IQ, parent- and self-reports of child anxiety and salivary cortisol in a sample of children with autism spectrum disorder.

This study examined the relation between IQ, parent-reported child anxiety, and salivary cortisol levels in youth with autism spectrum disorder (ASD) with a wide range of intellectual abilities using a prospective design. Results showed that IQ at time 1 (T1) positively predicted parent-reports of child anxiety at time 2 (T2); however, IQ at T1 negatively predicted cortisol levels from saliva samples taken at a research laboratory at T2. Parent reports of child anxiety at T1 and T2 were not associated with cortisol levels at T2. Implications for the assessment of anxiety in youth with ASD are discussed.

Brain structure and function in the fourth decade of life after extremely low birth weight: An MRI and EEG study.

OBJECTIVE: To examine potential long-term effects of extremely low birth weight (ELBW; ≤ 1000 g) on adult brain structure, brain function, and cognitive-behavioral performance. METHODS: A subset of survivors from the prospectively-followed McMaster ELBW Cohort (n = 23, MBW = 816 g) and their peers born at normal birth weight (NBW; ≥ 2500 g; n = 14, MBW = 3361 g) provided T1-weighted magnetic resonance imaging (MRI) brain scans, resting electroencephalographic (EEG) recordings, and behavioral responses to a face-processing task in their early thirties. RESULTS: Visual discrimination accuracy for human faces, resting EEG alpha power, and long-distance alpha coherence were lower in ELBW survivors than NBW adults, and volumes of white matter hypointensities (WMH) were higher. Across groups, face-processing performance was correlated positively with posterior EEG spectral power and long-distance alpha and theta coherence, and negatively with WMH. The associations between face-processing scores and parietal alpha power and theta coherence were reduced after adjustment for WMH. CONCLUSIONS: Electrocortical activity, brain functional connectivity, and higher-order processing ability may be negatively affected by WMH burden, which is greater in adults born extremely preterm. SIGNIFICANCE: Decrements in electrocortical activity and behavioral performance in adult ELBW survivors may be partly explained by increased WMH volumes in this vulnerable population.

Morphology of the prefrontal cortex predicts body composition in early adolescence: cognitive mediators and environmental moderators in the ABCD Study.

Morphological features of the lateral prefrontal cortex (PFC) in late childhood and early adolescence may provide important clues as to the developmental etiology of clinical conditions such as obesity. Body composition measurements and structural brain imaging were performed on 11 226 youth at baseline (age 9 or 10 years) and follow-up (age 11 or 12 years). Baseline morphological features of the lateral PFC were examined as predictors of body composition. Findings revealed reliable associations between middle frontal gyrus volume, thickness and surface area and multiple indices of body composition. These findings were consistent across both time points and remained significant after covariate adjustment. Cortical thicknesses of the inferior frontal gyrus and lateral orbitofrontal cortex were also reliable predictors. Morphology effects on body composition were mediated by performance on a non-verbal reasoning task. Modest but reliable moderation effects were observed with respect to environmental self-regulatory demand after controlling for sex, race/ethnicity, income and methodological variables. Overall findings suggest that PFC morphology is a reliable predictor of body composition in early adolescence, as mediated through select cognitive functions and partially moderated by environmental characteristics.

Morphometry of the lateral orbitofrontal cortex is associated with eating dispositions in early adolescence: findings from a large population-based study.

Early adolescence is a critical period for eating behaviors as children gain autonomy around food choice and peer influences increase in potency. From a neurodevelopmental perspective, significant structural changes take place in the prefrontal cortex during this time, including the orbitofrontal cortex (OFC), which is involved in socially contextualized decision-making. We examined the morphological features of the OFC in relation to food choice in a sample of 10 309 early adolescent children from the Adolescent Brain and Cognitive Development Study. Structural parameters of the OFC and insula were examined for relationships with two important aspects of food choice: limiting the consumption of fast/fried food and maximizing the consumption of nutritious foods. Raw, partially adjusted and fully adjusted models were evaluated. Findings revealed that a larger surface area of the lateral OFC was associated with higher odds of limiting fast/fried food consumption in raw [odds ratio (OR) = 1.07, confidence interval (CI): 1.02, 1.12, P = 0.002, PFDR = 0.012], partially adjusted (OR = 1.11, CI: 1.03, 1.19, P = 0.004, PFDR = 0.024) and fully adjusted models (OR = 1.11, CI: 1.03, 1.19, P = 0.006, PFDR = 0.036). In contrast, a larger insula volume was associated with lower odds of maximizing healthy foods in raw (OR = 0.94, CI: 0.91, 0.97, P <0.001, PFDR = 0.003) and partially adjusted (OR = 0.93, CI: 0.88, 0.98, P = 0.008, PFDR = 0.048) models. These findings refine our understanding of the OFC as a network node implicated in socially mediated eating behaviors.

Structural Connectivity and Emotion Recognition Impairment in Children and Adolescents with Chromosome 22q11.2 Deletion Syndrome.

Children with chromosome 22q11.2 deletion syndrome (22q11.2DS) exhibit impaired ability to process and understand emotions in others. We measured structural connectivity in children and adolescents with 22q11.2DS (n = 28) and healthy controls (n = 29). Compared to controls, those with 22q11.2DS had poorer social skills and more difficulty recognizing facial emotions. Children with 22q11.2DS also had higher fractional anisotropic diffusion in right amygdala to fusiform gyrus white matter pathways. Right amygdala to fusiform gyrus fractional anisotropy values partially mediated the relationship between 22q11.2DS and social skills, as well as the relationship between 22q11.2DS and emotion recognition accuracy. These findings provide insight into the neural origins of social skills deficits seen in 22q11.2DS and may serve as a biomarker for risk of future psychiatric problems.

Age Differences in Expression of Generalized and Social Anxiety Among Youth with Autism Spectrum Disorder.

This study examined differences in generalized and social anxiety symptoms across two age groups of children with autism spectrum disorder (ASD) while accounting for overall anxiety level, gender, and intellectual functioning. Older children (12-18 years) expressed more overall and social anxiety symptoms than younger children (6-11 years), and social anxiety symptoms were predominant in the older group. Younger children expressed more generalized anxiety symptoms than the older youth, and there was a trend for generalized anxiety symptoms to be more dominant in the younger group. Findings are consistent with theory of differential expression of specific anxiety symptoms across different ages seen with typically developing children, yet social evaluative concerns may be even stronger for adolescents with ASD.

Working Memory Impairments in Chromosome 22q11.2 Deletion Syndrome: The Roles of Anxiety and Stress Physiology.

Stress and anxiety have a negative impact on working memory systems by competing for executive resources and attention. Broad memory deficits, anxiety, and elevated stress have been reported in individuals with chromosome 22q11.2 deletion syndrome (22q11.2DS). We investigated anxiety and physiological stress reactivity in relation to visuospatial working memory impairments in 20 children with 22q11.2DS and 32 typically developing (TD) children ages 7 to 16. Children with 22q11.2DS demonstrated poorer working memory, reduced post-stress respiratory sinus arrhythmia recovery, and overall increased levels of cortisol in comparison to TD children. Anxiety, but not physiological stress responsivity, mediated the relationship between 22q11.2DS diagnosis and visuospatial working memory impairment. Findings indicate that anxiety exacerbates impaired working memory in children with 22q11.2DS.

Processing of different types of social threat in shyness: Preliminary findings of distinct functional neural connectivity.

Current theory suggests that the processing of different types of threat is supported by distinct neural networks. Here we tested whether there are distinct neural correlates associated with different types of threat processing in shyness. Using fMRI and multivariate techniques, we compared neural responses and functional connectivity during the processing of imminent (i.e., congruent angry/angry face pairs) and ambiguous (i.e., incongruent angry/neutral face pairs) social threat in young adults selected for high and low shyness. To both types of threat processing, non-shy adults recruited a right medial prefrontal cortex (mPFC) network encompassing nodes of the default mode network involved in automatic emotion regulation, whereas shy adults recruited a right dorsal anterior cingulate cortex (dACC) network encompassing nodes of the frontoparietal network that instantiate active attentional and cognitive control. Furthermore, in shy adults, the mPFC interacted with the dACC network for ambiguous threat, but with a distinct network encompassing nodes of the salience network for imminent threat. These preliminary results expand our understanding of right mPFC function associated with temperamental shyness. They also provide initial evidence for differential neural networks associated with shy and non-shy profiles in the context of different types of social threat processing.

The failure of anxiolytic therapies in early clinical trials: what needs to be done.

INTRODUCTION: Anxiety spectrum disorders (ASDs) are highly prevalent psychiatric illnesses that affect millions of people worldwide. Strongly associated with stress, common ASDs include generalized anxiety disorder, panic, social anxiety, phobias and drug-abuse-related anxiety. In addition to ASDs, several other prevalent psychiatric illnesses represent trauma/stressor-related disorders, such as post-traumatic stress disorder and acute stress disorder. Anxiolytic drugs, commonly prescribed to treat ASDs and trauma/stressor-related disorders, form a highly heterogenous group, modulating multiple neurotransmitters and physiological mechanisms. However, overt individual differences in efficacy and the potential for serious side-effects (including addiction and drug interaction) indicate a need for further drug development. Yet, over the past 50 years, there has been relatively little progress in the development of novel anxiolytic medications, especially when promising candidate drugs often fail in early clinical trials. AREAS COVERED: Herein, the authors present recommendations of the Task Force on Anxiolytic Drugs of the International Stress and Behavior Society on how to improve anxiolytic drug discovery. These recommendations cover a wide spectrum of aspects, ranging from methodological improvements to conceptual insights and innovation. EXPERT OPINION: In order to improve the success of anxiolytic drugs in early clinical trials, the goals of preclinical trials may need to be adjusted from a clinical perspective and better synchronized with those of clinical studies. Indeed, it is important to realize that the strategic goals and approaches must be similar if we want to have a smoother transition between phases.

Identifying patterns of anxiety and depression in children with chromosome 22q11.2 deletion syndrome: comorbidity predicts behavioral difficulties and impaired functional communications.

BACKGROUND: Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a complex genetic disorder with a variable clinical presentation that can include cardiac, neural, immunological, and psychological issues. Previous studies have measured elevated anxiety and depression in children with 22q11.2DS. Comorbity of anxiety and depression is well established in the pediatric literature but the nature of comorbidity patterns has not been empirically established in children with 22q11.2DS. Comorbidity of anxiety and depression has important implications for treatment and prognosis, and may be a marker of risk in this population of children at high-risk for developing schizophrenia. METHOD: Participants were 131 boys and girls ages 8-14 with (n=76) and without (n=55) 22q11.2DS and their mothers. Children and mothers independently completed self- and parent-report measures of anxiety and depression. Mothers also completed measures of behavioral functioning including the Behavioral Assessment for Children, 2nd ed. (BASC-2). Cluster analyses were conducted to test if theoretically based groupings of anxiety and depression could be identified. We hypothesized four psychological profiles based on child- and mother-reports: low/no anxiety and low/no depression, higher depression and low/no anxiety, higher anxiety and no/low depression, and a comorbid profile of higher anxiety and higher depression. BASC-2 subscale scores were then compared across subgroups of children to determine if a comorbid profile would predict greater behavioral difficulties. RESULTS: In the full sample of children both with and without 22q11.2DS, cluster analyses of self and maternal reported anxiety and depression revealed the expected subgroups: (1) a group of children with higher anxiety/lower depression (anxious); (2) a group with primary depression (lower anxiety/higher depression (depressed)); (3) a comorbid group with higher anxiety/higher depression (comorbid); and, (4) a lowest anxiety/lowest depression group (NP). Mothers' reports produced highly similar groupings. Furthermore, the 22q11.2DS youth were more likely to be in anxiety, depressed or comorbid clusters than the typically developing (TD) youth. Children with 22q11.2DS comorbid for anxiety and depression exhibited the worst functional outcomes (e.g., poor poorer functional communication, and reduced daily life activities). CONCLUSIONS: Anxiety, comorbid with depression may be of particular concern in children with 22q11.2DS who arguably carry a greater burden on their stress coping resources than children without a complex genetic disorder. Furthermore, the manifestation of negative mood, anxiety and difficult behavior is likely to reverberate between the child and her or his environment. This can lead to negative interactions with family, peers, and teachers, which in turn further taxes coping resources. Comorbidity of anxiety and depression within a vulnerable population highlights the need for the development of tailored interventions.

Common and specific impairments in attention functioning in girls with chromosome 22q11.2 deletion, fragile X or Turner syndromes.

BACKGROUND: Chromosome 22q11.2 deletion syndrome (22q11.2DS), fragile X syndrome (FXS), and Turner syndrome (TS) are complex and variable developmental syndromes caused by different genetic abnormalities; yet, they share similar cognitive impairments in the domains of numbers, space, and time. The atypical development of foundational neural networks that underpin the attentional system is thought to result in further impairments in higher-order cognitive functions. The current study investigates whether children with similar higher-order cognitive impairments but different genetic disorders also show similar impairments in alerting, orienting, and executive control of attention. METHODS: Girls with 22q11.2DS, FXS, or TS and typically developing (TD) girls, aged 7 to 15 years, completed an attention network test, a flanker task with alerting and orienting cues. Exploration of reaction times and accuracy allowed us to test for potential commonalities in attentional functioning in alerting, orienting, and executive control. Linear regression models were used to test whether the predictors of group and chronological age were able to predict differences in attention indices. RESULTS: Girls with 22q11.2DS, FXS, or TS demonstrated unimpaired function of the alerting system and impaired function of the executive control system. Diagnosis-specific impairments were found such that girls with FXS made more errors and had a reduced orienting index, while girls with 22q11.2DS showed specific age-related deficits in the executive control system. CONCLUSIONS: These results suggest that the control but not the implementation of attention is selectively impaired in girls with 22q11.2DS, TS or FXS. Additionally, the age effect on executive control in girls with 22q11.2DS implies a possible altered developmental trajectory.

Revisiting shyness and sociability: a preliminary investigation of hormone-brain-behavior relations.

Shyness and sociability are two fundamental personality dimensions that are conceptually and empirically orthogonal and are conserved across cultures, development, and phylogeny. However, we know relatively little regarding how shyness and sociability are represented and maintained in the brain. Here we examined neural responses to the processing of different types of social threat using event-related fMRI, the salivary cortisol awakening response (CAR), and sociability in young adults selected for high and low shyness. Shy adults who exhibited a relatively higher CAR displayed neural activity in putative brain regions involved in emotional conflict and awareness, and were more sociable. In contrast, shy adults who displayed a relatively lower CAR exhibited neural activity in putative brain regions linked to fear and withdrawal, and were unsociable. Results revealed no systematic brain responses to social threat processing that correlated with the CAR in non-shy adults. These preliminary results suggest that individual differences in waking morning cortisol levels may influence neural processes that facilitate either social approach or withdrawal among people who are shy. Findings are discussed in relation to their theoretical and clinical implications for moving beyond longstanding descriptive to explanatory models of shyness and sociability and for understanding individual differences in social behavior in general.

Processing of affective faces varying in valence and intensity in shy adults: an event-related fMRI study

Recent behavioral and electrocortical studies have found that shy and socially anxious adults are hypersensitive to the processing of negative and ambiguous facial emotions. We attempted to extend these findings by examining the neural correlates of affective face processing in shy adults using an event-related fMRI design. We presented pairs of faces that varied in affective valence and intensity. The faces were morphed to alter the degree of intensity of the emotional expressive faces. Twenty-four (12 shy and 12 non-shy) young adult participants then made same/different judgments to these faces while in an MR scanner. We found that shy adults exhibited greater neural activation across a distinct range of brain regions to pairs of faces expressing negative emotions, moderate levels of emotional intensity, and emotional faces that were incongruent with one another. In contrast, non-shy individuals exhibited greater neural activation across a distinct range of brain regions to pairs of faces expressing positive emotions, low levels of emotional intensity, and emotional faces that were congruent with one another. Findings suggest that there are differences in neural responses between shy and non-shy adults when viewing affective faces that vary in valence, intensity, and discrepancy.(AU)

Processing of affective faces varying in valence and intensity in shy adults: an event-related fMRI study

Recent behavioral and electrocortical studies have found that shy and socially anxious adults are hypersensitive to the processing of negative and ambiguous facial emotions. We attempted to extend these findings by examining the neural correlates of affective face processing in shy adults using an event-related fMRI design. We presented pairs of faces that varied in affective valence and intensity. The faces were morphed to alter the degree of intensity of the emotional expressive faces. Twenty-four (12 shy and 12 non-shy) young adult participants then made same/different judgments to these faces while in an MR scanner. We found that shy adults exhibited greater neural activation across a distinct range of brain regions to pairs of faces expressing negative emotions, moderate levels of emotional intensity, and emotional faces that were incongruent with one another. In contrast, non-shy individuals exhibited greater neural activation across a distinct range of brain regions to pairs of faces expressing positive emotions, low levels of emotional intensity, and emotional faces that were congruent with one another. Findings suggest that there are differences in neural responses between shy and non-shy adults when viewing affective faces that vary in valence, intensity, and discrepancy.

An examination of the relationship of anxiety and intelligence to adaptive functioning in children with chromosome 22q11.2 deletion syndrome.

OBJECTIVE: This study investigates the relationship between anxiety symptoms and adaptive function in children with chromosome 22q11.2 deletion syndrome (22q11.2DS). METHODS: Seventy-eight children between 7 and 14 years of age with 22q11.2DS and 36 typically developing (TD) children without known genetic syndromes participated in a larger study of neurocognition. Parents completed questionnaires about their child's anxiety symptoms (Behavior Assessment System for Children, 2nd edition [BASC-2] and Spence Children's Anxiety Scale [SCAS]) and adaptive functioning (BASC-2 and Adaptive Behavior Assessment System, 2nd edition). Within the 22q11.2DS group, different DSM-IV anxiety domains were also analyzed using SCAS subscales. RESULTS: Based on parent report, 19% of children with 22q11.2DS had a prior diagnosis of an anxiety disorder versus 58% with at least 1 elevated anxiety score (BASC-2 or SCAS). Mean BASC-2 anxiety scores were significantly higher in 22q11.2DS (55.6 ± 12.5) than in TD children (48.3 ± 10; p = .003), and a greater percentage of children with 22q11.2DS (37%) had an elevated BASC-2 anxiety scores compared with TD children (14%; p = .01). Higher anxiety scores were related to lower adaptive function (r = -.27; p = .015), but there was no relationship between Wechsler Intelligence Scale for Children, 4th edition Full Scale Intelligence Quotient and BASC-2 adaptive skills (r = -.06; p = .6) in the 22q11.2DS group. For the individual SCAS anxiety subscales, panic-agoraphobia (r = -.38; p = .03), physical injury (r = -.34; p = .05), and obsessive-compulsive disorder (r = -.47; p = .005) were significantly negatively related to adaptive function in 22q11.2DS. CONCLUSION: Despite the known risk, anxiety is underidentified in children with 22q11.2DS. The presence of anxiety symptoms, but not intelligence levels, in children with 22q11.2DS negatively correlated with adaptive function and impacts everyday living skills.

Impaired multiple object tracking in children with chromosome 22q11.2 deletion syndrome.

BACKGROUND: Chromosome 22q11.2 Deletion Syndrome (22q11.2DS) occurs in approximately 1:4,000 live births with a complex and variable presentation that includes medical, socioemotional and psychological symptoms with intellectual impairment. Cognitive impairments in spatiotemporal and visuospatial attention have also been reported. However, maintenance of selective attention to dynamic and interacting objects has not been systematically investigated in children with 22q11.2DS. METHODS: We used a multiple object tracking task to assay capacity and resolution performance of children with 22q11.2DS aged 7 to 14 years versus age-matched typically developing (TD) peers. RESULTS: Children with 22q11.2DS but not TD children demonstrated impaired performance when task demands increased due to an increase in the number of targets presented, but not from an increase in object speed. Task performance in children with 22q11.2DS was also unrelated to intelligence or measures of attention deficit hyperactivity disorder. CONCLUSIONS: These findings suggest that children with 22q11.2DS may be particularly susceptible to dynamic crowding of objects with increasing cognitive demands related to monitoring multiple targets reflecting a reduced acuity in spatiotemporal cognitive representation.

How might stress contribute to increased risk for schizophrenia in children with chromosome 22q11.2 deletion syndrome?

The most common human microdeletion occurs at chromosome 22q11.2. The associated syndrome (22q11.2DS) has a complex and variable phenotype with a high risk of schizophrenia. While the role of stress in the etiopathology of schizophrenia has been under investigation for over 30 years (Walker et al. 2008), the stress-diathesis model has yet to be investigated in children with 22q11.2DS. Children with 22q11.2DS face serious medical, behavioral, and socioemotional challenges from infancy into adulthood. Chronic stress elevates glucocorticoids, decreases immunocompetence, negatively impacts brain development and function, and is associated with psychiatric illness in adulthood. Drawing knowledge from the extant and well-developed anxiety and stress literature will provide invaluable insight into the complex etiopathology of schizophrenia in people with 22q11.2DS while suggesting possible early interventions. Childhood anxiety is treatable and stress coping skills can be developed thereby improving quality of life in the short-term and potentially mitigating the risk of developing psychosis.

Atypical functional brain activation during a multiple object tracking task in girls with Turner syndrome: neurocorrelates of reduced spatiotemporal resolution.

Turner syndrome is associated with spatial and numerical cognitive impairments. We hypothesized that these nonverbal cognitive impairments result from limits in spatial and temporal processing, particularly as it affects attention. To examine spatiotemporal attention in girls with Turner syndrome versus typically developing controls, we used a multiple object tracking task during functional magnetic resonance (fMRI) imaging. Participants actively tracked a target among six distracters or passively viewed the animations. Neural activation in girls with Turner syndrome during object tracking overlapped with but was dissimilar to the canonical frontoparietal network evident in typically developing controls and included greater limbic activity. Task performance and atypical functional activation indicate anomalous development of cortical and subcortical temporal and spatial processing circuits in girls with Turner syndrome.

Increased incidence and size of cavum septum pellucidum in children with chromosome 22q11.2 deletion syndrome.

Chromosome 22q11.2 deletion syndrome (22q11.2DS) is a result of a hemizygotic microdeletion that results in a variety of impairments in children including greater risk for psychiatric ailments in adulthood. We used high-resolution magnetic resonance imaging to accurately quantify the length and, for the first time, volume, of the cavum septum pellucidum (CSP) in children aged 7 to 14years with 22q11.2DS and typically developing (TD) controls. Significantly greater anteroposterior length and greater CSP volumes were found in children with 22q11.2DS compared with controls. Furthermore, the largest CSP were found only in the 22q11.2DS group and with a much higher incidence than previously reported in the literature. Given the significant midline anomalies in the brains of those affected by 22q11.2DS, large CSP may be a biomarker of atypical brain development. The implication of these larger CSP for cognitive and behavioral development is a topic in need of further investigation.