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.

Cytokine Levels in Panic Disorder: Evidence for a Dose-Response Relationship.

OBJECTIVE: Several studies have investigated possible biological correlates of mental disorders. Although some studies have consistently reported elevated levels of serum inflammatory markers in depression, very few have evaluated cytokine levels in patients with lifetime panic disorder (PD). METHODS: Seventy-eight adults (75% women) from an anxiety disorders outpatient unit were categorized according to their PD status: current or in remission. Serum levels of interleukin (IL)-6, tumor necrosis factor α, and IL-10 were evaluated using flow cytometry with enhanced sensitivity flex sets. Data on clinical comorbidity, lipid profile, fasting blood glucose, C-reactive protein, and PD severity were also obtained. RESULTS: Significantly higher mean levels of serum IL-6 (0.83 vs 0.60 pg/mL [95% confidence interval {CI}for the log-transformed mean difference, -0.41 to -0.57], p = .008) but not of tumor necrosis factor-α (0.18 vs 0.14 pg/mL [95% CI, -1.12 to 0.11]; p = 0.53) or IL-10 (0.21 vs 0.26 [95% CI, -0.20 to 0.44]; p = 0.16), were associated with current PD compared to remitted PD. Higher Panic Disorder Severity Scale (standardized ß = 0.36; p = .013), body mass index (standardized ß = 0.53, p < .001) and fasting blood glucose 5.6 mmol/L or greater (standardized ß = 0.23, p = .038) were significantly associated with higher levels of IL-6 in the multivariate linear regression model. CONCLUSIONS: Our findings support a proinflammatory state in patients with current PD that is independent of possible confounders. Although there are important implications of these findings, replication is required.

Decreased comfort food intake and allostatic load in adolescents carrying the A3669G variant of the glucocorticoid receptor gene.

BACKGROUND: The A3669G single nucleotide polymorphism (SNP) of the glucocorticoid receptor (GR) gene NR3C1 is associated with altered tissue sensitivity to glucocorticoids (GCs). GCs modulate the food reward circuitry and are implicated in increased intake of palatable foods, which can lead to the metabolic syndrome and obesity. We hypothesized that presence of the G variant of the A3669G SNP would affect preferences for palatable foods and alter metabolic, behavioural, and neural outcomes. METHODS: One hundred thirty-one adolescents were genotyped for the A3669G polymorphism, underwent anthropometric assessment and nutritional evaluations, and completed behavioural measures. A subsample of 74 subjects was followed for 5 years and performed a brain functional magnetic resonance imaging (fMRI) paradigm to verify brain activity in response to food cues. RESULTS: Sugar and total energy consumption were lower in A3669G G allele variant carriers. On follow-up, this group also had reduced serum insulin concentrations, increased insulin sensitivity, and lower anxiety scores. Because of our unbalanced sample sizes (31/37 participants non-G allele carriers/total), our imaging data analysis failed to find whole brain-corrected significant results in between-group t-tests. CONCLUSION: These results highlight that a genetic variation in the GR gene is associated, at the cellular level, with significant reduction in GC sensitivity, which, at cognitive and behavioural levels, translates to altered food intake and emotional stress response. This genetic variant might play a major role in decreasing risk for metabolic and psychiatric diseases.

Thrifty-Eating Behavior Phenotype at the Food Court - Programming Goes Beyond Food Preferences.

Introduction: Prenatal growth impairment leads to higher preference for palatable foods in comparison to normal prenatal growth subjects, which can contribute to increased body fat mass and a higher risk for developing chronic diseases in small-for-gestational-age (SGA) individuals throughout life. This study aimed to investigate the effect of SGA on feeding behavior in children and adolescents, as well as resting-state connectivity between areas related to reward, self-control, and value determination, such as orbitofrontal cortex (OFC), dorsolateral prefrontal cortex (DL-PFC), amygdala and dorsal striatum (DS). Methods: Caregivers and their offspring were recruited from two independent cohorts in Brazil (PROTAIA) and Canada (MAVAN). Both cohorts included anthropometric measurements, food choice tasks, and resting-state functional magnetic resonance imaging (fMRI) data. Results: In the Brazilian sample (17 ± 0.28 years, n=70), 21.4% of adolescents were classified as SGA. They exhibited lower monetary-related expenditure to buy a snack compared to controls in the food choice test. Decreased functional connectivity (n=40) between left OFC and left DL-PFC; and between right OFC and: left amygdala, right DS, and left DS were observed in the Brazilian SGA participants. Canadian SGA participants (14.9%) had non-significant differences in comparison with controls in a food choice task at 4 years old ( ± 0.01, n=315). At a follow-up brain scan visit (10.21 ± 0.140 years, n=49), SGA participants (28.6%) exhibited higher connectivity between the left OFC and left DL-PFC, also higher connectivity between the left OFC and right DL-PFC. We did not observe significant anthropometric neither nutrients' intake differences between groups in both samples. Conclusions: Resting-state fMRI results showed that SGA individuals had altered connectivity between areas involved in encoding the subjective value for available goods and decision-making in both samples, which can pose them in disadvantage when facing food options daily. Over the years, the cumulative exposure to particular food cues together with the altered behavior towards food, such as food purchasing, as seen in the adolescent cohort, can play a role in the long-term risk for developing chronic non-communicable diseases.

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.

Anxiety disorders in childhood are associated with youth IL-6 levels: A mediation study including metabolic stress and childhood traumatic events.

Anxiety disorders (ADs) are chronic conditions that often have their onset in childhood and adolescence. Inflammation and oxidative stress markers have been associated with the vulnerability to ADs, however it is not known if ADs in childhood can influence these biomarkers levels longitudinally. This study aims to investigate a possible association between ADs and serum levels of IL-10, IL-6, IL-1ß, TNF-α, BDNF, and protein carbonyl content, assessed after 5 years of follow-up. Moreover, we studied possible mediators for these associations, including physical activity, metabolic markers and childhood trauma. From 240 individuals evaluated at baseline, 73 were re-evaluated in the follow-up. Psychiatric diagnoses were assessed with the K-SADS or the MINI and child trauma questionnaire (CTQ) to evaluate presence of trauma. We searched serum levels of IL-10, IL-6, IL-1ß and TNF-α (flow cytometry), BDNF (sandwich-ELISA) and carbonyl content in proteins (PCC method). We found a significant direct association between ADs at baseline and log IL-6 (B = 0.34, S.E. = 0.11, p = 0.002) and between AD and log BDNF (B = -0.10, S.E. = 0.05, p = 0.033) five years later. Searching for possible mediators of these association, we found that levels of HDL-cholesterol (ΔB = -0.148) partially mediated the association between ADs and IL-6. No significant mediators were found in the association between ADs and BDNF. Moreover, this association is no longer significant after controlling for the presence of depression. Our results demonstrated that previous AD diagnosis was associated with higher levels of IL-6 in the follow-up evaluation, suggesting that the presence of anxiety in childhood could influence altered inflammatory markers.

DNA methylation in adolescents with anxiety disorder: a longitudinal study.

Anxiety disorders (AD) typically manifest in children and adolescents and might persist into adulthood. However, there are still few data concerning epigenetic mechanisms associated with onset, persistence or remission of AD over time. We investigated a cohort of adolescents and young adults at baseline (age; 13.19 ± 2.38) and after 5 years and classified them according to the AD diagnosis and their longitudinal trajectories into 4 groups: (1) Typically Developing Comparisons (TDC; control group, n = 14); (2) Incident (AD in the second evaluation only, n = 11); (3) Persistent (AD in both evaluations, n = 14) and (4) Remittent (AD in the first evaluation only, n = 8). DNA methylation was evaluated with the Infinium HumanMethylation450 BeadChip from saliva samples collected at both evaluations. Gene set enrichment analysis was applied to consider biological pathways. We found decreased DNA methylation in TDC group while the chronic cases of AD presented hypermethylation in central nervous system development pathways. Moreover, we showed that this persistent group also presented hypermethylation while the other three groups were associated with hypomethylation in nervous system development pathway. Incidence and remission groups were associated with increased and decreased methylation in neuron development pathways, respectively. Larger studies are likely to detect specific genes relevant to AD.

What can HPA axis-linked genes tell us about anxiety disorders in adolescents?

INTRODUCTION: Anxiety disorders (AD) share features of both anxiety and fear linked to stress response. The hypothalamic-pituitary-adrenal (HPA) axis is considered the core biological pathway of the stress system and it is known that an inappropriate response to environmental stimuli may be related to individual genetic vulnerability in HPA-linked genes. Despite the biological plausibility of a relationship between the HPA axis and AD, few studies have investigated associations between genetic polymorphisms linked to the HPA axis and this complex disorder. OBJECTIVE: To investigate whether AD are associated with genetic polymorphisms in HPA-linked genes in adolescents. METHODS: Our study consisted of a cross-sectional evaluation of a community sample comprising a total of 228 adolescents (131 cases of AD). We extracted DNA from saliva and genotyped polymorphisms in HPA-linked genes (FKBP5: rs3800373, rs9296158, rs1360780, rs9470080 and rs4713916; NR3C1: rs6198; CRHR1: rs878886; and SERPINA6: rs746530) with real time polymerase chain reaction (PCR). The instruments used to diagnose and assess the severity of AD were the Schedule for Affective Disorder and Schizophrenia for School-Age Children - Present and Lifetime (K-SADS-PL) and the Screen for Child and Anxiety related Emotional Disorders (SCARED). RESULTS: We failed to detect any associations between AD and genetic polymorphisms in HPA-linked genes (p > 0.05). CONCLUSION: To our knowledge, this is the first study evaluating these specific polymorphisms in relation to AD in adolescents, which encourages us to design further research on the subject.

Anxiety disorders and anxiety-related traits and serotonin transporter gene-linked polymorphic region (5-HTTLPR) in adolescents: case-control and trio studies.

The role of the serotonin transporter gene-linked polymorphic region (5-HTTLPR) in anxiety disorder and anxiety-related traits is controversial. Besides this study, few studies have evaluated the triallelic genotype in adolescents. The aim of this study was to investigate whether anxiety disorders and anxiety-related traits are associated with 5-HTTLPR (biallelic and triallelic) in adolescents, integrating both case-control-based and family-based designs in a community sample. This is a cross-sectional community study of 504 individuals and their families: 225 adolescents (129 adolescents with anxiety disorder and 96 controls) and their biological families. We assessed psychiatric diagnosis using the Kiddie Schedule for Affective Disorders and Schizophrenia. The Temperament and Character Inventory and the Resnick Behavioral Inhibition Scale were used to evaluate harm avoidance and behavioral inhibition. DNA was extracted from saliva and genotyped, including biallelic and triallelic 5-HTTLPR classification, by PCR-RFLP followed by agarose gel electrophoresis. We were not able to find any associations between 5-HTTLPR and anxiety-related phenotypes in both case-control and trio analyses. Further investigation and meta-analytic studies are needed to better clarify the inconsistent results with regard to the association between 5-HTTLPR and anxiety-related phenotypes in adolescents.

Mineralocorticoid receptor genotype moderates the association between physical neglect and serum BDNF.

The objective of this study is to investigate if a polymorphism in the NR3C2 gene moderates the association between childhood trauma on serum levels of brain derived neurothrophic factor (sBDNF). sBDNF was used here as a general marker of alteration in brain function. This is a community cross sectional study comprising 90 adolescents (54 with anxiety disorders). DNA was extracted from saliva in order to genotype the MR-2G/C (rs2070951) polymorphism using real time PCR. Blood was collected for sBDNF Elisa immunoassay. The Childhood Trauma Questionnaire (CTQ) was used to evaluate childhood abuse and neglect. Main effects and gene environment interactions were tested using linear regression models. Anxiety disorders were not associated with the MR-2G/C polymorphism or with sBDNF levels, but the number of C alleles of the MR-2G/C polymorphism was significantly associated with higher sBDNF levels (b = 8.008; p-value = 0.001). Subjects with intermediate and high exposure to physical neglect showed higher sBDNF levels if compared to subjects non-exposed (b = 11.955; p = 0.004 and b = 16.186; p = 0.009, respectively). In addition, we detected a significant physical neglect by MR-2G/C C allele interaction on sBDNF levels (p = 0.005), meaning that intermediate and high exposure to childhood neglect were only associated with increased sBDNF levels in subjects with the CC genotype, but not in subjects with other genotypes. Our findings suggest that genetic variants in NR3C2 gene may partially explain plastic brain vulnerability to traumatic events. Further studies are needed to investigate the moderating effects of NR3C2 gene in more specific markers of alteration in brain function.

Evidence of association between Val66Met polymorphism at BDNF gene and anxiety disorders in a community sample of children and adolescents.

Different lines of evidence support BDNF as a candidate gene in mood and anxiety modulation. More recently, the Met allele of the BDNF Val66Met polymorphism has been implicated in anxiety in animal models and anxiety-traits in humans. The aim of this study is to evaluate the a priori hypothesis that the association between anxiety disorders and Val66Met polymorphism at the BDNF gene would be replicated in a community sample of children and adolescents. 240 subjects from a total sample of 2457 children and adolescents aged 10-17 years from the public schools in the catchment area of the primary care unit of a university hospital participated in this case-control study and were assessed for psychopathology using the K-SADS-PL. A sample of saliva was collected for DNA analysis of Val66Met polymorphism. BDNF was the single gene evaluated in this sample. We found a significant association between carrying one copy of the Met allele and higher chance of anxiety disorders in children and adolescents. The association remained positive even after the adjustment for potential confounders (228 subjects; OR=3.53 (CI95% 1.77-7.06; p<0.001)). Our results support the a priori hypothesis of an association between anxiety and the polymorphism Val66Met. To our knowledge, this is the first study documenting a potential role of this polymorphism in a community sample of anxious children and adolescents.

The multidimensional evaluation and treatment of anxiety in children and adolescents: rationale, design, methods and preliminary findings.

OBJECTIVE: This study aims to describe the design, methods and sample characteristics of the Multidimensional Evaluation and Treatment of Anxiety in Children and Adolescents - the PROTAIA Project. METHOD: Students between 10 and 17 years old from all six schools belonging to the catchment area of the Primary Care Unit of Hospital de Clínicas de Porto Alegre were included in the project. It comprises five phases: (1) a community screening phase; (2) a psychiatric diagnostic phase; (3) a multidimensional assessment phase evaluating environmental, neuropsychological, nutritional, and biological factors; (4) a treatment phase, and (5) a translational phase. RESULTS: A total of 2,457 subjects from the community were screened for anxiety disorders. From those who attended the diagnostic interview, we identified 138 individuals with at least one anxiety disorder (apart from specific phobia) and 102 individuals without any anxiety disorder. Among the anxiety cases, generalized anxiety disorder (n = 95; 68.8%), social anxiety disorder (n = 57; 41.3%) and separation anxiety disorder (n = 49; 35.5%) were the most frequent disorders. CONCLUSION: The PROTAIA Project is a promising research project that can contribute to the knowledge of the relationship between anxiety disorders and anxiety-related phenotypes with several genetic and environmental risk factors.

The multidimensional evaluation and treatment of anxiety in children and adolescents: rationale, design, methods and preliminary findings / Avaliação multidimensional e tratamento da ansiedade em crianças e adolescentes: marco teórico, desenho, métodos e resultados preliminares

OBJECTIVE: This study aims to describe the design, methods and sample characteristics of the Multidimensional Evaluation and Treatment of Anxiety in Children and Adolescents - the PROTAIA Project. METHOD: Students between 10 and 17 years old from all six schools belonging to the catchment area of the Primary Care Unit of Hospital de Clínicas de Porto Alegre were included in the project. It comprises five phases: (1) a community screening phase; (2) a psychiatric diagnostic phase; (3) a multidimensional assessment phase evaluating environmental, neuropsychological, nutritional, and biological factors; (4) a treatment phase, and (5) a translational phase. RESULTS: A total of 2,457 subjects from the community were screened for anxiety disorders. From those who attended the diagnostic interview, we identified 138 individuals with at least one anxiety disorder (apart from specific phobia) and 102 individuals without any anxiety disorder. Among the anxiety cases, generalized anxiety disorder (n = 95; 68.8 percent), social anxiety disorder (n = 57; 41.3 percent) and separation anxiety disorder (n = 49; 35.5 percent) were the most frequent disorders. CONCLUSION: The PROTAIA Project is a promising research project that can contribute to the knowledge of the relationship between anxiety disorders and anxiety-related phenotypes with several genetic and environmental risk factors.

OBJETIVO: o objetivo deste estudo é descrever o desenho, os métodos e as características amostrais da Avaliação Multidimensional e Tratamento da Ansiedade em Crianças e Adolescentes - Projeto PROTAIA. MÉTODO: Escolares entre 10 e 17 anos de todas as escolas pertencentes à área de abrangência da unidade de atenção primária do Hospital de Clínicas de Porto Alegre foram incluídos no projeto. O projeto compreende cinco fases: 1) triagem comunitária; 2) diagnóstico psiquiátrico; 3) avaliação multidimensional, incluindo fatores ambientais, neuropsicológicos, nutricionais e marcadores biológicos; 4) tratamento; e 5) fase translacional. RESULTADOS: Um total de 2.457 sujeitos foram triados para transtornos de ansiedade na comunidade. Dos indivíduos que compareceram à avaliação diagnóstica, 138 foram detectados com ao menos um transtorno de ansiedade (excluindo fobia específica) e 102 indivíduos sem nenhum transtorno de ansiedade. Dentre os casos de ansiedade, o transtorno de ansiedade generalizada (n = 95; 68,8 por cento), transtorno de ansiedade social (n = 57; 41,3 por cento) e o transtorno de ansiedade de separação (n = 49; 35,5 por cento) foram os mais frequentes. CONCLUSÃO: O projeto PROTAIA é um projeto de pesquisa promissor que pode contribuir para o entendimento da relação entre transtornos de ansiedade e fenótipos relacionados à ansiedade com vários fatores de risco, tanto genéticos quanto ambientais.