Bronwyn Glaser

Diurnal salivary cortisol in pediatric posttraumatic stress disorder

BACKGROUND The hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the pathophysiology of posttraumatic stress disorder (PTSD). Additional information on basal cortisol levels in children exposed to trauma and experiencing PTSD symptoms may contribute to the understanding of the role of this axis in PTSD. METHODS Fifty-one children (30 boys and 21 girls, mean age 10.7 years) with a history of exposure to trauma and PTSD symptoms were compared with 31 age- and gender-matched healthy control subjects. Salivary cortisol was obtained from participants during home measurements and was collected four times a day (prebreakfast, prelunch, predinner, and prebed) for up to 3 consecutive days. RESULTS The clinical group demonstrated significantly elevated cortisol levels when compared with the control group. In addition, exploratory analyses revealed that girls with PTSD symptoms had significantly elevated cortisol levels when compared with boys with PTSD symptoms. CONCLUSIONS The physiologic response of children with history of trauma and with PTSD symptoms may be characterized by heightened adrenal activity.

Psychiatric Disorders and Intellectual Functioning Throughout Development in Velocardiofacial (22q11.2 Deletion) Syndrome

OBJECTIVE Velocardiofacial syndrome (VCFS) is associated with cognitive deficits and high rates of schizophrenia and other neuropsychiatric disorders. We report the data from two large cohorts of individuals with VCFS from Israel and Western Europe to characterize the neuropsychiatric phenotype from childhood to adulthood in a large sample. METHOD Individuals with VCFS (n = 172) aged 5 to 54 years were evaluated with structured clinical interviews for psychiatric disorders and age-appropriate versions of the Wechsler intelligence tests. RESULTS The frequency of psychiatric disorders was high and remarkably similar between samples. Psychotic disorders and depression were uncommon during childhood but increased in rates during adulthood (depressive disorders: 40.7% in young adults [aged 18-24 years]; psychotic disorders: 32.1% in adults [age >24 years]). Cognitive scores were inversely associated with age in subjects with VCFS, including patients without psychosis. Specifically, Verbal IQ (VIQ) scores negatively correlated with age, and the subjects with VCFS and psychotic disorders had significantly lower VIQ scores than nonpsychotic VCFS subjects. CONCLUSIONS Neuropsychiatric deficits in individuals with VCFS seem to follow a developmental pattern. The VIQ scores are negatively associated with age and rates of mood, and psychotic disorders increase dramatically during young adulthood. The data presented here support careful monitoring of psychiatric symptoms during adolescence and young adulthood in VCFS. Prospective longitudinal studies are needed to examine the nature of age-related cognitive changes and their association with psychiatric morbidity in VCFS.

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.

Functional brain activation during arithmetic processing in females with fragile X syndrome is related to FMR1 protein expression

Arithmetic processing deficits in persons with fragile X Syndrome (fraX), the most common heritable cause of mental retardation, are well known. In this study, we characterize the neural underpinnings of these performance deficits using functional MRI. Given that a single gene defect (FMR1) is known to be responsible for this disorder, we also assess whether brain activation in arithmetic processing areas is related to amount of FMR1 protein expression (FMRP). Subjects included 16 females with fraX, and 16 female age‐matched controls. Subjects viewed arithmetic equations with two (1 + 3 = 4) or three (2 + 3 − 1 = 5) operands, and were asked to judge whether the results were correct or not. Subjects with fraX showed significant impairment in behavioral performance on the 3‐operand but not the 2‐operand arithmetic equations. Significant brain activation was observed bilaterally in the prefrontal and parietal cortices for unaffected subjects, and bilateral prefrontal and left angular gyrus for subjects with fraX, for both trial types. Subjects with fraX exhibited less overall activation than did unaffected subjects in both types of trials; and, unlike the unaffected group, did not show increased extent of activation in association with greater task difficulty. During the 3‐operand trials, activation in bilateral prefrontal and motor/premotor, and left supramarginal and angular gyri were positively correlated with FMRP, suggesting that decreased FMR1 protein expression underlies deficits in math performance in persons with fraX. More broadly, this investigation demonstrates a unique bridging of cognitive and molecular neuroscience and represents a useful approach for the study of brain development and function. Hum. Brain Mapping 16:206–218, 2002.

Cortisol and behavior in fragile X syndrome

OBJECTIVE The purpose of this study was to determine if children with fragile X syndrome, who typically demonstrate a neurobehavioral phenotype that includes social anxiety, withdrawal, and hyper-arousal, have increased levels of cortisol, a hormone associated with stress. The relevance of adrenocortical activity to the fragile X phenotype also was examined. METHOD One hundred and nine children with the fragile X full mutation (70 males and 39 females) and their unaffected siblings (51 males and 58 females) completed an in-home evaluation including a cognitive assessment and a structured social challenge task. Multiple samples of salivary cortisol were collected throughout the evaluation day and on two typical non-school days. Measures of the fragile X mental retardation (FMR1) gene, child intelligence, the quality of the home environment, parental psychopathology, and the effectiveness of educational and therapeutic services also were collected. Linear mixed-effects analyses were used to examine differences in cortisol associated with the fragile X diagnosis and gender (fixed effects) and to estimate individual subject and familial variation (random effects) in cortisol hormone levels. Hierarchical multiple regression analyses were conducted to determine whether adrenocortical activity is associated with behavior problems after controlling for significant genetic and environmental factors. RESULTS Results showed that children with fragile X, especially males, had higher levels of salivary cortisol on typical days and during the evaluation. Highly significant family effects on salivary cortisol were detected, consistent with previous work documenting genetic and environmental influences on adrenocortical activity. Increased cortisol was significantly associated with behavior problems in boys and girls with fragile X but not in their unaffected siblings. CONCLUSIONS These results provide evidence that the function of the hypothalamic-pituitary-adrenal axis may have an independent association with behavioral problems in children with fragile X syndrome.

Differential development of selectivity for faces and bodies in the fusiform gyrus.

Viewing faces or bodies activates category-selective areas of visual cortex, including the fusiform face area (FFA), fusiform body area (FBA), and extrastriate body area (EBA). Here, using fMRI, we investigate the development of these areas, focusing on the right FFA and FBA. Despite the overlap of functionally defined FFA and FBA (54%-75% overlap), we found that these regions developed along different trajectories. With age (7-32 years old), the FFA gradually increased in size and selectivity, and was significantly larger and more face-selective in adults than children. By contrast, the size and selectivity of the FBA did not correlate with age, and were equivalent in children and adults. Whereas in adults the FFA and FBA were comparable in size, in children the FBA was on average 70% larger than the FFA. These findings suggest that, in children, the fusiform gyrus is predominantly selective for bodies, with commensurate face-selective responses apparent later in development. Moreover, differences in the development of the FFA and FBA indicate that overlapping functional brain areas, supported by the same anatomical structure, can develop along different trajectories.

Deviant trajectories of cortical maturation in 22q11.2 deletion syndrome (22q11DS): A cross-sectional and longitudinal study

22q11.2 deletion syndrome (22q11DS) is associated with an increased susceptibility to develop schizophrenia. Despite a large body of literature documenting abnormal brain structure in 22q11DS, cerebral changes associated with brain maturation in 22q11DS remained largely unexplored. To map cortical maturation from childhood to adulthood in 22q11.2 deletion syndrome, we used cerebral MRI from 59 patients with 22q11DS, aged 6 to 40, and 80 typically developing controls; three year follow-up assessments were also available for 32 patients and 31 matched controls. Cross-sectional cortical thickness trajectories during childhood and adolescence were approximated in age bins. Repeated-measures were also conducted with the longitudinal data. Within the group of patients with 22q11DS, exploratory measures of cortical thickness differences related to COMT polymorphism, IQ, and schizophrenia were also conducted. We observed deviant trajectories of cortical thickness changes with age in patients with 22q11DS. In affected preadolescents, larger prefrontal thickness was observed compared to age-matched controls. Afterward, we observed greater cortical loss in 22q11DS with a convergence of cortical thickness values by the end of adolescence. No compelling evidence for an effect of COMT polymorphism on cortical maturation was observed. Within 22q11DS, significant differences in cortical thickness were related to cognitive level in children and adolescents, and to schizophrenia in adults. Deviant trajectories of cortical thickness from childhood to adulthood provide strong in vivo cues for a defect in the programmed synaptic elimination, which in turn may explain the susceptibility of patients with 22q11DS to develop psychosis.

Decreased frontal gyrification correlates with altered connectivity in children with autism

The structural correlates of functional dysconnectivity in autism spectrum disorders (ASD) have been seldom explored, despite the fact that altered functional connectivity is one of the most frequent neuropathological observations in the disorder. We analyzed cerebral morphometry and structural connectivity using multi-modal imaging for 11 children/adolescents with ASD and 11 matched controls. We estimated regional cortical and white matter volumes, as well as vertex-wise measures of cortical thickness and local Gyrification Index (lGI). Diffusion Tensor Images (DTI) were used to measure Fractional Anisotropy (FA) and tractography estimates of short- and long-range connectivity. We observed four clusters of lGI reduction in patients with ASD, three were located in the right inferior frontal region extending to the inferior parietal lobe, and one was in the right medial parieto-occipital region. Reduced volume was found in the anterior corpus callosum, along with fewer inter-hemispheric frontal streamlines. Despite the spatial correspondence of decreased gyrification and reduced long connectivity, we did not observe any significant relationship between the two. However, a positive correlation between lGI and local connectivity was present in all four clusters in patients with ASD. Reduced gyrification in the inferior fronto-parietal and posterior medial cortical regions lends support for early-disrupted cortical growth in both the mirror neuron system and midline structures responsible for social cognition. Early impaired neurodevelopment in these regions may represent an initial substrate for altered maturation in the cerebral networks that support complex social skills. We also demonstrate that gyrification changes are related to connectivity. This supports the idea that an imbalance between short- and long-range white matter tracts not only impairs the integration of information from multiple neural systems, but also alters the shape of the brain early on in autism.

Abnormal patterns of cortical gyrification in velo-cardio-facial syndrome (deletion 22q11.2): An MRI study

Velo-cardio-facial syndrome (VCFS), also known as 22q11.2 deletion syndrome, is a common genetic condition associated with increased risk for developing schizophrenia. Given that cortical malformations play an integral role in the pattern of neuroanatomical alterations associated with VCFS, the aim of the present study was to quantify and localize gyral abnormalities. Magnetic resonance images were obtained on a 1.5 T scanner. The gyrification index (GI), a measure of the degree of cortical complexity, was differentially calculated for each lobe using a semi-automated protocol. The GI was calculated for 37 patients affected by VCFS as well as for 36 comparison individuals group-matched for age, handedness, and gender. The subjects affected by VCFS showed a significant decrease in the GI in the frontal and parietal lobes compared with the control group. The pattern of decreased gyrification in the frontal and parietal lobes further defines the structural changes associated with the syndrome and suggests underlying abnormalities in neural connectivity. Aberrant connectivity may be partially responsible for the cognitive and behavioral impairments in the syndrome, as well as the high incidence of schizophrenia among affected individuals.

Risk Factors and the Evolution of Psychosis in 22q11.2 Deletion Syndrome: A Longitudinal 2-Site Study

OBJECTIVE 22q11.2 Deletion syndrome (22q11.2DS) is associated with high rates of schizophrenia, other neuropsychiatric disorders, and cognitive deficits. The objectives of this 2-center study were to longitudinally assess the trajectories of psychiatric disorders in 22q11.2DS from childhood to adulthood, and to identify risk factors for their emergence. METHOD A total of 125 children and adults with 22q11.2DS were evaluated at 2 time points, baseline and follow-up (4 years apart), using standardized psychiatric and cognitive measures. RESULTS The rate of mood disorders tended to decrease during childhood and increase during late adolescence. Statistically significant predictors for the presence of a psychotic disorder as well as the severity of positive symptoms at follow-up were identical, and consisted of an anxiety disorder at baseline, lower baseline Full Scale IQ, and a greater decrease in verbal IQ scores between time points. Nine of 10 individuals with an emerging psychotic disorder had an anxiety disorder at baseline. The age of onset for a psychotic disorder was between 14 and 22 years in 82.6% of cases. CONCLUSIONS It is important to evaluate the presence of anxiety disorders in children and adolescents with 22q11.2DS, as they are major risk factors for the emergence of psychotic disorders, which usually occur during late adolescence in this at-risk population.