Abnormalities in brain white matter in adolescents with 22q11.2 deletion syndrome and psychotic symptoms

Background

22q11.2 Deletion Syndrome (22q11DS) is considered to be a promising cohort to explore biomarkers of schizophrenia risk based on a 30 % probability of developing schizophrenia in adulthood. In this study, we investigated abnormalities in the microstructure of white matter in adolescents with 22q11DS and their specificity to prodromal symptoms of schizophrenia.

Methods

Diffusion Magnetic Resonance Imaging (dMRI) data were acquired from 50 subjects with 22q11DS (9 with and 41 without prodromal psychotic symptoms), and 47 matched healthy controls (mean age 18 +/?2 years). DMRI measures, including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were calculated and compared between groups using the Tract Based Spatial Statistics (TBSS) method. Additionally, correlations between dMRI measures and scores on positive symptoms were performed.

Results

Reductions in MD, AD and RD (but not FA) were found in the corpus callosum (CC), left and right superior longitudinal fasciculus (SLF), and left and right corona radiata in the entire 22q11DS group. In addition, the 22q11DS subgroup with prodromal symptoms showed reductions in AD and MD, but no changes in RD when compared to the non-prodromal subgroup, in CC, right SLF, right corona radiata and right internal capsule. Finally, AD values in these tracts correlated with the scores on the psychosis subscale.

Conclusion

Microstructural abnormalities in brain white matter are present in adolescent subjects with prodromal psychotic symptoms.

     

The social brain network in 22q11.2 deletion syndrome: a diffusion tensor imaging study

Background

Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a neurogenetic disorder that is associated with a 25-fold increase in schizophrenia. Both individuals with 22q11.2DS and those with schizophrenia present with social cognitive deficits, which are putatively subserved by a network of brain regions that are involved in the processing of social cognitive information. This study used two-tensor tractography to examine the white matter tracts believed to underlie the social brain network in a group of 57 young adults with 22q11.2DS compared to 30 unaffected controls.

Results

Results indicated that relative to controls, participants with 22q11.2DS showed significant differences in several DTI metrics within the inferior fronto-occipital fasciculus, cingulum bundle, thalamo-frontal tract, and inferior longitudinal fasciculus. In addition, participants with 22q11.2DS showed significant differences in scores on measures of social cognition, including the Social Responsiveness Scale and Trait Emotional Intelligence Questionnaire. Further analyses among individuals with 22q11.2DS demonstrated an association between DTI metrics and positive and negative symptoms of psychosis, as well as differentiation between individuals with 22q11.2DS and overt psychosis, relative to those with positive prodromal symptoms or no psychosis.

Conclusions

Findings suggest that white matter disruption, specifically disrupted axonal coherence in the right inferior fronto-occipital fasciculus, may be a biomarker for social cognitive difficulties and psychosis in individuals with 22q11.2DS.

     

Hippocampal volume reduction in chromosome 22q11.2 deletion syndrome (22q11.2DS): A longitudinal study of morphometry and symptomatology

Recent studies observed an association between the structural integrity of the hippocampal structure and the manifestations of clinically significant psychotic symptoms in participants at high risk for psychosis. The present study sought to investigate the longitudinal trajectory of the hippocampal volume and its subregions among a sample of participants affected by 22q11.2 deletion syndrome (22q11.2DS), a neurogenetic disorder associated with elevated risk for psychosis. We specifically investigated possible correlations between hippocampal volumes, as measured by magnetic resonance imaging (MRI), and the manifestation of positive psychotic symptoms (hallucinations and delusions). Regional hippocampal volumes were measured twice with cerebral MRI obtained at 3-year intervals in 30 healthy participants and 31 gender-matched 22q11.2 microdeletion carriers aged 6 to 22. We examined potential associations between psychotic symptom manifestations and volumetric parameters at both time points. We found a hippocampal body-driven significant reduction in hippocampal volume among patients with 22q11DS compared to controls. No significant group by time interaction for the total or the subregional volumes were observed. In patients, larger hippocampal head at baseline was associated with the presence of hallucinations at follow-up. We first discuss the reduced hippocampal body finding in light of potentially abnormal mesiocortical circuits. We further discuss the association between baseline hippocampal head volume in participants with 22q11DS as a possible marker related to the later unfolding of psychotic symptoms.     

Schizophrenia and 22q11.2 deletion syndrome

22q11.2 deletion syndrome (22qDS) is a genetic syndrome associated with a chromosome 22q11.2 deletion and variable phenotypic expression that commonly includes schizophrenia. Approximately 1% of patients with schizophrenia have 22qDS. The schizophrenia in 22qDS appears broadly similar to that found in the general population with respect to core signs and symptoms, treatment response, neurocognitive profile, and MRI brain anomalies. However, individuals with a 22qDS form of schizophrenia typically have distinguishable physical features, have a lower IQ, and may differ in auxiliary clinical features. IQ, length of 22q11.2 deletions, and COMT functional allele do not appear to be major risk factors for schizophrenia in 22qDS. Ascertainment biases and small sample sizes are limitations of most studies. Larger studies over the lifespan and continuing education about this underrecognized condition are needed. 22qDS-schizophrenia is an important genetic subtype and a valuable model of neurodevelopmental mechanisms involved in the pathogenesis of schizophrenia.     

Prodromal symptoms in adolescents with 22q11.2 deletion syndrome and schizotypal personality disorder

Adolescents with 22q11.2 Deletion Syndrome (22q11.2DS) and Schizotypal Personality Disorder (SPD) are at increased risk for the development of psychosis based, respectively, on genetic or behavioral factors. Thus both groups would be expected to manifest heightened rates of the prodromal signs that typically precede psychosis. Although there are now standardized procedures for assessing prodromal symptoms, there has been little research on the manifestation of these symptoms in 22q11.2DS patients, and no studies of differences in prodromal symptom patterns between genetically and behaviorally defined at-risk groups. In this study, demographically matched groups of 23 SPD, 23 22q11.2DS, and 23 control participants were administered the Structured Interview for Prodromal Syndromes (SIPS). Both risk groups showed elevated positive, negative, disorganized, and general prodromal symptoms, as well as elevations on 10 of the same individual symptom items, relative to the control group. Approximately 60% of individuals in the 22q11.2DS group and 70% of individuals in the SPD group met symptom criteria for a prodromal psychosis syndrome. The 22q11.2DS group scored significantly higher than the SPD group on the "decreased ideational richness" item and showed a trend toward greater motor abnormalities. The results suggest that these two high-risk groups are similar in prodromal symptom presentation, possibly as a result of overlapping causal mechanisms, and that standardized measures of prodromal syndromes like the SIPS can be used to identify 22q11.2DS patients at greatest risk for conversion to psychosis.     

An fMRI study of facial emotion processing in children and adolescents with 22q11.2 deletion syndrome

Background

22q11.2 deletion syndrome (22q11DS, velo-cardio-facial syndrome [VCFS]) is a genetic disorder associated with interstitial deletions of chromosome 22q11.2. In addition to high rates of neuropsychiatric disorders, children with 22q11DS have impairments of face processing, as well as IQ-independent deficits in visuoperceptual function and social and abstract reasoning. These face-processing deficits may contribute to the social impairments of 22q11DS. However, their neurobiological basis is poorly understood.

Methods

We used event-related functional magnetic resonance imaging (fMRI) to examine neural responses when children with 22q11DS (aged 9–17 years) and healthy controls (aged 8–17 years) incidentally processed neutral expressions and mild (50%) and intense (100%) expressions of fear and disgust. We included 28 right-handed children and adolescents: 14 with 22q11DS and 14 healthy (including nine siblings) controls.

Results

Within groups, contrasts showed that individuals significantly activated ‘face responsive’ areas when viewing neutral faces, including fusiform-extrastriate cortices. Further, within both groups, there was a significant positive linear trend in activation of fusiform-extrastriate cortices and cerebellum to increasing intensities of fear. There were, however, also between-group differences. Children with 22q11DS generally showed reduced activity as compared to controls in brain regions involved in social cognition and emotion processing across emotion types and intensities, including fusiform-extrastriate cortices, anterior cingulate cortex (Brodmann area (BA) 24/32), and superomedial prefrontal cortices (BA 6). Also, an exploratory correlation analysis showed that within 22q11DS children reduced activation was associated with behavioural impairment—social difficulties (measured using the Total Difficulties Score from the Strengths and Difficulties Questionnaire [SDQ]) were significantly negatively correlated with brain activity during fear and disgust processing (respectively) in the left precentral gyrus (BA 4) and in the left fusiform gyrus (FG, BA 19), right lingual gyrus (BA 18), and bilateral cerebellum.

Conclusions

Regions involved in face processing, including fusiform-extrastriate cortices, anterior cingulate gyri, and superomedial prefrontal cortices (BA 6), are activated by facial expressions of fearful, disgusted, and neutral expressions in children with 22q11DS but generally to a lesser degree than in controls. Hypoactivation in these regions may partly explain the social impairments of children with 22q11DS.

Electronic supplementary material

The online version of this article (doi:10.1186/1866-1955-7-1) contains supplementary material, which is available to authorized users.     

Visuospatial working memory in children and adolescents with 22q11.2 deletion syndrome; an fMRI study

22q11.2 deletion syndrome (22q11DS) is a genetic disorder associated with a microdeletion of chromosome 22q11. In addition to high rates of neuropsychiatric disorders such as schizophrenia and attention deficit hyperactivity disorder, children with 22q11DS have a specific neuropsychological profile with particular deficits in visuospatial and working memory. However, the neurobiological substrate underlying these deficits is poorly understood. We investigated brain function during a visuospatial working memory (SWM) task in eight children with 22q11DS and 13 healthy controls, using fMRI. Both groups showed task-related activation in dorsolateral prefrontal cortex (DLPFC) and bilateral parietal association cortices. Controls activated parietal and occipital regions significantly more than those with 22q11DS but there was no significant between-group difference in DLPFC. In addition, while controls had a significant age-related increase in the activation of posterior brain regions and an age-related decrease in anterior regions, the 22q11DS children showed the opposite pattern. Genetically determined differences in the development of specific brain systems may underpin the cognitive deficits in 22q11DS, and may contribute to the later development of neuropsychiatric disorders.     

Shyness discriminates between children with 22q11.2 deletion syndrome and Williams syndrome and predicts emergence of psychosis in 22q11.2 deletion syndrome

Background

22q11.2 deletion syndrome (22q11.2DS) is a common neurogenetic syndrome associated with high rates of psychosis. The aims of the present study were to identify the unique temperament traits that characterize children with 22q11.2DS compared to children with Williams syndrome (WS) and typically developing (TD) controls, and to examine temperamental predictors of the emergence of psychosis in 22q11.2DS.

Methods

The temperament of 55 children with 22q11.2DS, 36 with WS, and 280 TD children was assessed using the Emotionality, Activity, Sociability (EAS) Temperament Survey, Parental Ratings. The presence of a psychotic disorder was evaluated in 49 children and adolescents with 22q11.2DS at baseline and again 5.43 ± 2.23 years after baseline temperament assessment.

Results

Children with 22q11.2DS scored higher on Shyness compared to WS and TD controls. Children with 22q11.2DS and WS scored higher on Emotionality and lower on Activity compared to TD controls. Shyness was more severe in older compared to younger children with 22q11.2DS. Baseline Shyness scores significantly predicted the later emergence of a psychotic disorder at follow-up, in children with 22q11.2DS.

Conclusions

Our results suggest that shyness is an early marker associated with the later emergence of psychosis in 22q11.2DS.     

Parental origin of the deletion 22q11.2 and brain development in velocardiofacial syndrome: a preliminary study

BACKGROUND: As children with velocardiofacial syndrome (VCFS) develop, they are at increased risk for psychopathology; one third will eventually develop schizophrenia. Because VCFS and the concomitant symptomatology result from a known genetic origin, the biological and behavioral characteristics of the syndrome provide an optimal framework for conceptualizing the associations among genes, brain development, and behavior. The purpose of this study was to investigate the effect of the parental origin of the 22q11.2 microdeletion on the brain development of children and adolescents with VCFS. METHODS: Eighteen persons with VCFS and 18 normal control subjects were matched individually for age and sex. Results of DNA polymorphism analyses determined the parental origin of the deletion. Nine persons with VCFS had a deletion on the maternally derived chromosome 22; 9 persons, on the paternally derived chromosome 22. High-resolution magnetic resonance imaging scans were analyzed to provide quantitative measures of gray and white matter brain tissue. RESULTS: Total brain volume was approximately 11% smaller in the VCFS group than in controls. Comparisons between VCFS subgroups (maternal vs paternal microdeletion 22q11.2) indicated a significant 9% volumetric difference in total volume of cerebral gray matter (volume was greater in patients with paternal microdeletion) but not cerebral white matter. Significant age-related changes in gray matter were detected for subjects whose 22q11.2 deletion was on the maternal chromosome. CONCLUSIONS: Children and adolescents with VCFS experience major alterations in brain volumes. Significant reduction in gray matter development is attributable to presence of 22q11.2 microdeletion on the maternal chromosome.     

Neurological manifestation of 22q11.2 deletion syndrome

Neurological Sciences - 22q11.2 deletion syndrome is the most common microdeletion syndrome. This article reviews the different neurological manifestations of 22q11.2 deletion syndrome. The...     

Facial emotion perception by intensity in children and adolescents with 22q11.2 deletion syndrome

Difficulties in the recognition of emotions in expressive faces have been reported in people with 22q11.2 deletion syndrome (22q11.2DS). However, while low-intensity expressive faces are frequent in everyday life, nothing is known about their ability to perceive facial emotions depending on the intensity of expression. Through a visual matching task, children and adolescents with 22q11.2DS as well as gender- and age-matched healthy participants were asked to categorise the emotion of a target face among six possible expressions. Static pictures of morphs between neutrality and expressions were used to parametrically manipulate the intensity of the target face. In comparison to healthy controls, results showed higher perception thresholds (i.e. a more intense expression is needed to perceive the emotion) and lower accuracy for the most expressive faces indicating reduced categorisation abilities in the 22q11.2DS group. The number of intrusions (i.e. each time an emotion is perceived as another one) and a more gradual perception performance indicated smooth boundaries between emotional categories. Correlational analyses with neuropsychological and clinical measures suggested that reduced visual skills may be associated with impaired categorisation of facial emotions. Overall, the present study indicates greater difficulties for children and adolescents with 22q11.2DS to perceive an emotion in low-intensity expressive faces. This disability is subtended by emotional categories that are not sharply organised. It also suggests that these difficulties may be associated with impaired visual cognition, a hallmark of the cognitive deficits observed in the syndrome. These data yield promising tracks for future experimental and clinical investigations.     

Risk factors for the emergence of psychotic disorders in adolescents with 22q11.2 deletion syndrome

OBJECTIVE: The 22q11.2 deletion syndrome is the most common known genetic risk factor for the development of schizophrenia. The authors conducted a longitudinal evaluation of adolescents with 22q11.2 deletion syndrome to identify early risk factors for the development of psychotic disorders. METHOD: Sixty children, 31 with 22q11.2 deletion syndrome and 29 comparison subjects with idiopathic developmental disability matched for age and IQ, underwent a baseline evaluation between 1998 and 2000; of these, 51 children (28 and 23 in the two groups, respectively) underwent follow-up evaluation between 2003 and 2005. A standardized comprehensive psychiatric, psychological, and adaptive functioning evaluation was conducted in both waves. Participants with 22q11.2 deletion syndrome were also genotyped for the catechol O-methyltransferase (COMT) Met/Val polymorphism and underwent magnetic resonance imaging scans. RESULTS: The two groups had similar baseline neuropsychiatric profiles. At follow-up, 32.1% of subjects with 22q11.2 deletion syndrome had developed psychotic disorders as compared with 4.3% of comparison subjects. In the 22q11.2 deletion syndrome group, baseline subthreshold psychotic symptoms interacted both with the COMT genotype and with baseline symptoms of anxiety or depression to predict 61% of the variance in severity of psychosis at follow-up evaluation. Lower baseline verbal IQ was also associated with more severe psychotic symptoms at follow-up evaluation. CONCLUSIONS: Genetic, cognitive, and psychiatric risk factors for the evolution of psychotic disorders in 22q11.2 deletion syndrome during adolescence were identified. Early intervention in the subgroup of children with subthreshold signs of psychosis and internalizing symptoms (especially anxiety symptoms) may reduce the risk of developing psychotic disorders during adolescence.     

Psychotic symptoms in children and adolescents with 22q11.2 deletion syndrome: Neuropsychological and behavioral implications

Individuals with 22q11.2 deletion syndrome (22q11DS) are at increased risk for developing schizophrenia: half of affected adolescents report transient psychotic experiences and up to 30% of adults are diagnosed with schizophrenia. Prospective studies have shown that psychotic symptoms in childhood are predictive of later schizophreniform disorders. The current study aimed to define the prevalence and correlates of psychotic symptoms (PS) in young children and adolescents with 22q11DS. Forty-three children and adolescents with 22q11DS (mean age = 10.62+/-11.19) participated in this study. The occurrence of PS and their neuropsychological and behavioral correlates were investigated through semi-structured interviews and standardized measures. Psychotic symptoms were reported in 28% of the total sample and 17% of pre-adolescent children, and associated with decreased verbal IQ scores [F(1) = 4.41, p = 0.042]. Compared to young patients without PS, young patients with PS were perceived by their parents as more anxious-depressed [F(1) = 4.76, p = 0.035] and withdrawn [F(1) = 7.63, p = 0.009], with reduced adaptive socialization skills [F(1) = 6.88, p = 0.012]. Results suggest that psychotic manifestations are present earlier than typically reported in youngsters with 22q11DS and are accompanied by reduced verbal IQ performance and decreased adaptative social skills. The symptomatic, neuropsychological and behavioral characteristics observed in the current study may constitute central markers of increased risk for psychosis in 22q11DS.     

Resting-state networks in adolescents with 22q11.2 deletion syndrome: associations with prodromal symptoms and executive functions

Atypical functional connectivity in the maturing brains of 22q11.2 deletion syndrome (22q11DS) may contribute to the expression of early psychotic symptoms commonly reported by these youths. This study's objective was to examine functional connectivity in cerebral networks at rest (Resting-State Networks; RSNs) and their relationship to symptomatic and neuropsychological characteristics putting them at very high risk factor for developing psychosis. Twenty-seven adolescents with 22q11DS and 33 typically developing control adolescents matched for age, gender and handedness underwent an 8-minute resting state functional MRI session. RSNs identification procedure employed Independent Component Analysis (ICA). We tested for potential group differences in functional connectivity within-networks. Then, we examined relationships between network connectivity and symptomatic/neuropsychological characteristics in the 22q11DS group. A total of nine resting-state networks were identified. Between-group differences suggested both increased and decreased functional connectivity in the 22q11DS group, involving the default-mode, sensorimotor, visuo-spatial, and high level visual networks. Finally, atypical connectivity in the default-mode network, specifically within the left superior frontal gyrus region, correlated with prodromal symptom intensity and neuropsychological performances in the 22q11DS group. The results suggest that atypical functional connectivity may sustain both increased vulnerability to psychosis and characteristic cognitive impairments in 22q11DS.