Mega-analysis methods in ENIGMA: The experience of the generalized anxiety disorder working group.

The ENIGMA group on Generalized Anxiety Disorder (ENIGMA-Anxiety/GAD) is part of a broader effort to investigate anxiety disorders using imaging and genetic data across multiple sites worldwide. The group is actively conducting a mega-analysis of a large number of brain structural scans. In this process, the group was confronted with many methodological challenges related to study planning and implementation, between-country transfer of subject-level data, quality control of a considerable amount of imaging data, and choices related to statistical methods and efficient use of resources. This report summarizes the background information and rationale for the various methodological decisions, as well as the approach taken to implement them. The goal is to document the approach and help guide other research groups working with large brain imaging data sets as they develop their own analytic pipelines for mega-analyses.

Diminished insulin sensitivity is associated with altered brain activation to food cues and with risk for obesity - Implications for individuals born small for gestational age.

While classically linked to memory, the hippocampus is also a feeding behavior modulator due to its multiple interconnected pathways with other brain regions and expression of receptors for metabolic hormones. Here we tested whether variations in insulin sensitivity would be correlated with differential brain activation following exposure to palatable food cues, as well as with variations in implicit food memory in a cohort of healthy adolescents, some of whom were born small for gestational age (SGA). Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) was positively correlated with activation in the cuneus, and negatively correlated with activation in the middle frontal lobe, superior frontal gyrus and precuneus when presented with palatable food images versus non-food images in healthy adolescents. Additionally, HOMA-IR and insulinemia were higher in participants with impaired food memory. SGA individuals had higher snack caloric density and greater chance for impaired food memory. There was also an interaction between the HOMA-IR and birth weight ratio influencing external eating behavior. We suggest that diminished insulin sensitivity correlates with activation in visual attention areas and inactivation in inhibitory control areas in healthy adolescents. Insulin resistance also associated with less consistency in implicit memory for a consumed meal, which may suggest lower ability to establish a dietary pattern, and can contribute to obesity. Differences in feeding behavior in SGA individuals were associated with insulin sensitivity and hippocampal alterations, suggesting that cognition and hormonal regulation are important components involved in their food intake modifications throughout life.

Cortical and subcortical brain structure in generalized anxiety disorder: findings from 28 research sites in the ENIGMA-Anxiety Working Group.

The goal of this study was to compare brain structure between individuals with generalized anxiety disorder (GAD) and healthy controls. Previous studies have generated inconsistent findings, possibly due to small sample sizes, or clinical/analytic heterogeneity. To address these concerns, we combined data from 28 research sites worldwide through the ENIGMA-Anxiety Working Group, using a single, pre-registered mega-analysis. Structural magnetic resonance imaging data from children and adults (5-90 years) were processed using FreeSurfer. The main analysis included the regional and vertex-wise cortical thickness, cortical surface area, and subcortical volume as dependent variables, and GAD, age, age-squared, sex, and their interactions as independent variables. Nuisance variables included IQ, years of education, medication use, comorbidities, and global brain measures. The main analysis (1020 individuals with GAD and 2999 healthy controls) included random slopes per site and random intercepts per scanner. A secondary analysis (1112 individuals with GAD and 3282 healthy controls) included fixed slopes and random intercepts per scanner with the same variables. The main analysis showed no effect of GAD on brain structure, nor interactions involving GAD, age, or sex. The secondary analysis showed increased volume in the right ventral diencephalon in male individuals with GAD compared to male healthy controls, whereas female individuals with GAD did not differ from female healthy controls. This mega-analysis combining worldwide data showed that differences in brain structure related to GAD are small, possibly reflecting heterogeneity or those structural alterations are not a major component of its pathophysiology.

Negative affect symptoms, anxiety sensitivity, and vasomotor symptoms during perimenopause

Objective: Vasomotor symptoms affect 60-80% of women during the menopausal transition. Anxiety, depression, and anxiety sensitivity can have an important role in the distressful experience of vasomotor symptoms. Our aim was to evaluate the prevalence and association of vasomotor and negative affect symptoms. Methods: A cross-sectional study was conducted with 89 perimenopausal women aged 45-55 years. Broad psychiatric and clinical evaluations were carried out. The primary outcome was the vasomotor symptom problem rating and the main study factor was anxiety sensitivity. Linear regression analyses were conducted to examine the associations between the study factors and the primary outcome, and a multiple regression model was created to assess which variables were independently associated with vasomotor symptom problem rating. Results: The prevalence of anxiety, depression, and vasomotor symptoms were 58, 62, and 73%, respectively. Negative affect symptoms were positively associated with vasomotor symptom problem rating. The association of anxiety sensitivity and vasomotor symptom problem rating remained significant after controlling for perimenopausal stage, thyrotropin, follicle-stimulating hormone levels, and psychotropic medication use (β = 0.314, p = 0.002). Conclusion: A better understanding of the experience of vasomotor symptoms is needed, especially the role of negative affect symptoms and anxiety sensitivity. New strategies focusing on related thoughts and behaviors could improve the quality of life of perimenopausal women.

Telomere length and epigenetic age acceleration in adolescents with anxiety disorders.

Evidence on the relationship between genetics and mental health are flourishing. However, few studies are evaluating early biomarkers that might link genes, environment, and psychopathology. We aimed to study telomere length (TL) and epigenetic age acceleration (AA) in a cohort of adolescents with and without anxiety disorders (N = 234). We evaluated a representative subsample of participants at baseline and after 5 years (n = 76) and categorized them according to their anxiety disorder diagnosis at both time points: (1) control group (no anxiety disorder, n = 18), (2) variable group (anxiety disorder in one evaluation, n = 38), and (3) persistent group (anxiety disorder at both time points, n = 20). We assessed relative mean TL by real-time quantitative PCR and DNA methylation by Infinium HumanMethylation450 BeadChip. We calculated AA using the Horvath age estimation algorithm and analyzed differences among groups using generalized linear mixed models. The persistent group of anxiety disorder did not change TL over time (p = 0.495). The variable group had higher baseline TL (p = 0.003) but no accelerated TL erosion in comparison to the non-anxiety control group (p = 0.053). Furthermore, there were no differences in AA among groups over time. Our findings suggest that adolescents with chronic anxiety did not change telomere length over time, which could be related to a delay in neuronal development in this period of life.

Negative affect symptoms, anxiety sensitivity, and vasomotor symptoms during perimenopause.

OBJECTIVE: Vasomotor symptoms affect 60-80% of women during the menopausal transition. Anxiety, depression, and anxiety sensitivity can have an important role in the distressful experience of vasomotor symptoms. Our aim was to evaluate the prevalence and association of vasomotor and negative affect symptoms. METHODS: A cross-sectional study was conducted with 89 perimenopausal women aged 45-55 years. Broad psychiatric and clinical evaluations were carried out. The primary outcome was the vasomotor symptom problem rating and the main study factor was anxiety sensitivity. Linear regression analyses were conducted to examine the associations between the study factors and the primary outcome, and a multiple regression model was created to assess which variables were independently associated with vasomotor symptom problem rating. RESULTS: The prevalence of anxiety, depression, and vasomotor symptoms were 58, 62, and 73%, respectively. Negative affect symptoms were positively associated with vasomotor symptom problem rating. The association of anxiety sensitivity and vasomotor symptom problem rating remained significant after controlling for perimenopausal stage, thyrotropin, follicle-stimulating hormone levels, and psychotropic medication use (ß = 0.314, p = 0.002). CONCLUSION: A better understanding of the experience of vasomotor symptoms is needed, especially the role of negative affect symptoms and anxiety sensitivity. New strategies focusing on related thoughts and behaviors could improve the quality of life of perimenopausal women.

Impulsivity influences food intake in women with generalized anxiety disorder

Objective: Eating behavior is affected by psychological and neurocognitive factors. However, little is known about this relationship in anxious patients. Our aim was to investigate the associations between impulsivity, inhibitory control, energy-dense food consumption, and body mass index (BMI) in women with generalized anxiety disorder (GAD). Methods: In this cross-sectional study, 51 adult females with GAD answered the Barratt Impulsiveness Scale (BIS-11) and participated in a go/no-go task using food images. Anthropometric measurements were evaluated. A food frequency questionnaire and a snack test were used to study eating behavior. Pearson correlation and multiple linear regression were performed to analyze the variables of interest, adjusted by age. Results: Impulsivity predicted intake of sugar (p = 0.016, 95%CI 0.67-6.05), total fat (p = 0.007, 95%CI 0.62-3.71), and saturated fat (p = 0.004, 95%CI 0.30-1.48). The snack test showed a positive correlation between presence of impulsivity and intake of biscuits (R = 0.296; p = 0.051). Response inhibition to food images in the go/no-go task paradigm did not predict BMI or food intake. Conclusion: Impulsivity was predictive of higher sugar and saturated fat intake in women diagnosed with GAD. Our findings add to the literature regarding the association between neuropsychological factors and food consumption in this specific population.

Memory and language impairments are associated with anxiety disorder severity in childhood.

Introduction Children with anxiety disorders have been suggested to possess deficits in verbal fluency, shifting and attention, with inconsistent results regarding working memory and its subcomponents. This study extends previous findings by analyzing the performance of children with anxiety disorders in a wide range of neuropsychological functions. Methods We evaluated 54 children with a primary diagnosis of an anxiety disorder according to diagnostic criteria from the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) using subtests of a neuropsychological battery. The severity of anxiety disorders was assessed using the Pediatric Anxiety Rating Scale (PARS). We calculated the frequency of neuropsychological impairments (-1.5 standard deviation of the normative sample). Comparisons between groups were performed based on the severity of anxiety symptoms, as well as in the presence of one vs. more diagnoses of anxiety disorder. Results We found higher impairment in visuospatial working memory (23.1%), semantic memory (27.8%), oral language (35.4%) and word writing (44.4%) in anxious children. Moreover, children with higher anxiety severity presented lower performance in visuospatial working memory, inferential processing, word reading, writing comprehension, copied writing, and semantic verbal fluency (d = 0.49 to 0.96 [Cohen's d]). The higher the number of anxiety diagnoses, the lower the performance in episodic memory and oral and written language (d = 0.56 to 0.77). Conclusion Our data suggested the presence of memory (visuospatial working memory and semantic memory) and language deficits (oral and writing) in some children with an anxiety disorder. Severity and number of anxiety diagnoses were associated with lower performance in memory and language domains in childhood.

Improved quality of life and reduced depressive symptoms in medical students after a single-session intervention

Objective: Anxiety and depression are prevalent among medical students. Brazilian medical students have higher levels of depression and lower quality of life than their U.S. counterparts, and no preventive intervention exists for this risk group in Brazil. The Unified Protocol for Transdiagnostic Treatment of Emotional Disorders (UP), a cognitive-behavioral treatment protocol for neuroticism, was recently adapted into a single-session, preventive intervention. This study tested the impact of this protocol on psychiatric symptoms and quality of life in Brazilian medical students. Methods: In this open trial, the intervention protocol was translated and adapted to Brazilian Portuguese. Medical students over 18 years of age without psychotic symptoms, severe depressive episodes, or acute psychiatric risk were included, undergoing a psychiatric clinical interview (Mini-International Neuropsychiatric Interview [MINI]) and evaluation at baseline and at 7 and 30 days after a single-session UP that included experimental avoidance, quality of life, self-esteem, empathy, and anxiety symptom scales. A new evaluation was performed 90 days after the intervention. Results: Sixty-two students participated. Ninety days after the intervention, there were significant reductions in the number of students who met the criteria for social anxiety disorder (p = 0.013) or panic disorder (p = 0.001). There were also significant improvements in depressive symptoms (Beck Depression Inventory, p < 0.001) and quality of life (Quality of Life Enjoyment and Satisfaction Questionnaire, p < 0.001). Conclusion: UP improved anxiety and depressive symptoms in medical students. The single-session group format could reduce costs and facilitate application. Future placebo-controlled studies are necessary to confirm these findings.

Impulsivity influences food intake in women with generalized anxiety disorder.

OBJECTIVE: Eating behavior is affected by psychological and neurocognitive factors. However, little is known about this relationship in anxious patients. Our aim was to investigate the associations between impulsivity, inhibitory control, energy-dense food consumption, and body mass index (BMI) in women with generalized anxiety disorder (GAD). METHODS: In this cross-sectional study, 51 adult females with GAD answered the Barratt Impulsiveness Scale (BIS-11) and participated in a go/no-go task using food images. Anthropometric measurements were evaluated. A food frequency questionnaire and a snack test were used to study eating behavior. Pearson correlation and multiple linear regression were performed to analyze the variables of interest, adjusted by age. RESULTS: Impulsivity predicted intake of sugar (p = 0.016, 95%CI 0.67-6.05), total fat (p = 0.007, 95%CI 0.62-3.71), and saturated fat (p = 0.004, 95%CI 0.30-1.48). The snack test showed a positive correlation between presence of impulsivity and intake of biscuits (R = 0.296; p = 0.051). Response inhibition to food images in the go/no-go task paradigm did not predict BMI or food intake. CONCLUSION: Impulsivity was predictive of higher sugar and saturated fat intake in women diagnosed with GAD. Our findings add to the literature regarding the association between neuropsychological factors and food consumption in this specific population.

Improved quality of life and reduced depressive symptoms in medical students after a single-session intervention.

OBJECTIVE: Anxiety and depression are prevalent among medical students. Brazilian medical students have higher levels of depression and lower quality of life than their U.S. counterparts, and no preventive intervention exists for this risk group in Brazil. The Unified Protocol for Transdiagnostic Treatment of Emotional Disorders (UP), a cognitive-behavioral treatment protocol for neuroticism, was recently adapted into a single-session, preventive intervention. This study tested the impact of this protocol on psychiatric symptoms and quality of life in Brazilian medical students. METHODS: In this open trial, the intervention protocol was translated and adapted to Brazilian Portuguese. Medical students over 18 years of age without psychotic symptoms, severe depressive episodes, or acute psychiatric risk were included, undergoing a psychiatric clinical interview (Mini-International Neuropsychiatric Interview [MINI]) and evaluation at baseline and at 7 and 30 days after a single-session UP that included experimental avoidance, quality of life, self-esteem, empathy, and anxiety symptom scales. A new evaluation was performed 90 days after the intervention. RESULTS: Sixty-two students participated. Ninety days after the intervention, there were significant reductions in the number of students who met the criteria for social anxiety disorder (p = 0.013) or panic disorder (p = 0.001). There were also significant improvements in depressive symptoms (Beck Depression Inventory, p < 0.001) and quality of life (Quality of Life Enjoyment and Satisfaction Questionnaire, p < 0.001). CONCLUSION: UP improved anxiety and depressive symptoms in medical students. The single-session group format could reduce costs and facilitate application. Future placebo-controlled studies are necessary to confirm these findings.

Group Cognitive Behavioral Therapy and Attention Bias Modification for Childhood Anxiety Disorders: A Factorial Randomized Trial of Efficacy.

BACKGROUND: The objective of this study is to assess group differences in symptom reduction between individuals receiving group cognitive behavioral therapy (G-CBT) and attention bias modification (ABM) compared to their respective control interventions, control therapy (CT), and attention control training (ACT), in a 2 × 2 factorial design. METHODS: A total of 310 treatment-naive children (7-11 years of age) were assessed for eligibility and 79 children with generalized, separation or social anxiety disorder were randomized and received G-CBT (n = 42) or CT (n = 37). Within each psychotherapy group, participants were again randomized to ABM (n = 38) or ACT (n = 41) in a 2 × 2 factorial design resulting in four groups: G-CBT + ABM (n = 21), G-CBT + ACT (n = 21), CT + ABM (n = 17), and CT + ACT (n = 20). Primary outcomes were responder designation as defined by Clinical Global Impression-Improvement (CGI-I) scale (≤2) and change on the Pediatric Anxiety Rating Scale (PARS). RESULTS: There were significant improvements of symptoms in all groups. No differences in response rates or mean differences in PARS scores were found among groups: G-CBT + ABM group (23.8% response; 3.9 points, 95% confidence interval [CI] -0.3 to 8.1), G-CBT + ACT (42.9% response; 5.6 points, 95% CI 2.2-9.0), CT + ABM (47.1% response; 4.8 points 95% CI 1.08-8.57), and CT + ACT (30% response; 0.8 points, 95% CI -3.0 to 4.7). No evidence or synergic or antagonistic effects were found, but the combination of G-CBT and ABM was found to increase dropout rate. CONCLUSIONS: We found no effect of G-CBT or ABM beyond the effects of comparison groups. Results reveal no benefit from combining G-CBT and ABM for anxiety disorders in children and suggest potential deleterious effects of the combination on treatment acceptability.

Polygenic Risk Score for Alzheimer's Disease: Implications for Memory Performance and Hippocampal Volumes in Early Life.

OBJECTIVE: Alzheimer's disease is a heritable neurodegenerative disorder in which early-life precursors may manifest in cognition and brain structure. The authors evaluate this possibility by examining, in youths, associations among polygenic risk score for Alzheimer's disease, cognitive abilities, and hippocampal volume. METHOD: Participants were children 6-14 years of age in two Brazilian cities, constituting the discovery (N=364) and replication samples (N=352). As an additional replication, data from a Canadian sample (N=1,029), with distinct tasks, MRI protocol, and genetic risk, were included. Cognitive tests quantified memory and executive function. Reading and writing abilities were assessed by standardized tests. Hippocampal volumes were derived from the Multiple Automatically Generated Templates (MAGeT) multi-atlas segmentation brain algorithm. Genetic risk for Alzheimer's disease was quantified using summary statistics from the International Genomics of Alzheimer's Project. RESULTS: Analyses showed that for the Brazilian discovery sample, each one-unit increase in z-score for Alzheimer's polygenic risk score significantly predicted a 0.185 decrement in z-score for immediate recall and a 0.282 decrement for delayed recall. Findings were similar for the Brazilian replication sample (immediate and delayed recall, ß=-0.259 and ß=-0.232, both significant). Quantile regressions showed lower hippocampal volumes bilaterally for individuals with high polygenic risk scores. Associations fell short of significance for the Canadian sample. CONCLUSIONS: Genetic risk for Alzheimer's disease may affect early-life cognition and hippocampal volumes, as shown in two independent samples. These data support previous evidence that some forms of late-life dementia may represent developmental conditions with roots in childhood. This result may vary depending on a sample's genetic risk and may be specific to some types of memory tasks.

Prevalence, clinical correlates and maternal psychopathology of deliberate self-harm in children and early adolescents: results from a large community study

Objectives: Little is known about the prevalence and correlates of deliberate self-harm (DSH) in children from low- and middle-income countries. We investigated the prevalence of DSH and its clinical and maternal psychopathological associations in Brazilian children (n=2,508, ages 6-14y) in a community-based study. Methods: Participants of the High Risk Cohort Study for the Development of Childhood Psychiatric Disorders (HRC) and their mothers were assessed in structured interviews. Current (last month) and lifetime DSH were estimated, including analysis stratified by age groups. Logistic regressions were performed to investigate the role of the children's clinical diagnoses and maternal psychopathology on DSH prevalence estimates, adjusting for potential confounding factors. Results: The prevalence of current DSH was 0.8% (children 0.6%, adolescents 1%) and lifetime DSH was 1.6% (1.8% and 1.5%, respectively). Current and lifetime DSH were more frequent in children with depression, attention-deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD), even in multiple models accounting for demographic variables and co-occurring psychiatric disorders. Maternal anxiety disorder was strongly associated with current and lifetime DSH in offspring; whereas current DSH, specifically in young children, was associated with maternal mood disorder. Conclusion: Diagnoses of depression, ADHD and ODD were consistently associated with DSH, as was having a mother with anxiety disorder.

Prevalence, clinical correlates and maternal psychopathology of deliberate self-harm in children and early adolescents: results from a large community study.

OBJECTIVES: Little is known about the prevalence and correlates of deliberate self-harm (DSH) in children from low- and middle-income countries. We investigated the prevalence of DSH and its clinical and maternal psychopathological associations in Brazilian children (n=2,508, ages 6-14y) in a community-based study. METHODS: Participants of the High Risk Cohort Study for the Development of Childhood Psychiatric Disorders (HRC) and their mothers were assessed in structured interviews. Current (last month) and lifetime DSH were estimated, including analysis stratified by age groups. Logistic regressions were performed to investigate the role of the children's clinical diagnoses and maternal psychopathology on DSH prevalence estimates, adjusting for potential confounding factors. RESULTS: The prevalence of current DSH was 0.8% (children 0.6%, adolescents 1%) and lifetime DSH was 1.6% (1.8% and 1.5%, respectively). Current and lifetime DSH were more frequent in children with depression, attention-deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD), even in multiple models accounting for demographic variables and co-occurring psychiatric disorders. Maternal anxiety disorder was strongly associated with current and lifetime DSH in offspring; whereas current DSH, specifically in young children, was associated with maternal mood disorder. CONCLUSION: Diagnoses of depression, ADHD and ODD were consistently associated with DSH, as was having a mother with anxiety disorder.

Specific and social fears in children and adolescents: separating normative fears from problem indicators and phobias

Objective: To distinguish normative fears from problematic fears and phobias. Methods: We investigated 2,512 children and adolescents from a large community school-based study, the High Risk Study for Psychiatric Disorders. Parent reports of 18 fears and psychiatric diagnosis were investigated. We used two analytical approaches: confirmatory factor analysis (CFA)/item response theory (IRT) and nonparametric receiver operating characteristic (ROC) curve. Results: According to IRT and ROC analyses, social fears are more likely to indicate problems and phobias than specific fears. Most specific fears were normative when mild; all specific fears indicate problems when pervasive. In addition, the situational fear of toilets and people who look unusual were highly indicative of specific phobia. Among social fears, those not restricted to performance and fear of writing in front of others indicate problems when mild. All social fears indicate problems and are highly indicative of social phobia when pervasive. Conclusion: These preliminary findings provide guidance for clinicians and researchers to determine the boundaries that separate normative fears from problem indicators in children and adolescents, and indicate a differential severity threshold for specific and social fears.

Specific and social fears in children and adolescents: separating normative fears from problem indicators and phobias.

OBJECTIVE:: To distinguish normative fears from problematic fears and phobias. METHODS:: We investigated 2,512 children and adolescents from a large community school-based study, the High Risk Study for Psychiatric Disorders. Parent reports of 18 fears and psychiatric diagnosis were investigated. We used two analytical approaches: confirmatory factor analysis (CFA)/item response theory (IRT) and nonparametric receiver operating characteristic (ROC) curve. RESULTS:: According to IRT and ROC analyses, social fears are more likely to indicate problems and phobias than specific fears. Most specific fears were normative when mild; all specific fears indicate problems when pervasive. In addition, the situational fear of toilets and people who look unusual were highly indicative of specific phobia. Among social fears, those not restricted to performance and fear of writing in front of others indicate problems when mild. All social fears indicate problems and are highly indicative of social phobia when pervasive. CONCLUSION:: These preliminary findings provide guidance for clinicians and researchers to determine the boundaries that separate normative fears from problem indicators in children and adolescents, and indicate a differential severity threshold for specific and social fears.