Source monitoring for actions in adolescents with 22q11.2 deletion syndrome (22q11DS)

BACKGROUND: Source monitoring consists in identifying the origin of mental events. Recent research suggests that confusions over internally generated mental events may represent a cognitive marker for increased proneness to psychotic symptoms and disorders. We have examined source monitoring for actions in adolescents with the 22q11.2 deletion syndrome (22q11DS), a neurogenetic disease associated with high rates of schizophrenia during adulthood, and expected to observe source monitoring deficits in comparison to IQ-matched and typically developing controls. METHOD: Eighteen adolescents with 22q11DS, 17 adolescents matched for age and IQ, and also 17 adolescents matched for age participated in this study. Our adapted action monitoring paradigm asked subjects to visualize a series of actions in three different conditions: (1) visualize themselves performing the action; (2) visualize the experimenter performing the action; or (3) simply repeat the action statements without visualization of the action performer. RESULTS: The adolescents with 22q11DS performed adequately in terms of recognition (hits), but in comparison to both control groups, they committed more source confusions on correctly recognized items. Further examination revealed that the adolescents were more likely to demonstrate confusions between exterior sources in which the self was not involved. CONCLUSIONS: Source monitoring deficits can be observed in adolescents with 22q11DS, a syndrome putting them at high risk for developing schizophrenia. These deficits are discussed in terms of early cognitive processes associated with genetic risk for schizophrenia.     

Exploring the potential association among sleep disturbances,cognitive impairments,and immune activation in 22q11.2 deletion syndrome

22q11.2 deletion syndrome (22q11.DS) is a neurogenetic disorder caused by a microdeletion in chromosome 22. Its phenotype includes high rates of psychiatric disorders, immune system abnormalities, and cognitive impairments. We assessed the quality of sleep in 22q11.2DS and its potential link to inflammatory markers and cognitive deficits. Thirty‐three 22q11.2DS individuals and 24 healthy controls were studied. Sleep parameters were assessed by the Pittsburgh sleep quality index (PSQI) questionnaire and correlated with serum cytokine levels and cognitive functioning, measured using the Penn computerized neurocognitive battery (CNB). The 22q11.2DS individuals had significantly worse sleep quality scores than the controls, unrelated to the psychiatric or physical comorbidities common to 22q11.2DS. Interleukin 6 levels were correlated with the overall score of the PSQI questionnaire for nonpsychotic 22q11.2DS participants only. Several domains of the CNB were associated with poorer sleep quality, suggesting that cognitive impairments in 22q11.2DS may be at least partially explained by poor sleep quality. Our findings confirm sleep impairments in individuals with 22q11.2DS, which might negatively affect their cognitive functioning, and corroborate a potential role of immunological pathways in the 22q11.2DS neuro‐phenotype.     

Emotional bias and inhibitory control processes in mania and depression

BACKGROUND: Despite markedly different clinical presentations, few studies have reported differences in neuropsychological functioning between mania and depression. The disinhibited behaviour characteristic of mania and evidence that subgenual prefrontal cortex is differentially activated in mania and depression both suggest that dissociable deficits will emerge on tasks that require inhibitory control and are subserved by ventromedial prefrontal cortex. METHODS: Manic patients and controls undertook computerized neuropsychological tests of memory and planning ability. In addition, manic and depressed patients were directly compared with controls on a novel affective shifting task that requires inhibitory control over different components of cognitive and emotional processing. RESULTS: Manic patients were impaired on tests of memory and planning. Importantly, affective shifting performance of manic patients differed from that of depressed patients. Manic patients were impaired in their ability to inhibit behavioural responses and focus attention, but depressed patients were impaired in their ability to shift the focus of attention. Depressed patients exhibited an affective bias for negative stimuli, and we believe this to be the first demonstration of an affective bias for positive stimuli in manic patients. CONCLUSIONS: Observed impairments on tests of memory and planning suggest a global pathology for mania consistent with previous profiles for this disorder and similar to established profiles for depression. The results on the affective shifting task demonstrate the presence of mood-congruent bias and dissociable components of inhibitory control in mania and depression. Against a background of memory and planning impairments in the two groups, these findings are consistent with a role for the ventromedial prefrontal cortex in mediating mood-cognition relationships.     

A multilevel analysis of cognitive dysfunction and psychopathology associated with chromosome 22q11.2 deletion syndrome in children

We present a multilevel approach to developing potential explanations of cognitive impairments and psychopathologies common to individuals with chromosome 22q11.2 deletion syndrome. Results presented support our hypothesis of posterior parietal dysfunction as a central determinant of characteristic visuospatial and numerical cognitive impairments. Converging data suggest that brain development anomalies, primarily tissue reductions in the posterior brain and changes to the corpus callosum, may affect parietal connectivity. Further findings indicate that dysfunction in "frontal" attention systems may explain some executive cognition impairments observed in affected children, and that there may be links between these domains of cognitive function and some of the serious psychiatric conditions, such as attention-deficit/hyperactivity disorder, autism, and schizophrenia, that have elevated incidence rates in the syndrome. Linking the neural structure and the cognitive processing levels in this way enabled us to develop an elaborate structure/function mapping hypothesis for the impairments that are observed. We show also, that in the case of the catechol-O-methyltransferase gene, a fairly direct relationship between gene expression, cognitive function, and psychopathology exists in the affected population. Beyond that, we introduce the idea that variation in other genes may further explain the phenotypic variation in cognitive function and possibly the anomalies in brain development.     

The role of the medial frontal cortex in the development of cognitive and social‐affective performance monitoring

Adolescence is a time of many cognitive and social‐affective changes that are important for rapid behavioral adjustment to a variety of environmental demands and social contexts. Performance monitoring is one of the most important processes for behavioral adjustment; it allows individuals to evaluate outcomes of actions and change behavior accordingly. Neuroimaging studies have demonstrated that dorsal and ventral subregions of the medial frontal cortex are differentially engaged in performance monitoring, depending on the cognitive or social‐affective dimensions of a task. Based on a review of neuroimaging, ERP, and heart rate studies, the implications of these modality‐dependent contributions are discussed for the development of performance monitoring in adolescence.     

Fear and Missing Out: Youth Anxiety and Functional Outcomes

Anxiety disorders are prevalent and associated with functional impairments. Outcome research has focused on symptom reduction, rather than positive factors such as life satisfaction and improved functioning. We review the impact of youth anxiety disorders and elevated anxiety symptoms on academic, occupational, family, social, and legal functioning. Emphasis is placed on the degree to which developmental trajectories differ for youth with and without anxiety disorders. In some areas, psychopathology generally, rather than anxiety specifically, is associated with functional impairment. Other studies support youth anxiety as a unique predictor of functional impairment. In particular, social anxiety is associated with impairments in social functioning throughout development. The short‐ and long‐term impacts of anxiety treatment in youth are discussed. Last, research directions are suggested.     

Sustained attention and inhibitory control in children with sickle cell syndrome.

Comparing sustained attention and inhibitory control among youth with sickle cell syndrome (SCS) and nondiseased sibling controls, this study found significant differences in multiple components of attention and inhibitory control as a function of chronological age. Older SCS youth were found to have increased attention and reflectivity. Although it has been argued that SCS youth without overt neurological impairments might evidence microvascular infarction, the present study, which employed commonly utilized neurocognitive and behavioral measures, does not lend support to the notion of generalized deficits in the absence of specific laboratory findings. Disease parameters including hemoglobin levels, days hospitalized, and emergency room visits were not significantly correlated with performance on any of the measures. Within the limitations of this particular study, results were interpreted to refute the notion of disease-related neurocognitive impairments for SCS youth. Further, the development of attentional skills for SCS youth is suggested to proceed similarly to that of normally developing youth.     

Schizophrenic-like neurocognitive deficits in children and adolescents with 22q11 deletion syndrome.

22q11.2 Deletion Syndrome (22q11DS) is the most common genetic microdeletion syndrome affecting humans. The syndrome is associated with general cognitive impairments and specific deficits in visual-spatial ability, non-verbal reasoning, and planning skills. 22q11DS is also associated with behavioral and psychiatric abnormalities, including a markedly elevated risk for schizophrenia. Research findings indicate that people with schizophrenia, as well as those identified as schizoptypic, show specific cognitive deficits in the areas of sustained attention, executive functioning, and verbal working memory. The present study examined such schizophrenic-like cognitive deficits in children and adolescents with 22q11DS (n = 26) and controls (n = 25) using a cross-sectional design. As hypothesized, 22q11DS participants exhibited deficits in intelligence, achievement, sustained attention, executive functioning, and verbal working memory compared to controls. Furthermore, deficits in attention and executive functioning were more pronounced in the 22q11DS sample relative to general cognitive impairment. These findings suggest that the same pattern of neuropsychological impairment seen in patients with schizophrenia is present in non-psychotic children identified as at-risk for the development of schizophrenia based on a known genetic risk marker.     

The role of COMT and plasma proline in the variable penetrance of autistic spectrum symptoms in 22q11.2 deletion syndrome

This paper examines how COMT¹⁵⁸ genotypes and plasma proline levels are associated with variable penetrance of social behavioural and social cognitive problems in 22q11.2 deletion syndrome (22q11DS). Severity of autistic spectrum symptoms of 45 participants with 22q11DS was assessed using the Autism Diagnostic Interview Revised. Face and facial emotion recognition was evaluated using standardized computer‐based test‐paradigms. Associations with COMT¹⁵⁸ genotypes and proline levels were examined. High proline levels and poor face recognition in individuals with the COMT^MET allele, and poor facial emotion recognition, explained almost 50% of the variance in severity of autism symptomatology in individuals with 22q11DS. High proline levels and a decreased capacity to break down dopamine as a result of the COMT^MET variant are both relevant in the expression of the social phenotype in patients. This epistatic interaction effect between the COMT¹⁵⁸ genotype and proline on the expression of social deficits in 22q11DS shows how factors other than the direct effects of the deletion itself can modulate the penetrance of associated cognitive and behavioural outcomes. These findings are not only relevant to our insight into 22q11DS, but also provide a model to better understand the phenomenon of variable penetrance in other pathogenic genetic variants.     

Father- and Youth-Reported Family Affective Expression Differentially Predicts Youth Internalizing and Externalizing Symptoms

Temperamental approach is associated with adolescent internalizing and externalizing symptoms. Negative family affective expression, or problematic communication about emotions, is also associated with youth’s risk for symptoms. However, it is unclear whether negative family affective expression differentially predicts symptoms based on (a) youth’s temperamental approach and (b) informants’ perceptions of negative family affective expression. To address these issues, we explored whether mother-, father-, and youth-reported negative family affective expression moderated the relation between youth temperamental approach and symptoms. Participants were 775 youths (71% male, 76% Caucasian) assessed at ages 10–12 (Time 1) and 12–14 (Time 2). Mothers, fathers, and youths reported on negative family affective expression and youths reported on temperamental approach at Time 1. Teachers reported on youth symptoms at Times 1 and 2. Youth- and father-reported, but not mother-reported, negative family affective expression moderated the relation between youth approach and symptoms. When youths reported higher negative family affective expression, youths lower in approach exhibited higher internalizing symptoms than youths higher in approach. In contrast, when fathers reported lower negative family affective expression, youths lower in approach exhibited higher internalizing and externalizing symptoms than youths higher in approach. Assessments and interventions for youth symptoms should include not only temperamental features, but also multiple informants’ perspectives of family affective expression. Such efforts could promote greater family communication, address problematic family dynamics, and potentially attenuate risk for youth symptoms.     

Riluzole effectively treats psychotic symptoms and improves cognition in 22q11.2 deletion syndrome: A clinical case

22q11.2 deletion syndrome (22q11DS) is a genetic disorder caused by a hemizygous microdeletion on the long arm of chromosome 22 and is associated with a high risk for psychosis and cognitive impairment. One of the genes located in the deleted region of 22q11DS is Proline Dehydrogenase (PRODH) which is important for conversion of proline to glutamate. Glutamate is the primary excitatory neurotransmitter and is involved in the pathophysiology of psychosis as well as in cognition. Excessive concentrations are toxic. Possibly, neuroprotective drugs modulating glutamatergic neurotransmission could be effective in treating psychotic symptoms and cognitive enhancement in patients with 22q11DS. Riluzole is a potent anti-glutamatergic drug that reduces glutamatergic neurotransmission. Here we report acute (single dose) and long-term effects of riluzole on glutamate and GABA levels in the anterior cingulate cortex (ACC) and striatum (measured with magnetic resonance spectroscopy, 1H-MRS) as well as on psychotic symptoms and cognitive functioning in a medication-free 23-year old woman with 22q11DS. Patient presented with frequent auditory and visual hallucinations and mild paranoid ideas. The ¹H-MRS measurements showed that after a single dose riluzole (50 mg), glutamate in the ACC and striatum was reduced whereas striatal GABA increased compared to baseline. Strikingly, hallucinations and paranoia disappeared. Therefore, riluzole treatment was initiated and patient was followed up after 18 months of treatment. At follow-up, patient reported no hallucinations or paranoia and several cognitive functions were improved. Furthermore, glutamate concentrations in the ACC and striatum decreased whereas GABA concentrations increased in the striatum but decreased in the ACC. These results suggests that riluzole may be an effective treatment option for psychotic symptoms and cognitive enhancement in 22q11DS. Results warrant replication in a bigger sample.     

Early language measures associated with later psychosis features in 22q11.2 deletion syndrome

The 22q11.2 deletion syndrome (22q11DS) is associated with impaired cognitive functions and increased risk for schizophrenia spectrum disorders. Speech and language deficits are prominent, with evidence of decline anteceding emergence of psychosis. There is paucity of data examining language function in children with 22q11DS with follow‐up assessment of psychosis spectrum (PS) symptoms. We examined the association between early language measures, obtained clinically, and PS status, obtained on average 10.1 years later, in 166 youths with 22q11DS, with repeated language testing in 48. Participants were administered the Preschool Language Scale (receptive/expressive), and/or, for school aged children, the Clinical Evaluation of Language Fundamentals (receptive/expressive), and age appropriate IQ tests. The structured interview for prodromal syndromes (SIPS) assessed PS symptoms. We found that performance on all preschool measures showed age associated decline, and males performed more poorly on core composite (receptive/expressive) and receptive language measures. For language assessment later in childhood, poorer performance was consistently associated with subsequent PS status. Furthermore, steeper age‐related decline was seen in the PS group across language measures and marginally for full‐scale IQ. These findings suggest that while preschool language testing is useful in characterizing performance decline in individuals with 22q11DS, it does not robustly differentiate those with subsequent PS from those without. However, language testing in the school age population can help identify individuals with 22q11DS who are at risk for psychosis. Such data are needed for elucidating a lifespan trajectory for affected individuals and may help understand pathways to psychosis applicable to the general population.     

Psychological functioning,brain morphology,and functional neuroimaging in Klinefelter syndrome

Klinefelter syndrome (KS; 47,XXY) impacts neurodevelopment and is associated with an increased risk of cognitive, psychological and social impairments, although significant heterogeneity in the neurodevelopmental profile is seen. KS is characterized by a specific cognitive profile with predominantly verbal deficits, preserved function in non‐verbal and visuo‐spatial domains, executive dysfunction and social impairments, and by an increased vulnerability toward psychiatric disorders. The neurobiological underpinnings of the observed neuropsychological profile have not been established. A distinct pattern of both global and regional brain volumetric differences has been demonstrated in addition to preliminary findings of functional brain alterations related to auditory, motor, language and social processing. When present, the combination of cognitive, psychological and social challenges has the potential to negatively affect quality of life. This review intends to provide information and insight to the neuropsychological outcome and brain correlates of KS. Possible clinical intervention and future directions of research will be discussed.     

Behavior in preschool children with the 22q11.2 deletion syndrome

Children with the 22q11.2 deletion syndrome (22q11DS) are at an increased risk of psychiatric problems from pre‐adolescence; little is known, however, about behavioral problems at a preschool age and the relationship between speech and behavior in this group. Parents of 90 children (aged 1.42–5.99 years) with 22q11DS filled out the Child Behavior Checklist, documenting behaviors including speech problems. Their profiles were compared with those of a comparison group consisting of 33 children with nonsyndromic orofacial clefts without 22q11DS, since both children with 22q11DS and children with clefts are expected to have speech problems. In the 22q11DS group, data on intelligence was acquired by means of formal tests. Parents of children with 22q11DS reported significantly higher mean scores on withdrawn behavior, affective problems and pervasive developmental problems compared to children with nonsyndromic clefts. Approximately 30% of children with 22q11DS had a score above the 97th percentile on at least one of the behavior subscales, indicating psychopathology. In children with 22q11DS, the reported behavioral problems were not associated with speech problems. Behavioral problems were found in 30% of young children with 22q11DS and were unlikely to be caused by speech problems. Within the 22q11DS group, behavioral problems were not related to the degree of cognitive impairment. This shows that many children with 22q11DS, known to be at an increased risk of psychiatric problems from pre‐adolescence, already show behavioral problems before the age of 6 years. © 2012 Wiley Periodicals, Inc.     

Specific cerebellar reductions in children with chromosome 22q11.2 deletion syndrome

Children with chromosome 22q11.2 deletion syndrome commonly are found to have morphological brain changes, cognitive impairments, and elevated rates of psychopathology. One of the most commonly and consistently reported brain changes is reduced cerebellar volume. Here, we demonstrate that, in addition to the global cerebellum reductions previously reported, volumetric reductions of the anterior lobule and the vermal region of the neo-cerebellum in the mid-sagittal plane best differentiate children with the deletion from typically developing children. These results suggest that the morphological changes of specific portions of the cerebellum may be an important underlying substrate of cognitive impairments and increased incidence of psychopathology in this group.     

Neural systems of threat processing in adolescents: role of pubertal maturation and relation to measures of negative affect

Adolescence ushers in dramatic social and affective changes and increased vulnerability for affective disorders. Yet, little is known about the effects of pubertal maturation on neural systems of social threat processing. We examined adolescents' brain function to social stimuli in relation to pubertal maturation, depressive symptoms, and real-world subjective negative affect. Compared with pre/early adolescents, mid/late adolescents exhibited less amygdala reactivity to emotionally neutral faces relative to non-face stimuli; less ventrolateral prefrontal cortex (VLPFC) reactivity to fearful faces relative to non-face stimuli, neutral faces, or angry faces; and more VLPFC reactivity to angry relative to neutral faces. Amygdala and VLPFC reactivity were correlated with negative affect and depressive symptoms. Threat-processing changes during puberty may facilitate changes in social behavior and negative affect.     

Error‐related electromyographic activity over the corrugator supercilii is associated with neural performance monitoring

Emerging research in social and affective neuroscience has implicated a role for affect and motivation in performance monitoring and cognitive control. No study, however, has investigated whether facial electromyography (EMG) over the corrugator supercilii—a measure associated with negative affect and the exertion of effort—is related to neural performance monitoring. Here, we explored these potential relationships by simultaneously measuring the error‐related negativity, error positivity (Pe), and facial EMG over the corrugator supercilii muscle during a punished, inhibitory control task. We found evidence for increased facial EMG activity over the corrugator immediately following error responses, and this activity was related to the Pe for both between‐ and within‐subject analyses. These results are consistent with the idea that early, avoidance‐motivated processes are associated with performance monitoring, and that such processes may also be related to orienting toward errors, the emergence of error awareness, or both.     

A study of psychological sense of community as a mediator between supportive social systems,school belongingness,and outcome behaviors among urban high school students of color

Psychological sense of community (SOC) has been examined minimally among the youth of color, and as a mediating variable, as well as construct implicated in promoting wellness. Using data from a sample of 401 students of color (M _age = 16.55, standard deviation = 1.31; 54.7% female; 57% Hispanic/Latina[o]) from an underserved northeastern US urban community, we examined the mediating relationship of psychological SOC between social support, participation in youth‐based community programs, and outcomes including school belongingness, risk behaviors such as substance use and violent behavior, and psychological symptoms, including depression. Results indicated that access to social supports and youth‐based community programs was negatively associated with risk behaviors and experiencing depressive symptoms, through both psychological SOC and school belongingness. Implications include the need for community‐based activities for youth that not only foster support but encourage a positive psychological SOC and in‐turn offset negative developmental trajectories and risk behaviors.     

Differentiation of executive and attention impairments in affective illness

BACKGROUND: Executive impairments have been reported in affective illness, but the influence of attention on executive performance has not been fully considered. The purpose of this study was to investigate whether executive impairments in affective illness were independent of attention impairments, and whether independent executive impairments were specific to bipolar (BP) affective illness. METHOD: Forty-two individuals with major affective disorders [20 unipolar (UP) depression and 22 BP disorder] were compared with 40 healthy controls on measures of attention and executive function. None of the patients were currently experiencing an episode of affective illness. RESULTS: As expected, both UP and BP patient groups showed significant neuropsychological impairments relative to controls. Significant differences in performance on executive function measures were also observed between UP and BP patients, even after the influence of attention had been taken into account. These impairments were not attributable to current levels of affective symptomatology or to medication. CONCLUSIONS: A single neuropsychological dissociation appears to be present between UP and BP affective illness, with BP individuals showing a specific executive deficit that is independent of attention impairment on the Hayling Sentence Completion Test (HSCT).     

Palmitoylation-dependent neurodevelopmental deficits in a mouse model of 22q11 microdeletion

Individuals with 22q11.2 microdeletions have cognitive deficits and a high risk of developing schizophrenia. Here we provide evidence that primary hippocampal neurons from a mouse model of 22q11.2 deletion (Df(16)A(+/-) mice) have decreased density of dendritic spines and glutamatergic synapses, as well as impaired dendritic growth. These deficits were prevented by introduction of the enzymatically active ZDHHC8 palmitoyltransferase encoded by a gene in the 22q11.2 locus, and they were also observed in primary cultures from Zdhhc8-deficient mice. Many of these deficits were also present in the hippocampi of adult Df(16)A(+/-) and Zdhhc8-deficient mice. Finally, we provide evidence that PSD95 is one of the substrates of ZDHHC8. Our analysis reveals that 22q11.2 microdeletion results in deficits in neuronal development and suggests that impaired neuronal protein palmitoylation contributes to many of these deficits.