Andrea Dietrich

Endocannabinoids and exercise

Exercise induces changes in mental status, particularly analgesia, sedation, anxiolysis, and a sense of wellbeing. The mechanisms underlying these changes remain unknown. Recent findings show that exercise increases serum concentrations of endocannabinoids, suggesting a possible explanation for a number of these changes. This article provides an overview of this emerging field.

Spontaneous baroreflex sensitivity in (pre)adolescents

Objective To present normal spontaneous baroreflex sensitivity (BRS) values and investigate the influence of posture, sex, age, pubertal stage, body mass index (BMI), and physical activity level on BRS in (pre)adolescents. BRS is a sensitive measure of both sympathetic and parasympathetic cardiovascular regulation that may help detect early subclinical autonomic dysfunction. Design A cross-sectional cohort study in a large sample of 10–13-year-old Dutch (pre)adolescents from the general population. Methods Short-term spontaneous BRS was determined non-invasively by Portapres in both the supine and standing position. BRS was calculated by power spectral analysis using the discrete Fourier method (frequency band 0.07–0.14 Hz). Univariate statistical methods and multiple regression analyses were applied. Results BRS in a standing position was lower than in a supine position (9.0 ± 4.9 versus 15.3 ± 9.1 ms/mmHg; t = 27.8, P < 0.001). Girls had lower BRS values than boys in both postures (supine 14.3 ± 8.7 versus 16.4 ± 9.4 ms/mmHg, β = 0.12, P < 0.001; standing 8.4 ± 4.4 versus 9.5 ± 5.4 ms/mmHg, β = 0.08, P = 0.012), independent of age, pubertal stage, BMI, and physical activity. Lower limits (P2.5) for normal BRS values in supine and standing positions were for girls 3.6 and 2.2 ms/mmHg and for boys 3.9 and 2.5 ms/mmHg, respectively. BRS declined with age in the standing position (β = −0.13, P < 0.001). In obese (pre)adolescents, BMI was negatively associated with BRS during standing (Kendalls τ = −0.26, P = 0.010). Conclusion The BRS of (pre)adolescents was negatively related to female sex, age, and obesity. A reduced BRS in obese (pre)adolescents might be a candidate predictor of future cardiovascular health, and therefore warrants further exploration.

Environmental factors in Tourette syndrome

Environmental exposures during the prenatal period, perinatal stages, and postnatal life may contribute to onset and course of Tourette syndrome (TS). Pregnancy-related noxious exposures may be more frequent in pregnancies of children who will develop TS, particularly maternal smoking and prenatal life stressors. Lower birth weight and use of forceps at delivery may be associated with tic severity in the offspring; moreover, low birth weight and maternal smoking during pregnancy may affect the risk of co-morbid attention-deficit/hyperactivity and obsessive-compulsive disorders. Group A streptococcal infections as risk-modifier for TS has not been convincingly demonstrated to date, although an interaction with stressors was suggested. The PANDAS hypothesis is currently undergoing a nosological revision. Only limited anecdotal evidence supports a link of TS to other pathogens. Nevertheless, the relationship between infections and TS may be complex. Recent data point to intrinsically altered immune regulation in TS, which might predispose to both infections and autoimmune mechanisms; however, evidence of cell-mediated and antibody-mediated autoimmunity in TS is still insufficient. Psychosocial stress remains the most important contextual factor influencing tic severity, as confirmed by prospective studies. This might in part be related to enhanced reactivity of the stress response in TS patients, the mechanisms of which need to be explored further. New studies on large prospective cohorts of patients of different age and the identification of reliable biomarkers or endophenotypes indicating early, prenatal exposure to environmental insults are needed.

Cortisol in the morning and dimensions of anxiety, depression, and aggression in children from a general population and clinic-referred cohort : An integrated analysis. The TRAILS study

Anxiety and depressive problems have often been related to higher hypothalamic-pituitary-adrenal (HPA)-axis activity (basal morning cortisol levels and cortisol awakening response [CAR]) and externalizing problems to lower HPA-axis activity. However, associations appear weaker and more inconsistent than initially assumed. Previous studies from the Tracking Adolescents Individual Lives Study (TRAILS) suggested sex-differences in these relationships and differential associations with specific dimensions of depressive problems in a general population sample of children (10-12 years). Using the TRAILS population sample (n=1604), we tested hypotheses on the association between single day cortisol (basal morning levels and CAR) and specifically constructed dimensions of anxiety (cognitive versus somatic), depressive (cognitive-affective versus somatic), and externalizing problems (reactive versus proactive aggression), and explored the modifying role of sex. Moreover, we repeated analyses in an independent same-aged clinic-referred sample (n=357). Structural Equation Modeling was used to investigate the association between cortisol and higher- and lower-order (thus, broad and specific) problem dimensions based on self-reports in an integrated model. Overall, findings were consistent across the population and clinic-referred samples, as well as with the existing literature. Most support was found for higher cortisol (mainly CAR) in relation to depressive problems. However, in general, associations were weak in both samples. Therefore, the present results shed doubt on the relevance of single day cortisol measurements for problem behaviors in the milder range. Associations may be stronger in more severe or persistent psychopathology.

Reproducibility of heart rate variability and baroreflex sensitivity measurements in children

Despite their extensive use, the reproducibility of cardiac autonomic measurements in children is not well-known. We investigated the reproducibility of short-term continuous measurements of heart rate (HR), heart rate variability (HRV, time and frequency domain), and spontaneous baroreflex sensitivity (BRS, frequency domain) in the supine and standing position in 57 children (11.2+/-0.7 years, 52.6% boys). Reproducibility between two sessions within a two-week interval was evaluated by intraclass correlation coefficients (ICCs), standard error of measurement, coefficients of variation (CVs), limits of agreement, and Bland-Altman plots. HR and HRV were moderately-to-highly (ICC=.63-.79; CV=5.7%-9.7%) and BRS moderately (ICC=.49-.63; CV=11.4%-14.0%) reproducible. While the BRS measurements were slightly less reproducible than the HR and HRV measurements, all can be reliably applied in research, thus implicating sufficient capacity to detect real differences between children. Still, clinical studies focusing on individual changes in cardiac autonomic functioning need to address the considerable random variations that may occur between test-retest measurements.

The Tourette International Collaborative Genetics (TIC Genetics) study, finding the genes causing Tourette syndrome: objectives and methods

Tourette syndrome (TS) is a neuropsychiatric disorder characterized by recurrent motor and vocal tics, often accompanied by obsessive–compulsive disorder and/or attention-deficit/hyperactivity disorder. While the evidence for a genetic contribution is strong, its exact nature has yet to be clarified fully. There is now mounting evidence that the genetic risks for TS include both common and rare variants and may involve complex multigenic inheritance or, in rare cases, a single major gene. Based on recent progress in many other common disorders with apparently similar genetic architectures, it is clear that large patient cohorts and open-access repositories will be essential to further advance the field. To that end, the large multicenter Tourette International Collaborative Genetics (TIC Genetics) study was established. The goal of the TIC Genetics study is to undertake a comprehensive gene discovery effort, focusing both on familial genetic variants with large effects within multiply affected pedigrees and on de novo mutations ascertained through the analysis of apparently simplex parent–child trios with non-familial tics. The clinical data and biomaterials (DNA, transformed cell lines, RNA) are part of a sharing repository located within the National Institute for Mental Health Center for Collaborative Genomics Research on Mental Disorders, USA, and will be made available to the broad scientific community. This resource will ultimately facilitate better understanding of the pathophysiology of TS and related disorders and the development of novel therapies. Here, we describe the objectives and methods of the TIC Genetics study as a reference for future studies from our group and to facilitate collaboration between genetics consortia in the field of TS.

Age-specific associations between cardiac vagal activity and functional somatic symptoms: a population-based study

Background: Functional somatic symptoms (FSS) are symptoms not explained by underlying organic pathology. It has frequently been suggested that dysfunction of the autonomic nervous system (ANS) contributes to the development of FSS. We hypothesized that decreased cardiac vagal activity is cross-sectionally and prospectively associated with the number of FSS in the general population. Methods: This study was performed in a population-based cohort of 774 adults (45.1% male, mean age ± SD 53.5 ± 10.7 years). Participants completed the somatization section of the Composite International Diagnostic Interview surveying the presence of 43 FSS. ANS function was assessed by spectral analysis of heart rate variability in the high-frequency band (HRV-HF), reflecting cardiac vagal activity. Follow-up measurements of HRV-HF and FSS were performed approximately 2 years later. Results: Linear regression analyses, with adjustments for gender, age, body mass index, anxiety, depression, smoking, alcohol use, and frequency of exercise, revealed an interaction of cardiac vagal activity with age: HRV-HF was negatively associated with FSS in adults ≤52 years of age (β = –0.12, t = –2.37, p = 0.018), but positively with FSS in adults aged >52 years (β = 0.13, t = 2.51, p = 0.012). Longitudinal analysis demonstrated a similar pattern. Conclusions: Decreased cardiac vagal activity is associated with a higher number of FSS in adults aged ≤52 years in the general population. The unexpected association between increased cardiac vagal activity and FSS in adults aged >52 years needs further exploration. The role of age should be acknowledged in future studies on ANS function in the etiology of FSS.

Temperamental activation and inhibition associated with autonomic function in preadolescents. The TRAILS study

We investigated the temperamental traits high-intensity pleasure (temperamental activation) and shyness (temperamental inhibition) in relation to autonomic function as measured by heart rate (HR), respiratory sinus arrhythmia (RSA), and baroreflex sensitivity (BRS) in 938 10-13-year-old preadolescents from a population cohort. Temperament was evaluated by parent reports on the Revised Early Adolescent Temperament Questionnaire. Autonomic measurements were obtained in supine and standing position. High-intensity pleasure was negatively associated with supine HR and positively with supine RSA and BRS in both genders. Shyness was positively related to supine BRS in girls only. Orthostatic-based autonomic reactivity (difference) scores adjusted for supine values were unrelated to temperamental measures. It appeared that higher scores on temperamental activation and inhibition are associated with higher cardiac vagal activity (RSA) and/or flexible regulation of autonomic balance (BRS), implicating healthy physiological functioning. Moreover, results suggest a physiological basis promoting the tendency towards engagement in high-intensity activities.

Fat depot-specific mRNA expression of novel loci associated with waist–hip ratio

Objective:We hypothesized that genes within recently identified loci associated with waist–hip ratio (WHR) exhibit fat depot-specific mRNA expression, which correlates with obesity-related traits.Methods:Adipose tissue (AT) mRNA expression of 6 genes (TBX15/WARS2, STAB1, PIGC, ZNRF3 and GRB14) within these loci showing coincident cis-expression quantitative trait loci was measured in 222 paired samples of human visceral (vis) and subcutaneous (sc) AT. The relationship of mRNA expression levels with obesity-related quantitative traits was assessed by Pearsons correlation analyses. Multivariate linear relationships were assessed by generalized linear regression models.Results:Whereas only PIGC, ZNFR3 and STAB1 mRNA expression in sc AT correlated nominally with WHR (P<0.05, adjusted for age and sex), mRNA expression of all studied genes in at least one of the fat depots correlated significantly with vis and/or sc fat area (P ranging from 0.05 to 4.0 × 106, adjusted for age and sex). Consistently, the transcript levels of WARS, PIGC and GRB14 were nominally associated with body mass index (BMI) (P ranging from 0.02 to 9.2 × 105, adjusted for age and sex). Moreover, independent of sex, obesity and diabetes status, differential expression between vis and sc AT was observed for all tested genes (P<0.01). Finally, the rs10195252 T-allele was nominally associated with increased GRB14 sc mRNA expression (P=0.025 after adjusting for age, sex and BMI).Conclusions:Our data including the inter-depot variability of mRNA expression suggests that genes within the WHR-associated loci might be involved in the regulation of fat distribution.

Basal Ganglia Structure in Tourette's Disorder and/or Attention-Deficit/Hyperactivity Disorder

Tourettes disorder and attention‐deficit/hyperactivity disorder often co‐occur and have both been associated with structural variation of the basal ganglia. However, findings are inconsistent and comorbidity is often neglected.