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.

Children with chromosome 22q11.2 Deletion Syndrome (22q11.2DS), Fragile X Syndrome (FXS), or Turner Syndrome (TS) are considered to belong to distinct genetic groups, as each disorder is caused by separate genetic alterations. Even so, they have similar cognitive and behavioral dysfunctions, particularly in visuospatial and numerical abilities. To assess evidence for common underlying neural microstructural alterations, we set out to determine whether these groups have partially overlapping white matter abnormalities, relative to typically developing controls. We scanned 101 female children between 7 and 14 years old: 25 with 22q11.2DS, 18 with FXS, 17 with TS, and 41 aged-matched controls using diffusion tensor imaging (DTI). Anisotropy and diffusivity measures were calculated and all brain scans were nonlinearly aligned to population and site-specific templates. We performed voxel-based statistical comparisons of the DTI-derived metrics between each disease group and the controls, while adjusting for age. Girls with 22q11.2DS showed lower fractional anisotropy (FA) than controls in the association fibers of the superior and inferior longitudinal fasciculi, the splenium of the corpus callosum, and the corticospinal tract. FA was abnormally lower in girls with FXS in the posterior limbs of the internal capsule, posterior thalami, and precentral gyrus. Girls with TS had lower FA in the inferior longitudinal fasciculus, right internal capsule and left cerebellar peduncle. Partially overlapping neurodevelopmental anomalies were detected in all three neurogenetic disorders. Altered white matter integrity in the superior and inferior longitudinal fasciculi and thalamic to frontal tracts may contribute to the behavioral characteristics of all of these disorders.

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 ages 7-14 years 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 ed.: BASC-2 and Spence Children’s Anxiety Scale: SCAS) and adaptive functioning (BASC-2 and Adaptive Behavior Assessment System, 2nd ed.: ABAS-II). 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 vs. 58% with at least one elevated anxiety score (BASC-2 and/or SCAS). Mean BASC-2 anxiety scores were significantly higher in 22q11.2DS (55.6+12.5) than TD (48.3+10; p=0.003) and a greater percentage of children with 22q11.DS (37%) had elevated BASC-2 anxiety scores compared with TD (14%; p=0.01). Higher anxiety scores were related to lower adaptive function (r=−0.27, p=0.015) but there was no relationship between WISC-IV FSIQ and BASC-2 adaptive skills (r=−0.06, p=0.6) in the 22q11.2DS group. For the individual SCAS anxiety subscales, panic-agoraphobia (r=−0.38, p=0.03), physical injury (r=−0.34, p=0.05), and obsessive compulsive disorder (r=−0.47, p=0.005) were significantly negatively related to adaptive function in 22q11.2DS. Conclusions Despite known risk, anxiety is under-identified in children with 22q11.2DS. The presence of anxiety symptoms, but not intelligence levels, in children with 22q11.2DS is negatively correlated with adaptive function and impacts everyday living skills.

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The shy-bold continuum is a fundamental behavioral trait conserved across human and nonhuman animals. Individual differences along the shy-bold continuum are presumed to arise from, and are maintained by, differences in the excitability of forebrain limbic areas involved in the evaluation of stimulus saliency. To test this hypothesis, the authors conducted an event-related functional MRI (fMRI) study in which brain scans were acquired on shy and bold adults during the presentation of neutral stranger and personally familiar faces. Shy adults exhibited greater bilateral amygdala activation during the presentation of stranger faces and greater left amygdala activation during personally familiar faces than their bold counterparts. Bold adults exhibited greater bilateral nucleus accumbens activation in response to stranger and personally familiar faces than shy adults. Findings suggest that there are distinct neural substrates underlying and maintaining individual differences along a shy-bold continuum in humans.