Of Scaredy Cats and Cold Fish: The autonomic nervous system and behaviour in young children

__Abstract__ The autonomic nervous system regulates the body’s internal functions. The goal of this regulation is to maintain bodily homeostasis in a changing external environment. The autonomic nervous system acts largely independent of volition and controls heart rate, respiratory rate, digestion, and perspiration. It is divided into two partially antagonistic systems: the sympathetic nervous system and the parasympathetic or vagal nervous system. In general, the vagal system primarily regulates “rest and digest” functions. In contrast, the sympathetic nervous system can elicit the “fi ght or fl ight” response with increased arousal and energy generation in response to stress or threat. Together with the hypothalamic-pituitary adrenal (HPA) axis, the autonomic nervous system mediates the body’s response to stress. Because of this central role in stress response and the close relation of stress with the onset and recurrence of psychiatric disorders, both systems are potential biomarkers for psychiatric disorders. The current thesis investigates possible determinants of stress regulation, as well as the associations of stress regulation with emotional and behavioural symptoms very young age. The majority of the studies in this thesis were performed within the Generation R study. The Generation R Study is a large population-based prospective cohort study from fetal life onwards. It was designed to identify early environmental as well as genetic causes of abnormal growth, development and health from fetal life onwards. In total, 9,778 mothers with a delivery date from April 2002 until January 2006 were enrolled in the study. The studies presented here concern children who participated in the Focus Cohort. The Focus Cohort consists of a randomly selected subgroup of Dutch children of Caucasian origin and their parents. Studies conducted in the Focus Cohort were able to utilise more in-depth assessments. The research discussed in chapter 6 was performed within the “Beren van de Weg” study. This is a clinical, outpatient study, conducted by the departments of Child and Adolescent Psychiatry of either the Erasmus Medical Center in Rotterdam and Leiden University Medical Center— Curium. All consecutive referrals with a primary diagnosis of Generalized Anxiety Disorder, Separation Anxiety Disorder, Social Phobia or Specifi c Phobia were eligible for inclusion . In chapter 2 we examined the potential impact of maternal psychopathology on infant heart rate and heart rate variability. We showed that a maternal history of psychopathology before childbirth was associated with increased heart rate and lower vagal modulation in the infant. Similarly, postnatal maternal symptoms, especially anxiety and depression symptoms, were related to increased heart rate in the infant. Both genetic and environmental mechanisms, which are certainly not mutually exclusive, could underlie the association between maternal psychopathology and infant heart rate. In chapter 3 we assessed the putative benefi cial effect of breastfeeding on child autonomic functioning. To address the issue of residual confounding, we compared the effect of breastfeeding with that of a contrasting variable, infant fruitpurée consumption. It is related to similar environmental epiphenomena as breastfeeding. We found that infants, who were exclusively breastfed at two months of age, had lower sympathetic modulation than infants not breastfed. However, our data showed that, similar to breastfeeding, infants who ate more fruitpurée had lower sympathetic modulation as well. Association does not imply causation. In fact, in both instances the causal pathways linking the risk factors to autonomic functioning remain unclear. Moreover, in the case of breast feeding, a limited effect size with a similar order of magnitude as the effect of another, seemingly trivial dietary component, calls into question the clinical relevance of the association, 8 105 even if it contains a causal component. In chapter 4 we addressed the relation between infant autonomic functioning at 14 months and behaviour at age 18 months. We found that the association between autonomic functioning and infant externalising behaviour, was moderated by maternal psychiatric symptoms. We observed that low heart rate was associated with aggressive behaviour, only in a subgroup of children whose mothers had high psychiatric symptoms. This suggests that in the presence of maternal risk factors, low autonomic arousal renders children particularly susceptible to externalising behaviour. This lends support to the fearlessness theory, which posits that low autonomic arousal in children is an indicator of fearlessness. We hypothesize that in the presence of maternal psychopathology, with less adequate parenting and maternal guidance in coping with fearless behaviour, these children actually develop aggressive behaviour. In chapter 5 we examined the association between a child’s heart rate at 14 months and behavior at 3 years. Low heart rate was specifi cally and strongly associated with the odds of the child lying during the gift delay task as well as with low levels of anxiety. We suggest that low anxiety and a tendency to lie are indicative of low levels of emotional reactivity. Low heart rate may thus delineate a small group of children that are composed and calculating, rather than overly emotionally reactive and overtly aggressive. However, we could not demonstrate an association between heart rate and parent rated aggressive behaviour. This could be because the children in our study were considerably younger than those in earlier studies. In young children aggressive behaviour is common, but usually time limited. Proactive, planned aggression, which is commonly accompanied by low levels of emotional reactivity, develops later in life than reactive aggression. Chapter 6 details the course of an anxiety disorder during treatment and the concomitant changes in cortisol levels in a clinical sample of 116 children and adolescents. When we compared cortisol levels at baseline and one-year follow-up, persistence of the anxiety disorder was associated with both increased daytime cortisol production and a trend towards a decreased cortisol morning rise. Persistence of an anxiety disorder may change HPA-axis functioning, underscoring the importance adequate treatment of anxiety disorders. Chapter 7 highlights the main results of the previous chapters and places them in a broader context. The main body of the chapter details the different methodological issues encountered during this research. Clinicial implications and recommendations for future research are discussed as well

Assessing methods of measuring medication adherence in chronically ill children-a narrative review

Nonadherence in children who use long-term medication is a serious problem and assessing adherence is an important step to provide solutions to this problem. Medication adherence can be measured by several methods, including (a) self-report questionnaires or structured interviews, (b) therapeutic drug monitoring (TDM), (c) electronic devices, and (d) pick-up/refill rates. The objective of this narrative review is to provide an overview of the literature about methods for the measurement of medication adherence in chronically ill children and adolescents. Therefore, we conducted a literature search by using multiple databases. Four methods of monitoring medication adherence are presented for the most described chronic diseases: asthma, HIV/AIDS, epilepsy, diabetes mellitus and ADHD. First, 10 commonly used self-report questionnaires and structured interviews are described, including the main characteristics, (dis)advantages and their validation studies. Second, the use of TDM in pediatric trials for medication adherence measurement is discussed. New sampling methods (e.g. dried blood spot) and sampling matrices (e.g. hair, saliva and urine) have shown their benefits for TDM in children. Third, electronic devices to measure medication adherence in children are presented, being developed for several drug administration routes. Fourth, the analyses, advantages and disadvantages of pharmacy data are discussed. The usage of this data requires specific calculations and interpretations to assess adherence. As presented in this review, every adherence method has specific (dis)advantages. When deciding which adherence method is applicable, validity and generalizability should be taken into account. Combining multiple methods seems to offer the best solution in the daily clinical practice

Assessing methods of measuring medication adherence in chronically ill children-a narrative review

Nonadherence in children who use long-term medication is a serious problem and assessing adherence is an important step to provide solutions to this problem. Medication adherence can be measured by several methods, including (a) self-report questionnaires or structured interviews, (b) therapeutic drug monitoring (TDM), (c) electronic devices, and (d) pick-up/refill rates. The objective of this narrative review is to provide an overview of the literature about methods for the measurement of medication adherence in chronically ill children and adolescents. Therefore, we conducted a literature search by using multiple databases. Four methods of monitoring medication adherence are presented for the most described chronic diseases: asthma, HIV/AIDS, epilepsy, diabetes mellitus and ADHD. First, 10 commonly used self-report questionnaires and structured interviews are described, including the main characteristics, (dis)advantages and their validation studies. Second, the use of TDM in pediatric trials for medication adherence measurement is discussed. New sampling methods (e.g. dried blood spot) and sampling matrices (e.g. hair, saliva and urine) have shown their benefits for TDM in children. Third, electronic devices to measure medication adherence in children are presented, being developed for several drug administration routes. Fourth, the analyses, advantages and disadvantages of pharmacy data are discussed. The usage of this data requires specific calculations and interpretations to assess adherence. As presented in this review, every adherence method has specific (dis)advantages. When deciding which adherence method is applicable, validity and generalizability should be taken int

Single-center versus multi-center biparametric MRI radiomics approach for clinically significant peripheral zone prostate cancer

Contains fulltext : 239809.pdf (Publisher’s version ) (Open Access

Maternal Sociodemographic Factors Are Associated With Methylphenidate Initiation in Children in the Netherlands: A Population-Based Study

Multiple factors may contribute to the decision to initiate methylphenidate treatment in children such as maternal sociodemographic factors of which relatively little is known. The objective was to investigate the association between these factors and methylphenidate initiation. The study population included 4243 children from the Generation R Study in the Netherlands. Maternal sociodemographic characteristics were tested as determinants of methylphenidate initiation through a timedependent Cox regression analysis. Subsequently, we stratifed by mother-reported ADHD symptoms (present in 4.2% of the study population). When ADHD symptoms were absent, we found that girls (adjusted HR 0.25, 95%CI 0.16–0.39) and children born to a mother with a non-western ethnicity (compared to Dutch-Caucasian) (adjusted HR 0.42, 95%CI 015–0.68) were less likely to receive methylphenidate. They were more likely to receive methylphenidate when their mother completed a low (adjusted HR 2.29, 95%CI 1.10–4.77) or secondary (adjusted HR 1.71, 95%CI 1.16–2.54) education. In conclusion, boys and children born to a mother of Dutch-Caucasian ethnicity were more likely to receive methylphenidate, irrespective of the presence of ADHD symptoms

Pridopidine selectively occupies sigma-1 rather than dopamine D2 receptors at behaviorally active doses

Dopamine stabilizers have stimulatory actions under low dopamine tone and inhibitory actions under high dopamine tone without eliciting catalepsy. These compounds are dopamine D-2 receptor (D2R) antagonists or weak partial agonists and may have pro-mnemonic and neuroprotective effects. The mechanism underlying their stimulatory and neuroprotective actions is unknown but could involve sigma-1R binding. The present study examined sigma-1R and D2R occupancy by the dopamine stabilizer pridopidine (ACR16) at behaviorally relevant doses in living rats. Rats were administered 3 or 15 mg/kg pridopidine, or saline, before injection of the radiotracer C-11-SA4503 (sigma-1R) or C-11-raclopride (D2R). Some animals received 60 mg/kg pridopidine and were only scanned with C-11-raclopride. Cerebral C-11-SA4503 binding was quantified using metabolite-corrected plasma input data and distribution volume (V (T)) calculated by Logan graphical analysis. C-11-raclopride binding was quantified using striatum-to-cerebellum ratios and binding potentials calculated with a simplified reference tissue model. Cunningham-Lassen plots indicated sigma-1R occupancies of 57 +/- 2 and 85 +/- 2 % after pretreatment of animals with 3 and 15 mg/kg pridopidine. A significant (44-66 %) reduction of C-11-raclopride binding was only observed at 60 mg/kg pridopidine. At doses shown to elicit neurochemical and behavioral effects, pridopidine occupied a large fraction of sigma-1Rs and a negligible fraction of D(2)Rs. Significant D2R occupancy was only observed at a dose 20-fold higher than was required for sigma-1R occupancy. The characteristics of dopamine stabilizers may result from the combination of high sigma-1R and low D2R affinity