syndrome.

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.

Characterizing Daily-Life Social Interactions in Adolescents and Young Adults with Neurodevelopmental Disorders: A Comparison Between Individuals with Autism Spectrum Disorders and 22q11.2 Deletion Syndrome.

Social impairments are common features of 22q11.2 deletion syndrome (22q11DS) and autism spectrum disorders (ASD). The Ecological Momentary Assessment (EMA) allowed access to daily-life information in order to explore the phenomenology of social interactions. 32 individuals with 22q11DS, 26 individuals with ASD and 44 typically developing peers (TD) aged 12-30 were assessed during 6 days 8 times a day using a mobile app. Participants with 22q11DS and ASD did not spend more time alone but showed distinct implication in the social sphere than TD. Distinct profiles emerged between the two conditions regarding the subjective experience of aloneness and the subjective experience of social interactions. This study highlights distinct social functioning profiles in daily-life in 22q11DS and ASD that points towards different therapeutic targets.

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].

Exploring associations between diurnal cortisol, stress, coping and psychopathology in adolescents and young adults with 22q11.2 deletion syndrome.

Background: 22q11.2 deletion syndrome (22q11DS) is a neurogenetic condition associated to a high risk for psychiatric disorders, including psychosis. Individuals with 22q11DS are thought to experience increased levels of chronic stress, which could lead to alterations in hypothalamic-pituitary-adrenocortical (HPA)-axis functioning. In the current study, we investigated for the first time diurnal salivary cortisol profiles in adolescents and young adults with 22q11DS as well as their link with stress exposure, coping strategies and psychopathology, including psychotic symptoms. Methods: Salivary cortisol was collected from adolescents and young adults with 22q11DS (n = 30, age = 19.7) and matched healthy controls (HC; n = 36, age = 18.5) six times a day for two days. Exposure to stressful life events, including peer victimization, coping strategies and general psychopathology were assessed with questionnaires. Psychotic symptoms and psychiatric comorbidities were evaluated with clinical interviews. Results: We observed similar daily levels and diurnal profiles of salivary cortisol in adolescents and young adults with 22q11DS compared to HCs. However, participants with 22q11DS reported less frequent exposure to stress than HCs. In 22q11DS, we observed a significant association between the use of non-adaptive coping strategies and the severity of psychotics symptoms. Cortisol level was not associated to severity of psychotic symptoms, but elevated cortisol awakening response (CAR) was found in participants with 22q11DS with higher levels of general psychopathology. Conclusions: Our results do not support earlier propositions of altered HPA-axis functioning in 22q11DS but highlight the need to further investigate diurnal cortisol as an indicator of HPA-axis functioning and its link with (earlier) stress exposure and psychopathology in this population. Interventions should target the development of adaptive coping skills in preventing psychosis in 22q11DS.

Contribution of schizophrenia polygenic burden to longitudinal phenotypic variance in 22q11.2 deletion syndrome.

While the recurrent 22q11.2 deletion is one of the strongest genetic risk factors for schizophrenia (SCZ), variability of its associated neuropsychiatric endophenotypes reflects its incomplete penetrance for psychosis development. To assess whether this phenotypic variability is linked to common variants associated with SCZ, we studied the association between SCZ polygenic risk score (PRS) and longitudinally acquired phenotypic information of the Swiss 22q11.2DS cohort (n = 97, 50% females, mean age 17.7 yr, mean visit interval 3.8 yr). The SCZ PRS with the best predictive performance was ascertained in the Estonian Biobank (n = 201,146) with LDpred. The infinitesimal SCZ PRS model showed the strongest capacity in discriminating SCZ cases from controls with one SD difference in SCZ PRS corresponding to an odds ratio (OR) of 1.73 (95% CI 1.57-1.90, P = 1.47 × 10-29). In 22q11.2 patients, random-effects ordinal regression modelling using longitudinal data showed SCZ PRS to have the strongest effect on social anhedonia (OR = 2.09, P = 0.0002), and occupational functioning (OR = 1.82, P = 0.0003) within the negative symptoms course, and dysphoric mood (OR = 2.00, P = 0.002) and stress intolerance (OR = 1.76, P = 0.0002) within the general symptoms course. Genetic liability for SCZ was additionally associated with full scale cognitive decline (ß = -0.25, P = 0.02) and with longitudinal volumetric reduction of the right and left hippocampi (ß = -0.28, P = 0.005; ß = -0.23, P = 0.02, respectively). Our results indicate that the polygenic contribution to SCZ acts upon the threshold-lowering first hit (i.e., the deletion). It modifies the endophenotypes of 22q11.2DS and augments the derailment of developmental trajectories of negative and general symptoms, cognition, and hippocampal volume.

Neural substrates of psychosis revealed by altered dependencies between brain activity and white-matter architecture in individuals with 22q11 deletion syndrome.

BACKGROUND: Dysconnectivity has been consistently proposed as a major key mechanism in psychosis. Indeed, disruptions in large-scale structural and functional brain networks have been associated with psychotic symptoms. However, brain activity is largely constrained by underlying white matter pathways and the study of function-structure dependency, compared to conventional unimodal analysis, allows a biologically relevant assessment of neural mechanisms. The 22q11.2 deletion syndrome (22q11DS) constitutes a remarkable opportunity to study the pathophysiological processes of psychosis. METHODS: 58 healthy controls and 57 deletion carriers, aged from 16 to 32 years old,underwent resting-state functional and diffusion-weighted magnetic resonance imaging. Deletion carriers were additionally fully assessed for psychotic symptoms. Firstly, we used a graph signal processing method to combine brain activity and structural connectivity measures to obtain regional structural decoupling indexes (SDIs). We use SDI to assess the differences of functional structural dependency (FSD) across the groups. Subsequently we investigated how alterations in FSDs are associated with the severity of positive psychotic symptoms in participants with 22q11DS. RESULTS: In line with previous findings, participants in both groups showed a spatial gradient of FSD ranging from sensory-motor regions (stronger FSD) to regions involved in higher-order function (weaker FSD). Compared to controls, in participants with 22q11DS, and further in deletion carriers with more severe positive psychotic symptoms, the functional activity was more strongly dependent on the structure in parahippocampal gyrus and subcortical dopaminergic regions, while it was less dependent within the cingulate cortex. This analysis revealed group differences not otherwise detected when assessing the structural and functional nodal measures separately. CONCLUSIONS: Our findings point toward a disrupted modulation of functional activity on the underlying structure, which was further associated to psychopathology for candidate critical regions in 22q11DS. This study provides the first evidence for the clinical relevance of function-structure dependency and its contribution to the emergence of psychosis.

Impact of the COVID-19 pandemic on mental health and family situation of clinically referred children and adolescents in Switzerland: results of a survey among mental health care professionals after 1 year of COVID-19.

The aim of this study was to assess the impact of the COVID-19 pandemic on mental well-being of clinically referred children and adolescents and on their families from the perspective of mental health care professionals in Switzerland during the first year of the pandemic. Psychiatrists and psychologists for children and adolescents participated in an anonymous survey conducted online in April/May 2021. The survey was completed by 454 mental health care professionals, most of them working in outpatient clinics for child and adolescent psychiatry or in independent practices. Most participants indicated an important increase of referrals for depression (86.8% of respondents), anxiety disorders (81.5%), crisis interventions (76.2%), psychosomatic disorders (66.1%), suicidality (63.8%), and behavioral addictions, e.g., excessive gaming (64.6%). In contrast, referrals or treatment demands for disorders such as autism spectrum disorder or psychosis showed no substantial change or a slight decrease, respectively. According to 69% of respondents, patients experienced the highest psychological burden in January/February/March 2021. Family problems very frequently reported by mental health professionals were parents' worries about loneliness/isolation of the child (49%), child's education and academic future (33%), increased media use due to missing options of recreational activities (37.6%), as well as multiple stresses of mothers (36.3%). To conclude, the pandemic has substantially changed the pattern of disorders and the number of clinical referrals of children and adolescents with mental health problems, which has serious consequences for the treatment supply in Switzerland.