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Objectives: The prospective longitudinal Mannheim Study of Children at Risk followed the development of children from the age of 2 years up to the age of 8 years. Are there differences between the developmental risk load in toddlers (psychopathology, cognition, motor or neurological development. and educational differences) who suffer from a hyperactive disorder at age 8 and that of undisturbed children of the same age? Are there specific harbingers of hyperkinetic disorders for the group concerned? Methods: In terms of their developmental risk load at the age of 2 years, 26 primary school children with hyperkinetic disorders were compared to 241 healthy primary school children, as well as to 25 children of the same age with emotional disturbances and 30 children of the same age with socially disruptive behavior. Results: A significant combination of predictors of later hyperkinetic disorders at primary school age proved to be increased fidgetiness and irritability, as well as a reduced language comprehension, at the age of two. Conclusions: The predictive value of symptoms in early childhood for later hyperkinetic disorder in children of primaryschool age is higher than that of symptoms assessed in infancy, which although expected is without relevant specificity.
Objectives: Are there any differences (organic, psychosocial, psychopathological, cognitive or educational, respectively differences in the motor or neurological development) between infants who later on at the age of 8 years suffer from a hyperactive disorder and those who later on at the same age are undisturbed? Are there specific harbingers for hyperactive disorders in the group concerned? Methods: With regard to their developmental risk load at the age of 3 months, 26 primary school children with hyperactive disorders were compared with 241 healthy children, 25 children with emotional disturbances, and 30 children with socially disruptive behaviour, all of the same age. Results: Identified as the most important predictors for the onset of hyperactive disorders were a reduced birth weight, the mother's origin from a shattered family, early contact impairments on the part of the child, and the mother's neglect of the infant. Conclusions: Altogether, however, the prediction of later hyperactivity in primary school children on the basis of salient features in the infant children remains unsatisfactory and unspecific.
Ventral striatum and amygdala activity as convergence sites for early adversity and conduct disorder
(2017)
Childhood family adversity (CFA) increases the risk for conduct disorder (CD) and has been associated with alterations in regions of affective processing like ventral striatum (VS) and amygdala. However, no study so far has demonstrated neural converging effects of CFA and CD in the same sample. At age 25 years, functional MRI data during two affective tasks, i.e. a reward (N = 171) and a face-matching paradigm (N = 181) and anatomical scans (N = 181) were acquired in right-handed currently healthy participants of an epidemiological study followed since birth. CFA during childhood was determined using a standardized parent interview. Disruptive behaviors and CD diagnoses during childhood and adolescence were obtained by diagnostic interview (2–19 years), temperamental reward dependence was assessed by questionnaire (15 and 19 years).
CFA predicted increased CD and amygdala volume. Both exposure to CFA and CD were associated with a decreased VS response during reward anticipation and blunted amygdala activity during face-matching. CD mediated the effect of CFA on brain activity. Temperamental reward dependence was negatively correlated with CFA and CD and positively with VS activity. These findings underline the detrimental effects of CFA on the offspring's affective processing and support the importance of early postnatal intervention programs aiming to reduce childhood adversity factors.
Brain activation stability is crucial to understanding attention lapses. EEG methods could provide excellent markers to assess neuronal response variability with respect to temporal (intertrial coherence) and spatial variability (topographic consistency) as well as variations in activation intensity (low frequency variability of single trial global field power).
We calculated intertrial coherence, topographic consistency and low frequency amplitude variability during target P300 in a continuous performance test in 263 15-year-olds from a cohort with psychosocial and biological risk factors.
Topographic consistency and low frequency amplitude variability predicted reaction time fluctuations (RTSD) in a linear model. Higher RTSD was only associated with higher psychosocial adversity in the presence of the homozygous 6R-10R dopamine transporter haplotype.
We propose that topographic variability of single trial P300 reflects noise as well as variability in evoked cortical activation patterns. Dopaminergic neuromodulation interacted with environmental and biological risk factors to predict behavioural reaction time variability. (C) 2015 Elsevier B.V. All rights reserved.
Ungeduldige Winzlinge und ihre Entwicklung : was schützt Frühgeborene vor Entwicklungsstörungen
(1997)
Background: Dopamine plays an important role in orienting and the regulation of selective attention to relevant stimulus characteristics. Thus, we examined the influences of functional variants related to dopamine inactivation in the dopamine transporter (DAT1) and catechol-O-methyltransferase genes (COMT) on the time-course of visual processing in a contingent negative variation (CNV) task.
Methods: 64-channel EEG recordings were obtained from 195 healthy adolescents of a community-based sample during a continuous performance task (A-X version). Early and late CNV as well as preceding visual evoked potential components were assessed.
Results: Significant additive main effects of DAT1 and COMT on the occipito-temporal early CNV were observed. In addition, there was a trend towards an interaction between the two polymorphisms. Source analysis showed early CNV generators in the ventral visual stream and in frontal regions. There was a strong negative correlation between occipito-temporal visual post-processing and the frontal early CNV component. The early CNV time interval 500-1000 ms after the visual cue was specifically affected while the preceding visual perception stages were not influenced.
Conclusions: Late visual potentials allow the genomic imaging of dopamine inactivation effects on visual post-processing. The same specific time-interval has been found to be affected by DAT1 and COMT during motor post-processing but not motor preparation. We propose the hypothesis that similar dopaminergic mechanisms modulate working memory encoding in both the visual and motor and perhaps other systems.
Converging evidence has highlighted the association between poverty and conduct disorder (CD) without specifying neurobiological pathways. Neuroimaging research has emphasized structural and functional alterations in the orbitofrontal cortex (OFC) as one key mechanism underlying this disorder. The present study aimed to clarify the long-term influence of early poverty on OFC volume and its association with CD symptoms in healthy participants of an epidemiological cohort study followed since birth. At age 25 years, voxel-based morphometry was applied to study brain volume differences. Poverty (0 = non-exposed (N = 134), I = exposed (N = 33)) and smoking during pregnancy were determined using a standardized parent interview, and information on maternal responsiveness was derived from videotaped mother infant interactions at the age of 3 months. CD symptoms were assessed by diagnostic interview from 8 to 19 years of age. Information on life stress was acquired at each assessment and childhood maltreatment was measured using retrospective self-report at the age of 23 years. Analyses were adjusted for sex, parental psychopathology and delinquency, obstetric adversity, parental education, and current poverty. Individuals exposed to early life poverty exhibited a lower OFC volume. Moreover, we replicated previous findings of increased CD symptoms as a consequence of childhood poverty. This effect proved statistically mediated by OFC volume and exposure to life stress and smoking during pregnancy, but not by childhood maltreatment and maternal responsiveness. These findings underline the importance of studying the impact of early life adversity on brain alterations and highlight the need for programs to decrease income-related disparities.
Recent evidence suggests that heterogeneity in the age at onset could explain the inconsistent findings of association studies relating the dopamine transporter (DAT1) gene with alcohol and nicotine consumption. The aim of this study was to examine interactions between two DAT1 polymorphisms and different initiation ages with regard to alcohol and tobacco consumption levels and dependence. Two hundred and ninety-one young adults (135 males, 156 females) participating in the Mannheim Study of Children at Risk were genotyped for the 40-bp variable number of tandem repeats (VNTR) and rs27072 polymorphisms of DAT1. Age at initiation was assessed at age 15 and 19 years. Information about current alcohol and tobacco consumption was obtained at age 19 years using self-report measures and structured interviews. Results suggest that age at onset of intensive consumption moderated the association of the DAT1 gene with early adult substance use and dependence, revealing a DAT1 effect only among individuals homozygous for the 10r allele of the 40-bp VNTR who had started daily smoking or being intoxicated early in life. Equally, carriers of the T allele of the rs27072 polymorphism reporting an early age at first intoxication showed higher current alcohol consumption at age 19 years. In contrast, no interaction between rs27072 and the age at first cigarette with regard to later smoking was observed. These findings provide evidence that the DAT1 gene interacts with an early heavy or regular drug exposure of the maturing adolescent brain to predict substance (ab)use in young adulthood. Further studies are required to confirm these findings.
Background:
Recent studies have identified a Child Behavior Checklist profile that characterizes children with severe affective and behavioral dysregulation (CBCL-dysregulation profile, CBCL-DP). In two recent longitudinal studies the CBCL-DP in childhood was associated with heightened rates of comorbid psychiatric disorders, among them bipolar disorder, an increased risk for suicidality, and marked psychosocial impairment at young-adult follow-up. This is the first study outside the US that examines the longitudinal course of the CBCL-DP.
Methods:
We studied the diagnostic and functional trajectories and the predictive utility of the CBCL-DP in the Mannheim Study of Children at Risk, an epidemiological cohort study on the outcome of early risk factors from birth into adulthood. A total of 325 young adults (151 males, 174 females) participated in the 19-year assessment.
Results:
Young adults with a higher CBCL-DP score in childhood were at increased risk for substance use disorders, suicidality and poorer overall functioning at age 19, even after adjustment for parental education, family income, impairment and psychiatric disorders at baseline. Childhood dysregulation was not related to bipolar disorder in young adulthood. The CBCL-DP was neither a precursor of a specific pattern of comorbidity nor of comorbidity in general.
Conclusions:
Children with high CBCL-DP values are at risk for later severe, psychiatric symptomatology. The different developmental trajectories suggest that the CBCL-DP is not simply an early manifestation of a single disease process but might rather be an early developmental risk marker of a persisting deficit of self-regulation of affect and behavior.
Recent studies have identified a Child Behavior Checklist profile that characterizes children with severe affective and behavioral dysregulation (CBCL-dysregulation profile, CBCL-DP). In two recent longitudinal studies the CBCL-DP in childhood was associated with heightened rates of comorbid psychiatric disorders, among them bipolar disorder, an increased risk for suicidality, and marked psychosocial impairment at young-adult follow-up. This is the first study outside the US that examines the longitudinal course of the CBCL-DP. Methods: We studied the diagnostic and functional trajectories and the predictive utility of the CBCL-DP in the Mannheim Study of Children at Risk, an epidemiological cohort study on the outcome of early risk factors from birth into adulthood. A total of 325 young adults (151 males, 174 females) participated in the 19-year assessment. Results: Young adults with a higher CBCL-DP score in childhood were at increased risk for substance use disorders, suicidality and poorer overall functioning at age 19, even after adjustment for parental education, family income, impairment and psychiatric disorders at baseline. Childhood dysregulation was not related to bipolar disorder in young adulthood. The CBCL-DP was neither a precursor of a specific pattern of comorbidity nor of comorbidity in general. Conclusions: Children with high CBCL-DP values are at risk for later severe, psychiatric symptomatology. The different developmental trajectories suggest that the CBCL-DP is not simply an early manifestation of a single disease process but might rather be an early developmental risk marker of a persisting deficit of self-regulation of affect and behavior.
In a high-risk community sample, we examined the role of regulative temperament and emotionality as well as the extent of gender specificity in the development of externalizing problems. 151 boys and 157 girls born at differing degrees of obstetric and psychosocial risk were followed from birth into adolescence. In infancy and childhood, NYLS- derived temperamental characteristics were assessed by a highly structured parent interview and standardized behavioral observations. At age 15 years, externalizing problems were measured by the Child Behavior Checklist. As revealed by multiple linear regression and logistic regression, low regulative abilities predicted adolescent behavioral and attentional problems over and above obstetric and psychosocial risks. Gender specificity was found in the strength of the association rather than in the kind with a stronger long-term prediction from infant and toddler temperament in girls. Compared to regulative abilities, temperament factors describing aspects of mood and fear/withdrawal versus approach tendencies played a minor role in the development of externalizing problems. Findings are discussed in terms of gender-specific risk factors and possible differential developmental trajectories to subtypes of disruptive behavior.
Objective: Despite theoretical discrepancies between different concepts of temperament, some core dimensions are thought to be common to the various models. We compared temperamental traits derived from the New York Longitudinal Study (NYLS) model and the Cloninger dimensions in the developmental course and investigated the associations of temperament with sex as well as with obstetric risks or psychosocial risks present at birth. - Methods: Participants were 151 boys and 157 girls born at differing degrees of obstetric and psychosocial risk from a longitudinal study on a high-risk community sample. In infancy and childhood, NYLS-derived temperamental characteristics were assessed by a highly structured parent interview and standardized behavioral observations. At age 15 years, the Junior Temperament and Character Inventory/1218 was administered. - Results: Moderate correlations were found between Junior Temperament and Character Inventory scales in adolescence and NYLS-derived factors in childhood. The psychosocial risk load seemed to influence the expression of novelty seeking or corresponding NYLS-derived factors, whereas the obstetric risks did not contribute to variation in temperament. Our findings further support highly sex-specific gene x environment interactions on temperament in the developmental course. - Conclusion: The content of our NYLS-derived factors and the specific type of association across different temperament constructs fit into the increasing consensus regarding a small number of higher-order temperamental traits. (c) 2007 Elsevier Inc. All rights reserved.
Telomere length (TL) is a marker of biological aging, and numerous studies have shown associations between TL and somatic or psychiatric disorders. Research also indicates an association between maternal stress during pregnancy and TL in the offspring. The present study investigated possible associations between TL and: (1) maternal perceived stress during pregnancy; (2) a maternal lifetime history of psychiatric disorder (lifetime PD); and (3) paternal age. TL was analyzed in 319 newborns and 318 mothers from a predominantly Caucasian sample (n= 273 Caucasian newborns and n= 274 Caucasian mothers). Two key findings were observed. First, maternal perceived stress during pregnancy was associated with shorter telomeres in newborns but not with maternal TL. Second, maternal lifetime PD was associated with shorter maternal telomeres, but not with TL in newborns. Paternal age was not associated with TL in newborns. The finding that maternal stress during pregnancy is associated with shorter telomeres in newborns supports the results of smaller previous studies. The fact that a relation between maternal prenatal stress and TL was observed in the offspring but not in mothers may be attributable to a high vulnerability to stress during intrauterine development of a maturing organism. To our knowledge, this is the largest study to date to show that maternal stress during pregnancy but not maternal lifetime PD is associated with shorter telomeres in the offspring.
Prenatal maternal stress is an established risk factor for somatic and psychological health of the offspring. A dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in offspring has been suggested as an important mechanism. However, the impact of prenatal stress on stress reactivity in preschool-aged children is not yet well understood. This is partly due to the fact that for this age group there is no stress test as well established as for older children and adults. In the present work a previously published stress test (Kryski et al., 2011) was evaluated in a large sample of 45-month-old children (n = 339). Furthermore, the relation between measures of prenatal maternal stress and cortisol reactivity was investigated. Prenatal stress was defined as psychopathology (self-report available for n = 339; expert-rating available for a subsample of n = 246) and perceived stress (n = 244) during pregnancy. The stress paradigm elicited significant increases in salivary cortisol 30 and 40 min after the test, and 60.8% of the children were classified as responders. Lower cortisol levels after the stress test were observed in the group of children with prenatal stress defined as maternal psychopathology (both self-reported and expert-rated). Maternal perceived stress as a continuous measure was not significantly associated with cortisol levels. However, when comparing children in the highest quartile of maternal perceived stress to all other children, significantly lower cortisol values were observed in the prenatally stressed group. The present study confirms the paradigm by Kryski et al. as an effective stress test for preschool-aged children. Moreover, it provides further evidence that prenatal stress impacts HPA axis reactivity. Future studies should target the timing, nature, and intensity of prenatal stressors and their effect on the stress response in offspring at different developmental stages.
Reports of current ADHD symptoms in adults with a childhood diagnosis of ADHD are often discrepant: While one subgroup reports a particularly high level of current ADHD symptoms, another reports—in contrast—a very low level. The reasons for this difference remain unclear. Although sex might play a moderating role, it has not yet been examined in this regard. In an epidemiological cohort study from birth to young adulthood, childhood ADHD diagnoses were assessed at the ages of 4.5, 8, and 11 years based on parent ratings. Sex-specific development of ADHD symptoms was analyzed from the age of 15 to 25 years via self-reported ADHD symptoms in participants with (n = 47) and without childhood ADHD (n = 289) using a random coefficient regression model. The congruence between parent reports and adolescents’ self-ratings was examined, and the role of childhood ADHD diagnosis, childhood OCC/CD, and childhood internalizing disorder as possible sex-specific predictors of self-reported ADHD symptoms at age 25 years was investigated. With regard to self-reported ADHD symptoms, females with a childhood ADHD diagnosis reported significantly more ADHD symptoms compared to females without childhood ADHD and males with and without ADHD throughout adolescence and young adulthood. In contrast, males with childhood ADHD did not differ from control males either at age 15 or at age 25 years. Only in females did a childhood diagnosis of an externalizing disorder (ADHD and CD/ODD) predict self-reported ADHD symptoms by age 25 years. Our findings suggest that self-reports of young adults with a childhood diagnosis of ADHD are influenced by sex. Specifically, females with childhood ADHD report increased levels of ADHD symptoms upon reaching adulthood. To correctly evaluate symptoms and impairment in this subgroup, other, more objective, sources of information may be advisable, such as neurophysiological measures.
Accumulating evidence suggests a role of FKBP5, a co-chaperone regulating the glucocorticoid receptor sensitivity, in the etiology of depression and anxiety disorders. Based on recent findings of altered amygdala activity following childhood adversity, the present study aimed at clarifying the impact of genetic variation in FKBP5 on threat-related neural activity and coupling as well as morphometric alterations in stress-sensitive brain systems. Functional magnetic resonance imaging during an emotional face-matching task was performed in 153 healthy young adults (66 males) from a high-risk community sample followed since birth. Voxel-based morphometry was applied to study structural alterations and DNA was genotyped for FKBP5 rs1360780. Childhood adversity was measured using retrospective self-report (Childhood Trauma Questionnaire) and by a standardized parent interview assessing childhood family adversity. Depression was assessed by the Beck Depression Inventory. There was a main effect of FKBP5 on the left amygdala, with T homozygotes showing the highest activity, largest volume and increased coupling with the left hippocampus and the orbitofrontal cortex (OFC). Moreover, amygdala-OFC coupling proved to be associated with depression in this genotype. In addition, our results support previous evidence of a gene-environment interaction on right amygdala activity with respect to retrospective assessment of childhood adversity, but clarify that this does not generalize to the prospective assessment. These findings indicated that activity in T homozygotes increased with the level of adversity, whereas the opposite pattern emerged in C homozygotes, with CT individuals being intermediate. The present results point to a functional involvement of FKBP5 in intermediate phenotypes associated with emotional processing, suggesting a possible mechanism for this gene in conferring susceptibility to stress-related disorders.
Enhanced endocannabinoid signaling has been implicated in typically adolescent behavioral features such as increased risk-taking, impulsivity and novelty seeking. Research investigating the impact of genetic variants in the cannabinoid receptor 1 gene (CNR1) and of early rearing conditions has demonstrated that both factors contribute to the prediction of impulsivity-related phenotypes. The present study aimed to test the hypothesis of an interaction of the two most studied CNR1 polymorphisms rs806379 and rs1049353 with early psychosocial adversity in terms of affecting impulsivity in 15-year-olds from an epidemiological cohort sample followed since birth. In 323 adolescents (170 girls, 153 boys), problems of impulse control and novelty seeking were assessed using parent-report and self-report, respectively. Exposure to early psychosocial adversity was determined in a parent interview conducted at the age of 3 months. The results indicated that impulsivity increased following exposure to early psychosocial adversity, with this increase being dependent on CNR1 genotype. In contrast, while individuals exposed to early adversity scored higher on novelty seeking, no significant impact of genotype or the interaction thereof was detected. This is the first evidence to suggest that the interaction of CNR1 gene variants with the experience of early life adversity may play a role in determining adolescent impulsive behavior. However, given that the reported findings are obtained in a high-risk community sample, results are restricted in terms of interpretation and generalization. Future research is needed to replicate these findings and to identify the mediating mechanisms underlying this effect.
Anhand von Daten der Mannheimer Risikokinderstudie, die sich mit der langfristigen Entwicklung von Kindern mit unterschiedlichen Risikobelastungen beschäftigt, wird gezeigt, wie Schutzfaktoren aufseiten des Kindes und seines familiären Umfelds im Verlauf der Entwicklung wirksam werden und zur Entstehung von Resilienz beitragen können. Eine besondere Rolle kommt dabei positiven frühen Eltern-Kind-Beziehungen zu (sowohl Mutter- als auch Vater-Kind-Interaktionen). Daneben spielen auch Interaktionserfahrungen im Alter von zwei Jahren des Kindes eine bedeutsame Rolle; diese schützen Risikokinder davor, eine ungünstige Entwicklung zu nehmen und tragen dazu bei, dass sich Kinder, die in psychosozialen Hochrisikofamilien aufwachsen, trotz ungünstiger „Startbedingungen“ positiv entwickeln. Neben Merkmalen der sozialen Umwelt nehmen auch sprachliche, sozial-emotionale und internale Kompetenzen des Kindes im Entwicklungsverlauf eine wichtige Rolle ein. Diese Kompetenzen ermöglichen es Risikokindern auch unter widrigen Lebensumständen (psychosoziale Hochrisikofamilien, Aufwachsen in Armutsverhältnissen) erfolgreich zu bestehen. Darüber hinaus zeigt die Arbeit, dass Resilienz ein Persönlichkeitsmerkmal ist, das ab dem frühen Erwachsenenalter eine hohe Stabilität besitzt. Mit diesen Befunden verweist die Arbeit auf die große Bedeutung der Resilienz bei der Vorhersage der langfristigen Entwicklung von Risikokindern.
Anhand von Daten der Mannheimer Risikokinderstudie, die sich mit der langfristigen Entwicklung von Kindern mit unterschiedlichen Risikobelastungen beschäftigt, wird gezeigt, wie Schutzfaktoren aufseiten des Kindes und seines familiären Umfelds im Verlauf der Entwicklung wirksam werden und zur Entstehung von Resilienz beitragen können. Eine besondere Rolle kommt dabei positiven frühen Eltern-Kind-Beziehungen zu (sowohl Mutter- als auch Vater-Kind-Interaktionen). Daneben spielen auch Interaktionserfahrungen im Alter von zwei Jahren des Kindes eine bedeutsame Rolle; diese schützen Risikokinder davor, eine ungünstige Entwicklung zu nehmen und tragen dazu bei, dass sich Kinder, die in psychosozialen Hochrisikofamilien aufwachsen, trotz ungünstiger „Startbedingungen“ positiv entwickeln. Neben Merkmalen der sozialen Umwelt nehmen auch sprachliche, sozial-emotionale und internale Kompetenzen des Kindes im Entwicklungsverlauf eine wichtige Rolle ein. Diese Kompetenzen ermöglichen es Risikokindern auch unter widrigen Lebensumständen (psychosoziale Hochrisikofamilien, Aufwachsen in Armutsverhältnissen) erfolgreich zu bestehen. Darüber hinaus zeigt die Arbeit, dass Resilienz ein Persönlichkeitsmerkmal ist, das ab dem frühen Erwachsenenalter eine hohe Stabilität besitzt. Mit diesen Befunden verweist die Arbeit auf die große Bedeutung der Resilienz bei der Vorhersage der langfristigen Entwicklung von Risikokindern.
Evidence from animal research has revealed that less maternal care results in disturbed emotionality in the offspring. In the present study, the long-term impact of maternal responsiveness and stimulation during early mother child interaction on depressive psychopathology was examined until adulthood. Data are from an epidemiological cohort study of the long-term outcome of early risk factors assessed at birth. At age 3 months, mothers and infants were videotaped during a nursing and playing situation. Maternal responsiveness and stimulation as well as infant responsiveness were evaluated by trained raters. At age 19 years, 314 participants (145 males, 169 females) were characterized on measures of depression through interview and questionnaire. In addition, measures of depression and anxiety were available from assessments in childhood. Results indicated that less maternal stimulation during early interaction was associated with a higher risk of depression in the offspring until the age of 19 years. In addition, children of less stimulating mothers showed more depressive symptoms at age 19 years and displayed more anxiety and depressive symptoms between the ages of 4.5 and 15 years. In contrast, maternal responsiveness was unrelated to children's outcome. In accordance with findings from animal research, the present study provides first longitudinal evidence in humans of a continuous and long-term influence of early maternal interaction behavior on the offspring's psychological adjustment until adulthood. The results suggest that the amount of maternally initiated contact behavior in a very early developmental stage may be crucial for children's mental health, regardless of child and maternal responsiveness.
Prenatal stress (PS) has been related to altered hypothalamic-pituitary-adrenal (HPA) axis activity later in life. So far, studies in children assessing HPA axis functioning have focused on salivary cortisol, reflecting daytime activity. The present work is part of a prospective study and aims to extend knowledge about the association between PS and HPA axis regulation in children. To do so, we investigated cortisol, cortisone, and the ratio cortisone/(cortisone + cortisol) in the first morning urine of 45-month-old children in relation to several measures of maternal stress during pregnancy. Urinary cortisol and cortisone were measured by online turbulent flow chromatography coupled with high performance liquid chromatography-tandem mass spectrometry. PS was defined as: perceived stress for aim 1 (Perceived Stress Scale; n = 280); presence of self-reported (n = 371) and expert-rated psychopathology for aim 2 (Mini International Neuropsychiatric Interview; n = 281); continuous measures of anxiety and depression for exploratory aim 3 (State-Trait Anxiety Inventory and Edinburgh Postnatal Depression Scale; n = 280). The ratio cortisone/(cortisone + cortisol) as a global marker for the balance between the enzymes metabolizing cortisol to cortisone and vice versa (11 beta-hydroxysteroid dehydrogenases type 1 and 2; 11 beta-HSD1 and 2) was not associated with any measure of maternal PS (aims 1-3). The present study provides insight into possible programming effects of PS on nocturnal HPA axis activity and a proxy of 11 beta-HSD in a large sample. The results suggest that the nocturnal rate of cortisol production is lower in children exposed to PS, but do not support the hypothesis of divergent 11 beta-HSD activity.
Objective: The delineation of developmental pathways to juvenile depressive symptoms is of major clinical interest because these are known to be predictive for adult mood disorders and for a range of other mental health problems. This study investigates the impact of child temperament and early maternal distress, both of which are known to influence children's emotional development, on preadolescent depression. Methods: In a prospective, longitudinal at-risk sample (163 boys, 178 girls), we assessed temperament at the age of 3 months and at 2 years, 4.5 years, and 8 years, respectively, and chronic maternal distress during infancy. Hierarchical linear regression analysis was used to investigate the prediction of depressive symptoms at the age of 11 years measured by the Child Depression Inventory. In addition, we controlled for psychosocial and obstetric perinatal risks and gender. Results: Psychosocial risks and self-control temperament made significant independent contributions to preadolescent depression, whereas fearful, difficult temperament and obstetric risks were unrelated to depressive outcome. Interestingly, a clear gender difference emerged with a significant prediction from maternal distress only in girls. Conclusions: Our data extend previous findings of a concurrent association between regulative temperament and juvenile depression to a predictive view. Furthermore, the results point toward gender-specific pathways to preadolescent depression and support earlier findings indicating that subclinical maternal distress may exert as detrimental effects on child development as clinical depression.
Background: Cannabis is the most commonly used illegal substance among adolescents and young adults. Problematic cannabis use is often associated with comorbid psychopathological problems. The purpose of the current study was to elucidate the underlying developmental processes connecting externalizing and internalizing psychopathology in childhood and adolescence with problematic cannabis use in young adulthood. Methods: Data were drawn from the Mannheim Study of Children at Risk, an ongoing epidemiological cohort study from birth to adulthood. For n = 307 participants, symptom scores of conduct/oppositional defiant disorder, attention problems, hyperactivity/impulsivity, and internalizing disorders were available for the periods of childhood (4.5-11 years) and adolescence (15 years). At age 25 years, problematic cannabis use was assessed via clinical interview and a self-rating questionnaire. Results: At age 25 years, problematic cannabis use was identified in n = 28 participants (9.1%). Childhood conduct/oppositional behavior problems were predictive of problematic cannabis use during young adulthood when comorbid symptoms were controlled for. No such effect was found for childhood attention, hyperactivity/impulsivity or internalizing problems. With respect to psychopathological symptoms during adolescence, only attention problems were significantly related to later problematic cannabis use when controlling for comorbidity. Conclusions: The current study highlights the role of conduct/oppositional behavior problems during childhood and attention problems during adolescence in later problematic cannabis use. It sheds more light on the developmental sequence of childhood and adolescence psychopathology and young adult cannabis use, which is a prerequisite for effective prevention approaches. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
Positive coping styles and perigenual ACC volume: two related mechanisms for conferring resilience?
(2016)
Stress exposure has been linked to increased rates of depression and anxiety in adults, particularly in females, and has been associated with maladaptive changes in the anterior cingulate cortex (ACC), which is an important brain structure involved in internalizing disorders. Coping styles are important mediators of the stress reaction by establishing homeostasis, and may thus confer resilience to stress-related psychopathology. Anatomical scans were acquired in 181 healthy participants at age 25 years. Positive coping styles were determined using a self-report questionnaire (German Stress Coping Questionnaire, SVF78) at age 22 years. Adult anxiety and depression symptoms were assessed at ages 22, 23 and 25 years with the Young Adult Self-Report. Information on previous internalizing diagnoses was obtained by diagnostic interview (2-19 years). Positive coping styles were associated with increased ACC volume. ACC volume and positive coping styles predicted anxiety and depression in a sex-dependent manner with increased positive coping and ACC volume being related to lower levels of psychopathology in females, but not in males. These results remained significant when controlled for previous internalizing diagnoses. These findings indicate that positive coping styles and ACC volume are two linked mechanisms, which may serve as protective factors against internalizing disorders.
ResultsUnder conditions of elevated prenatal maternal stress, children carrying one or two DRD4 7r alleles were at increased risk of a diagnosis of CD/ODD. Moreover, homozygous carriers of the DRD4 7r allele displayed more externalizing behavior following exposure to higher levels of prenatal maternal stress, while homozygous carriers of the DRD4 4r allele turned out to be insensitive to the effects of prenatal stress.
ConclusionsThis study is the first to report a gene-environment interaction related to DRD4 and prenatal maternal stress using data from a prospective study, which extends earlier findings on the impact of prenatal maternal stress with respect to childhood antisocial behavior.
Recent research suggests an important role of FKBP5, a glucocorticoid receptor regulating co-chaperone, in the development of stress-related diseases such as depression and anxiety disorders. The present study aimed to replicate and extend previous evidence indicating that FKBP5 polymorphisms moderate hypothalamus-pituitary-adrenal (HPA) function by examining whether FKBP5 rs1360780 genotype and different measures of childhood adversity interact to predict stress-induced cortisol secretion. At age 19 years, 195 young adults (90 males, 105 females) participating in an epidemiological cohort study completed the Trier Social Stress Test (TSST) to assess cortisol stress responsiveness and were genotyped for the FKBP5 rs1360780. Childhood adversity was assessed using the Childhood Trauma Questionnaire (CTQ) and by a standardized parent interview yielding an index of family adversity. A significant interaction between genotype and childhood adversity on cortisol response to stress was demonstrated for exposure to childhood maltreatment as assessed by retrospective self-report (CTQ), but not for prospectively ascertained objective family adversity. Severity of childhood maltreatment was significantly associated with attenuated cortisol levels among carriers of the rs1360780 CC genotype, while no such effect emerged in carriers of the T allele. These findings point towards the functional involvement of FKBP5 in long-term alterations of neuroendocrine stress regulation related to childhood maltreatment, which have been suggested to represent a premorbid risk or resilience factor in the context of stress-related disorders. (C) 2013 Elsevier B.V. and ECNR This is an open access article under the CC BY-NC-ND license.
Maternal stimulation in infancy predicts hypothalamic-pituitary-adrenal axis reactivity in young men
(2013)
Evidence from animal research has demonstrated the effect of early maternal care on the offspring's endocrine and behavioral stress response in adulthood. The present prospective study investigates, in humans, the long-term impact of maternal responsiveness and stimulation during early mother-child interaction on adrenocorticotropic hormone (ACTH) and cortisol response to a psychosocial laboratory stressor in adulthood. The data are from an epidemiological cohort study of the long-term outcome of early risk factors assessed at birth. At age 3 months, mothers and infants were videotaped during a 10-min standardized nursing and playing situation and evaluated by trained raters for maternal stimulation and infant and maternal responsiveness. At age 19 years, 270 participants (146 females, 124 males) completed the Trier Social Stress Test. The results indicated that less maternal stimulation during early interaction at age 3 months predicted diminished plasma ACTH and cortisol increase in response to acute psychosocial stress in male, but not female offspring. In contrast, maternal responsiveness was found to be unrelated to hypothalamic-pituitary-adrenal (HPA) reactivity. In accordance with the findings from animal research, the present study provides prospective evidence in humans of a long-term association between early maternal interaction behavior and the offspring's hormonal stress response in young adulthood, suggesting that poor maternal stimulation in early infancy may result in reduced HPA axis reactivity to an acute psychosocial stressor in males.
Background: Prenatal maternal stress might be a risk for the developing fetus and may have long-lasting effects on child and adult vulnerability to somatic and psychiatric disease. Over-exposure of the unborn to excess glucocorticoids and subsequent alteration of fetal development is hypothesized to be one of the key mechanisms linking prenatal stress with negative child outcome. Methods: In this prospective longitudinal study, mothers-to-be (n = 405) in late pregnancy (36.8 +/- 1.9 weeks of gestational age) and their singleton neonates were studied. We investigated the impact of different prenatal stress indices derived from six stress variables (perceived stress, specific prenatal worries, negative life events, symptoms of depression, trait anxiety, neuroticism) and diurnal maternal saliva cortisol secretion on gestational age and anthropometric measures at birth.
Theoretischer Hintergrund: Zur Erforschung der Entwicklungsepidemiologie psychischer Störungen gilt die prospektive Untersuchung von Risikogruppen als Königsweg. Fragestellung: Beschreibung der Entwicklungsmuster von Kindern mit frühen Belastungen, Ermittlung von Risiko- und Schutzfaktoren für unterschiedliche Entwicklungsresultate und Identifikation von Mechanismen, die differentiellen Verläufen zugrunde liegen. Methode: In einer prospektiven Längsschnittstudie (mit Erhebungswellen im Alter von 0;3, 2, 4 , 8 und 11 Jahren) wurden die Entstehung und der Verlauf von Entwicklungs- und Verhaltensstörungen bei 384 Kindern untersucht. Organische (prä- und perinatale Komplikationen) und psychosoziale Risiken (familiäre Belastungen) wurden in einem zwei- faktoriellen Design variiert. Ergebnisse: Die negativen Folgen früher Risiken waren bis zum Schulalter nachweisbar. Während organische Risiken vor allem die motorische und kognitive Entwicklung beeinträchtigten, konzentrierten sich die Auswirkungen psychosozialer Belastungen auf kognitive und sozial-emotionale Funktionen. Beide Risiken addierten sich in ihren negativen Konsequenzen. Schlussfolgerungen: Frühkindliche Risiken haben spezifische und langfristige Auswirkungen. Kinder mit multiplen Risikobelastungen sind in ihrer Entwicklung am stärksten gefährdet.
Lower P300 amplitude in eight-year-old offspring of alcoholic fathers with a delinquent history
(2006)
The aim of the present study was to investigate the P300 amplitude as a possible vulnerability marker in children of alcoholic (COA) fathers with and without paternal delinquency. Event-related potentials (ERPs) of 122 children aged 8 years (63 boys, 59 girls) were compared depending on father's alcoholism subtype: 30 COAs without paternal delinquency, 10 COAs with paternal delinquency, and 82 children of non-alcoholic and non-delinquent fathers. ERPs were recorded from Fz, Cz, and Pz, using an auditory oddball paradigm. Sinus tones of 60 dB HL were presented binaurally at 1,000 Hz (standard stimulus) and 2,000 Hz (target stimulus), at a relative frequency ratio of 80:20. Two trial blocks of 250 stimuli each were collected. Results indicated that only COAs with paternal delinquency displayed significant differences from the control group, characterized by reduced P300 amplitude at frontal site and in the second trial block. Thus, the combination of fathers' alcoholism and delinquency was more likely to relate to attenuated P300 amplitude in the offspring than paternal alcoholism alone. Our results suggest that both alcoholic and delinquent family history appear to play a role in P300 amplitude reduction in the offspring.
Background: Self-harm is highly prevalent in adolescence, often serving an emotion regulation function. Social stressors such as bullying are associated with self-harm. The neurobiological background of the relationship between social stressors and self-harm needs to be further understood to inform prevention and therapy. Methods: Participants were members of an epidemiological cohort study. 130 female participants underwent the Trier Social Stress Test (TSST) at age 19. Of them, 21 reported a history of self-harm as assessed by the Youth Self Report. Psychiatric diagnoses were recorded. Results: Participants with a history of self-harm showed significantly lower blood cortisol levels throughout the TSST. Early psychosocial adversity did not significantly differ between groups with and without self-harm, with self-harming participants reporting more childhood adversities. Conclusion: These results add to the limited field of studies showing an altered HPA axis activity in females with self-harm. Future studies need to address the causal mechanisms behind this association.
In einer prospektiven Längsschnittstudie wurden Auswirkungen früher psychosozialer Risiken bis ins junge Erwachsenenalter untersucht und dabei die Rolle von affektiver und behavioraler Dysregulation im Kindesalter als vermittelndem Faktor überprüft. Drei Monate nach der Geburt wurde das Vorliegen von 11 psychosozialen Belastungsfaktoren erfasst. Im Alter von 8 – 15 Jahren wurde dreimal das Child Behavior Checklist-Dysregulationsprofil (CBCL-DP) erhoben. Mit 25 Jahren wurde ein Strukturiertes Klinisches Interview durchgeführt und 309 der Teilnehmer füllten den Young Adult Self-Report aus. Frühe psychosoziale Risiken gingen mit einem erhöhten Risiko für das Vorliegen eines Substanzmissbrauchs im jungen Erwachsenenalter sowie mit erhöhtem externalisierendem und internalisierendem Problemverhalten einher. Der Zusammenhang zwischen frühen psychosozialen Risiken und späterem externalisierendem bzw. internalisierendem Problemverhalten wurde durch das CBCL-DP vermittelt.
In einer prospektiven Längsschnittstudie wurden Auswirkungen früher psychosozialer Risiken bis ins junge Erwachsenenalter untersucht und dabei die Rolle von affektiver und behavioraler Dysregulation im Kindesalter als vermittelndem Faktor überprüft. Drei Monate nach der Geburt wurde das Vorliegen von 11 psychosozialen Belastungsfaktoren erfasst. Im Alter von 8 – 15 Jahren wurde dreimal das Child Behavior Checklist-Dysregulationsprofil (CBCL-DP) erhoben. Mit 25 Jahren wurde ein Strukturiertes Klinisches Interview durchgeführt und 309 der Teilnehmer füllten den Young Adult Self-Report aus. Frühe psychosoziale Risiken gingen mit einem erhöhten Risiko für das Vorliegen eines Substanzmissbrauchs im jungen Erwachsenenalter sowie mit erhöhtem externalisierendem und internalisierendem Problemverhalten einher. Der Zusammenhang zwischen frühen psychosozialen Risiken und späterem externalisierendem bzw. internalisierendem Problemverhalten wurde durch das CBCL-DP vermittelt.
Alcohol abuse and dependence have proven to be complex genetic traits that are influenced by environmental factors. Primate and human studies have shown that early life stress increases the propensity for alcohol abuse in later life. The reinforcing properties of alcohol are mediated by dopaminergic signaling; however, there is little evidence to indicate how stress alters alcohol reinforcement. KCNJ6 (the gene encoding G-protein-coupled inwardly rectifying potassium channel 2 (GIRK2)) is a brain expressed potassium channel with inhibitory effects on dopaminergic tone. The properties of GIRK2 have been shown to be enhanced by the stress peptide corticotrophin-releasing hormone. Therefore, we sought to examine the role of KCNJ6 polymorphisms in adult alcohol dependence and stress-related alcohol abuse in adolescents. We selected 11 SNPs in the promoter region of KCNJ6, which were genotyped in 1152 adult alcohol dependents and 1203 controls. One SNP, rs2836016, was found to be associated with alcohol dependence (p = 0.01, false discovery rate). We then assessed rs2836016 in an adolescent sample of 261 subjects, which were characterized for early life stress and adolescent hazardous drinking, defined using the Alcohol Use Disorders Identification Test (AUDIT), to examine gene-environment interactions. In the adolescent sample, the risk genotype of rs2836016 was significantly associated with increased AUDIT scores, but only in those individuals exposed to high levels of psychosocial stress in early life (p = 0.01). Our findings show that KCNJ6 is associated with alcohol dependence and may moderate the effect of early psychosocial stress on risky alcohol drinking in adolescents. We have identified a candidate gene for future studies investigating a possible functional link between the response to stress and alcohol reinforcement.
Epidemiological studies have reported elevated rates of legal drug consumption among adolescents in Germany. The aim of this study was to ascertain patterns and parameters of smoking and drinking in early-users as well as to examine possible determinants of risky patterns of use. Participants were from a longitudinal study of a birth cohort of 384 children at risk. Assessments of adolescent drug consumption as well as of individual and social determinants were obtained at age 15. Adolescents drinking and smoking during the same period (past four weeks) were characterized by more excessive and impulsive consumption and by higher rates of cannabis use. No specific determinants of concurrent use could be found. These findings suggest that adolescents displaying early concurrent tobacco and alcohol use may be at higher risk for substance use problems and should be targeted by prevention programs.
Background: The appetite-stimulating hormone ghrelin is a fundamental regulator of human energy metabolism. A series of studies support the notion that long-term appetite and weight regulation may be already programmed in early life and it could be demonstrated that the intrauterine environment affects the ghrelin system of the offspring. Animal studies have also shown that intrauterine programming of orexigenic systems persists even until adolescence/adulthood. Methods: We hypothesized that plasma ghrelin concentrations in adulthood may be associated with the intrauterine exposure to cigarette smoke. We examined this hypothesis in a sample of 19-year-olds followed up since birth in the framework of the Mannheim Study of Children at Risk, an ongoing epidemiological cohort study of the long-term outcome of early risk factors. Results: As a main finding, we found that ghrelin plasma concentrations in young adults who had been exposed to cigarette smoke in utero were significantly higher than in those without prenatal smoke exposure. Moreover, individuals with intrauterine nicotine exposure showed a significantly higher prevalence of own smoking habits and lower educational status compared to those in the group without exposure. Conclusion: Smoking during pregnancy may be considered as an adverse intrauterine influence that may alter the endocrine-metabolic status of the offspring even until early adulthood.
Accumulating research suggests a moderating role for the corticotropin-releasing hormone receptor 1 gene (CRHR1) in the association between childhood adversity and adult depression. The present study aims to replicate recent findings using different genetic variants and measures of early adversity assessed both prospectively and retrospectively. Data were collected in the context of an ongoing epidemiological cohort study following the outcome of early risk factors from birth into adulthood. 300 participants (137 males, 163 females) were genotyped for four CRHR1 SNPs (rs7209436, rs110402, rs242924, and rs17689882) and completed the Beck Depression Inventory at ages 19, 22 and 23 years. Childhood adversity was assessed using the Childhood Trauma Questionnaire and by a standardized parent interview yielding an index of family adversity. Our results indicate that CRHR1 and childhood adversity interacted to predict depressive symptoms in young adults. Specifically, we found that the impact of childhood maltreatment on adult depressive symptoms was significantly higher in individuals (i) with two copies of the CRHR1 TAT haplotype, and (ii) homozygous for the G allele of rs17689882. The interaction was demonstrated for exposure to childhood maltreatment as assessed by retrospective self-report, but not to prospectively ascertain objective family adversity. The present study partially replicates recent findings of a CRHR1 by childhood adversity interaction with regard to adult depression highlighting the subjective characteristics of the environmental pathogen that is operative in this interaction.
Objective To demonstrate that children homozygous for the 10-repeat allele of the common dopamine transporter (DAT1) polymorphism who were exposed to maternal prenatal smoke exhibited significantly higher hyperactivity-impulsivity than children without these environmental or genetic risks. Study design We performed a prospective longitudinal study from birth into early adulthood monitoring the long-term outcome of early risk factors. Maternal prenatal smoking was determined during a standardized interview with the mother when the child was 3 months old. At age 15 years, 305 adolescents participated in genotyping for the DAT1 40 base pair variable number of tandem repeats polymorphism and assessment of inattention, hyperactivity-impulsivity, and oppositional defiant/conduct disorder symptoms with die Kiddie- Sads-Present and Lifetime Version. Results There was no bivariate association between DAT1 genotype, prenatal smoke exposure and symptoms of attention deficit hyperactivity disorder. However, a significant interaction between DAT1 genotype and prenatal smoke exposure emerged (P =.012), indicating that males with prenatal smoke exposure who were homozygous for the DAT1 10r allele had higher hyperactivity-impulsivity than males from all other groups. In females, no significant main effects of DAT1 genotype or prenatal smoke exposure or interaction effects on any symptoms were evident (all P >.25). Conclusions This study provides further evidence for the multifactorial nature of attention deficit hyperactivity disorder and the importance of studying both genetic and environmental factors and their interaction.
Previous research examining gene-environment interaction (G x E) with regard to vulnerability to depression and anxiety has yielded conflicting results. The present study was designed to further investigate G x F between 5-HTTLPR and exposure to environmental adversity, using different phenotypic and genotypic characterizations as well as different types of adversity within a prospective study design. Data were available from an ongoing epidemiological cohort Study following the outcome of early risk factors from birth to adulthood. At age 19 yr, 309 participants (142 males, 167 females) were characterized on measures of depression and anxiety through interview and questionnaire (DSM-IV diagnosis, Beck Depression Inventory, Harm Avoidance). Environmental adversity was assessed at birth (family adversity), and at age 19 yr (stressful life events). Bi- and tri-allelic 5-HTTLPR genotypes were obtained from genomic DNA. Results indicated that depression and anxiety in 19-yr-olds were strongly associated with both family adversity and stressful life events. Individuals with the LL genotype of 5-HTTLPR who were exposed to high family adversity displayed significantly higher rates of depressive or anxiety disorders and had more depressive symptoms than those without either condition. This G x E replicates recent findings from an epidemiological cohort study of adolescents but is in contrast to many previous reports suggesting an interaction with the S allele. No evidence for G x E was obtained with regard to current stressful life events and trait anxiety. One possible source for the conflicting findings might be attributed to heterogeneity in depression phenotypes and environmental adversity.
Considerable evidence suggests that genetic factors combine with environmental influences to impact on the development of aggressive behavior. A genetic variant that has repeatedly been reported to render individuals more sensitive to the presence of adverse experiences, including stress exposure during fetal life, is the seven-repeat allele of the dopamine D4 receptor (DRD4) gene.
The present investigation concentrated on the interplay of prenatal maternal stress and DRD4 genotype in predicting self-reported aggression in young adults. As disruption of the hypothalamic-pituitary-adrenal system has been discussed as a pathophysiological pathway to aggression, cortisol stress reactivity was additionally examined.
As part of an epidemiological cohort study, prenatal maternal stress was assessed by maternal interview 3 months after childbirth. Between the ages of 19 and 23 years, 298 offspring (140 males, 158 females) completed the Young Adult Self-Report to measure aggressive behavior and were genotyped for the DRD4 gene. At 19 years, 219 participants additionally underwent the Trier Social Stress Test to determine cortisol reactivity.
Extending earlier findings with respect to childhood antisocial behavior, the results revealed that, under conditions of higher prenatal maternal stress, carriers of the DRD4 seven-repeat allele displayed more aggression in adulthood (p = 0.032). Moreover, the same conditions which seemed to promote aggression were found to predict attenuated cortisol secretion (p = 0.028).
This is the first study to indicate a long-term impact of prenatal stress exposure on the cortisol stress response depending on DRD4 genotype.
Interaction between CRHR1 gene and stressful life events predicts adolescent heavy alcohol use
(2007)
Background: Recent animal research suggests that alterations in the corticotropin releasing hormone receptor 1 (CRHR1) may lead to heavy alcohol use following repeated stress. The aim of this study was to examine interactions between two haplotype-tagging single nucleotide polymorphisms (SNPs) covering the CRHR1 gene and adverse life events on heavy drinking in adolescents. Methods: Data were available from the Mannheim Study of Children at Risk, an ongoing cohort study of the long-term outcome of early risk factors followed since birth. At age 15 years, 280 participants (135 males, 145 females) completed a self-report questionnaire measuring alcohol use and were genotyped for two SNPs (rs242938, rs1876831) of CRHR1. Assessment of negative life events over the past three years was obtained by a standardized interview with the parents. Results: Adolescents homozygous for the C allele of rs1876831 drank higher maximum amounts of alcohol per occasion and had greater lifetime rates of heavy drinking in relation to negative life events than individuals carrying the T allele. No gene X environment interactions were found for regular drinking and between rs242938 and stressful life events. Conclusions: These findings provide first evidence in humans that the CRHR1 gene interacts with exposure to stressful life events to predict heavy alcohol use in adolescents.
Background: Accumulating evidence suggests that altered dopamine transmission may increase the risk of mental disorders such as ADHD, schizophrenia or depression, possibly mediated by reward system dysfunction. This study aimed to clarify the impact of the COMT Val(158)Met polymorphism in interaction with environmental variation (G x E) on neuronal activity during reward processing. Methods: 168 healthy young adults from a prospective study conducted over 25 years participated in amonetary incentive delay task measured with simultaneous EEG-fMRI. DNA was genotyped for COMT, and childhood family adversity (CFA) up to age 11 was assessed by a standardized parent interview. Results: At reward delivery, a G x E revealed that fMRI activation for win vs. no-win trials in reward-related regions increased with the level of CFA in Met homozygotes as compared to Val/Met heterozygotes and Val homozygotes, who showed no significant effect. During the anticipation of monetary vs. verbal rewards, activation decreased with the level of CFA, which was also observed for EEG, in which the CNV declined with the level of CFA. Conclusions: These results identify convergent genetic and environmental effects on reward processing in a prospective study. Moreover, G x E effects during reward delivery suggest that stress during childhood is associated with higher reward sensitivity and reduced efficiency in processing rewarding stimuli in genetically at-risk individuals. Together with previous evidence, these results begin to define a specific system mediating interacting effects of early environmental and genetic risk factors, which may be targeted by early intervention and prevention. (C) 2016 Elsevier Inc. All rights reserved.
Context: Recent evidence suggests that gene X environment interactions could explain the inconsistent findings of association studies relating the dopamine transporter (DAT1) gene with attention-deficit/hyperactivity disorder (ADHD). 1bjective: To examine whether psychosocial adversity moderated the effect of genetic variation in DAT1 on ADHD symptoms in. adolescents from a high-risk community sample. Design: Prospective cohort study. Setting: Data were taken from the Mannheim Study of Children at Risk, an ongoing longitudinal study of the long-term outcomes of early risk factors followed up from birth on. Participants: Three hundred five adolescents (146 boys, 159 girls) participated in a follow-up assessment at age 15 years. Main Outcome Measures: Measures of ADHD symptoms according to DSM-IV were obtained using standardized structural interviews with adolescents and their parents. Psychosocial adversity was determined according to an "enriched" family adversity index as proposed by Rutter and Quinton. DNA was genotyped for the common DAT1 40-base pair (bp) variable number of tandem repeats (VNTR) polymorphism in the 3' untranslated region; 3 previously described single nucleotide polymorphisms in exon 15, intron 9, and exon 9; and a novel 30-bp VNTR polymorphism in intron 8. Results: Adolescents homozygous for the 10-repeat allele of the 40-bp VNTR polymorphism who grew up in greater psychosocial adversity exhibited significantly more inattention and hyperactivity-impulsivity than adolescents with other genotypes or who lived in less adverse family conditions (significant interaction, P=.013-017). This gene X environment interaction was also observed in individuals homozygous for the 6-repeat allele of the 30-bp VNTR polymorphism and the haplotype comprising both markers. Conclusions: These findings provide initial evidence that environmental risks as described by the Rutter Family Adversity Index moderate the impact of the DAT1 gene on ADHD symptoms, suggesting a DAT1 effect only in those individuals exposed to psychosocial adversity.
Recent longitudinal studies have indicated that affective and behavioral dysregulation in childhood is associated with an increased risk for various negative outcomes in later life. However, few studies to date have examined early mechanisms preceding dysregulation during early childhood. Aim of this study was to elucidate early mechanisms relating to dysregulation in later life using data from an epidemiological cohort study on the long-term outcome of early risk factors from birth to adulthood. At age 3 months, mothers and infants were videotaped during a nursing and playing situation. Maternal responsiveness was evaluated by trained raters. Infant regulatory problems were assessed on the basis of a parent interview and direct observation by trained raters. At age 8 and 11 years, 290 children (139 males) were rated on the Child Behavior Checklist (CBCL). Additionally, participants were genotyped for the dopamine D4 receptor (DRD4) exon 3 VNTR polymorphism. A significant three-way interaction between maternal responsiveness, DRD4 genotype and infant regulatory problems was detected predicting the CBCL-dysregulation profile (CBCL-DP). Carriers of the DRD4 7r allele with regulatory problems at age 3 months showed significantly more behavior problems associated with the CBCL-DP during childhood when exposed to less maternal responsiveness. In contrast, no effect of maternal responsiveness was observed in DRD4 7r carriers without infant regulatory problems and in non-carriers of the DRD4 7r allele. This prospective longitudinal study extends earlier findings regarding the association of the CBCL-DP with early parenting and later psychopathology, introducing both DRD4 genotype and infant regulatory problems as important moderators. (C) 2015 Elsevier Ltd. All rights reserved.
Findings on the etiology of aggressive behavior have provided evidence for an effect both of genetic factors, such as variation in the monoamine oxidase A (MAOA) gene, and adverse environmental factors. Recent studies have supported the existence of gene × environment interactions, with early experiences playing a key role. In the present study, the effects of prenatal nicotine exposure, MAOA genotype and their interaction on aggressive behavior during young adulthood were examined. In a sample of 272 young adults (129 males, 143 females) from an epidemiological cohort study, smoking during pregnancy was measured with a standardized parent interview at the offspring’s age of 3 months. Aggressive behavior was assessed between the ages of 19 and 25 years using the Young Adult Self-Report. DNA was genotyped for the MAOA 5′ untranslated region variable number of tandem repeats polymorphism (VNTR). Results revealed a significant interaction between MAOA and smoking during pregnancy, indicating higher levels of aggressive behavior in young adults carrying the MAOA low-expressing genotype who had experienced prenatal nicotine exposure (n = 8, p = .025). In contrast, in carriers of the MAOA high-expressing genotype, maternal smoking during pregnancy had no effect on aggressive behavior during young adulthood (n = 20, p = .145). This study extends earlier findings demonstrating an interaction between MAOA genotype and prenatal nicotine exposure on aggressive behavior into young adulthood. The results point to the long-term adverse effects of smoking during pregnancy on the offspring’s mental health, possibly underlining the importance of smoking cessation during pregnancy. According to the nature of the study (particularly sample size and power), analyses are exploratory and results need to be interpreted cautiously.
Objective: To investigate the association of the neuropeptide Y (NPY) promoter polymorphism rs16147 with body mass index (BMI) during the course of development from infancy to adulthood.
Design: Longitudinal, prospective study of a German community sample.
Subjects: n = 306 young adults (139 males, 167 females).
Measurements: Participants' body weight and height were assessed at the ages of 3 months and 2, 4.5, 8, 11, 15 and 19 years. NPY rs16147 was genotyped.
Results: Controlling for a number of possible confounders, homozygote carriers of the rs16147 C allele exhibited significantly lower BMI scores when compared with individuals carrying the T allele. In addition, a significant genotype by age interaction emerged, indicating that the genotype effect increased during the course of development.
Conclusions: This is the first longitudinal study to report an association between rs16147 and BMI during childhood and adolescence. The finding that this effect increased during the course of development may either be due to age-dependent alterations in gene expression or to maturation processes within the weight regulation circuits of the central nervous system.
Background: Cigarette smoking has severe adverse health consequences in adults and in the offspring of mothers who smoke during pregnancy. One of the most widely reported effects of smoking during pregnancy is reduced birth weight which is in turn associated with chronic disease in adulthood. Epigenome-wide association studies have revealed that smokers show a characteristic "smoking methylation pattern", and recent authors have proposed that DNA methylation mediates the impact of maternal smoking on birth weight. The aims of the present study were to replicate previous reports that methylation mediates the effect of maternal smoking on birth weight, and for the first time to investigate whether the observed mediation effects are sex-specific in order to account for known sex-specific differences in methylation levels. Methods: Methylation levels in the cord blood of 313 newborns were determined using the Illumina HumanMethylation450K Beadchip. A total of 5,527 CpG sites selected on the basis of evidence from the literature were tested. To determine whether the observed association between maternal smoking and birth weight was attributable to methylation, mediation analyses were performed for significant CpG sites. Separate analyses were then performed in males and females. Results: Following quality control, 282 newborns eventually remained in the analysis. A total of 25 mothers had smoked consistently throughout the pregnancy. The birthweigt of newborns whose mothers had smoked throughout pregnancy was reduced by >200g. After correction for multiple testing, 30 CpGs showed differential methylation in the maternal smoking subgroup including top "smoking methylation pattern" genes AHRR, MYO1G, GFI1, CYP1A1, and CNTNAP2. The effect of maternal smoking on birth weight was partly mediated by the methylation of cg25325512 (PIM1); cg25949550 (CNTNAP2); and cg08699196 (ITGB7). Sex-specific analyses revealed a mediating effect for cg25949550 (CNTNAP2) in male newborns. Conclusion: The present data replicate previous findings that methylation can mediate the effect of maternal smoking on birth weight. The analysis of sex-dependent mediation effects suggests that the sex of the newborn may have an influence. Larger studies are warranted to investigate the role of both the identified differentially methylated loci and the sex of the newborn in mediating the association between maternal smoking during pregnancy and birth weight.
BackgroundEarly alcohol use is one of the strongest predictors of later alcohol use disorders, with early use usually taking place during puberty. Many researchers have suggested drinking during puberty as a potential biological basis of the age at first drink (AFD) effect. However, the influence of the pubertal phase at alcohol use initiation on subsequent drinking in later life has not been examined so far.
MethodsPubertal stage at first drink (PSFD) was determined in N=283 young adults (131 males, 152 females) from an epidemiological cohort study. At ages 19, 22, and 23years, drinking behavior (number of drinking days, amount of alcohol consumed, hazardous drinking) was assessed using interview and questionnaire methods. Additionally, an animal study examined the effects of pubertal or adult ethanol (EtOH) exposure on voluntary EtOH consumption in later life in 20 male Wistar rats.
ResultsPSFD predicted drinking behavior in humans in early adulthood, indicating that individuals who had their first drink during puberty displayed elevated drinking levels compared to those with postpubertal drinking onset. These findings were corroborated by the animal study, in which rats that received free access to alcohol during the pubertal period were found to consume more alcohol as adults, compared to the control animals that first came into contact with alcohol during adulthood.
ConclusionsThe results point to a significant role of stage of pubertal development at first contact with alcohol for the development of later drinking habits. Possible biological mechanisms and implications for prevention are discussed.
Background: Evidence from animal studies supports a role for serotonin transporter gene promoter polymorphism (5-HTTLPR) gene-environment interaction (G X E) in the development of excessive alcohol intake. Few studies in humans have been conducted on this topic, yielding inconsistent results. The present study aims to further explore G x E between 5-HTTLPR and exposure to psychosocial adversity on alcohol consumption in a high-risk community sample of young adults. Methods: Data were collected as part of the Mannheim Study of Children at Risk, an ongoing epidemiological cohort study following the outcome of early risk factors from birth into young adulthood. At age 19 years, 309 participants (142 male participants, 167 female participants) were genotyped for the biallelic and triallelic 5-HTTLPR and were administered a 45-day alcohol timeline follow-back interview, providing measures of the total number of drinks and the number of binge drinking days. Psychosocial adversity was assessed at birth (family adversity) and at age 19 (negative life events). Results: In contrast to various previous reports, a significant G x E emerged, indicating that, when exposed to high psychosocial adversity, individuals with the LL genotype of 5-HTTLPR exhibited more hazardous drinking than those carrying the S allele or those without exposure to adversity. This effect, which was confined to male participants, held both for different classifications of 5-HTTLPR and different types of adversity. Conclusions: One explanation for the discrepant results might be heterogeneity in alcohol phenotypes. While the L allele relates more strongly to early-onset alcoholism, the S allele may be linked more closely to alcohol use associated with anxiety and depression.
Background:
Mother-infant interaction provides important training for the infant’s ability to cope with stress and the development of resilience. Prenatal stress (PS) and its impact on the offspring’s development have long been a focus of stress research, with studies highlighting both harmful and beneficial effects. The aim of the current study was to examine the possible influence of both psychological stress and hypothalamic-pituitary-adrenal (HPA) axis activity during pregnancy with mother-child dyadic behavior following stress exposure.
Methods:
The behavior of 164 mother-infant dyads during the still-face situation was filmed at six months postpartum and coded into three dyadic patterns: 1) both positive, 2) infant protesting-mother positive, and 3) infant protesting-mother negative. PS exposure was assessed prenatally according to psychological measures (i.e., psychopathological, perceived and psychosocial PS; n = 164) and HPA axis activity measures (maternal salivary cortisol, i.e., cortisol decline and area under the curve with respect to ground (AUCg); n = 134).
Results:
Mother-infant dyads in both the high- and low-stress groups showed decreasing positive and increasing negative dyadic behavior in the reunion episode, which is associated with the well-known “still-face” and “carry-over” effect. Furthermore, mother-infant dyads with higher psychosocial PS exhibited significantly more positive dyadic behavior than the low psychosocial PS group in the first play episode, but not in the reunion episode. Similarly, mother-infant dyads with high HPA axis activity (i.e. high AUCg) but steeper diurnal cortisol decline (i.e. cortisol decline) displayed significantly less negative behavior in the reunion episode than dyads with low HPA axis activity. No significant results were found for psychopathological stress and perceived stress.
Conclusions:
The results suggest a beneficial effect of higher psychosocial PS and higher prenatal maternal HPA axis activity in late gestation, which is in line with “stress inoculation” theories.
Objective: To examine prospectively whether early parental child-rearing behavior is a predictor of cardiometabolic outcome in young adulthood when other potential risk factors are controlled. Metabolic factors associated with increased risk for cardiovascular disease have been found to vary, depending on lifestyle as well as genetic predisposition. Moreover, there is evidence suggesting that environmental conditions, such as stress in pre- and postnatal life, may have a sustained impact on an individual's metabolic risk profile. Methods: Participants were drawn from a prospective, epidemiological, cohort study followed up from birth into young adulthood. Parent interviews and behavioral observations at the age of 3 months were conducted to assess child-rearing practices and mother-infant interaction in the home setting and in the laboratory. In 279 participants, anthropometric characteristics, low-density lipoprotein and high-density lipoprotein cholesterol, apolipoproteins, and triglycerides were recorded at age 19 years. In addition, structured interviews were administered to the young adults to assess indicators of current lifestyle and education. Results: Adverse early-life interaction experiences were significantly associated with lower levels of high- density lipoprotein cholesterol and apolipoprotein A1 in young adulthood. Current lifestyle variables and level of education did not account for this effect, although habitual smoking and alcohol consumption also contributed significantly to cardiometabolic outcomes. Conclusions: These findings suggest that early parental child-rearing behavior may predict health outcome in later life through its impact on metabolic parameters in adulthood.
Several lines of evidence have implicated the mesolimbic dopamine reward pathway in altered brain function resulting from exposure to early adversity. The present study examined the impact of early life adversity on different stages of neuronal reward processing later in life and their association with a related behavioral phenotype, i.e. attention deficit/hyperactivity disorder (ADHD). 162 healthy young adults (mean age = 24.4 years; 58% female) from an epidemiological cohort study followed since birth participated in a simultaneous EEG-fMRI study using a monetary incentive delay task. Early life adversity according to an early family adversity index (EFA) and lifetime ADHD symptoms were assessed using standardized parent interviews conducted at the offspring's age of 3 months and between 2 and 15 years, respectively. fMRI region-of-interest analysis revealed a significant effect of EFA during reward anticipation in reward-related areas (i.e. ventral striatum, putamen, thalamus), indicating decreased activation when EFA increased. EEG analysis demonstrated a similar effect for the contingent negative variation (CNV), with the CNV decreasing with the level of EFA. In contrast, during reward delivery, activation of the bilateral insula, right pallidum and bilateral putamen increased with EFA. There was a significant association of lifetime ADHD symptoms with lower activation in the left ventral striatum during reward anticipation and higher activation in the right insula during reward delivery. The present findings indicate a differential long-term impact of early life adversity on reward processing, implicating hyporesponsiveness during reward anticipation and hyperresponsiveness when receiving a reward. Moreover, a similar activation pattern related to lifetime ADHD suggests that the impact of early life stress on ADHD may possibly be mediated by a dysfunctional reward pathway.
There is ample evidence that the early initiation of alcohol use is a risk factor for the development of later alcohol-related problems. The purpose of the current study was to examine whether this association can be explained by indicators of a common underlying susceptibility or whether age at drinking onset may be considered as an independent predictor of later drinking behavior, suggesting a potential causal relationship. Participants were drawn from a prospective cohort study of the long-term outcomes of early risk factors followed up from birth onwards. Structured interviews were administered to 304 participants to assess age at first drink and current drinking behavior. Data on risk factors, including early family adversity, parental alcohol use, childhood psychopathology and stressful life events, were repeatedly collected during childhood using standardized parent interviews. In addition, information on genotype was considered. Results confirmed previous work demonstrating that hazardous alcohol consumption is related to early-adolescent drinking onset. A younger age of first drink was significantly predicted by 5-HTTLPR genotype and the degree of preceding externalizing symptoms, and both factors were related to increased consumption or harmful alcohol use at age 19. However, even after controlling for these potential explanatory factors, earlier age at drinking onset remained a strong predictor of heavy alcohol consumption in young adulthood. The present longitudinal study adds to the current literature indicating that the early onset - adult hazardous drinking association cannot solely be attributed to shared genetic and psychopathologic risk factors as examined in this study.
Objective: To clarify the nature of the association between dopamine genes and smoking by examining whether genetic variability in components of the dopamine pathway could explain refined phenotypes in adolescent smoking progression. Method: Data are from an ongoing prospective study of the long-term outcome of early risk factors studied since birth. At age 15 years, 220 participants (108 males, 112 females) completed a self-report questionnaire measuring smoking behavior and were genotyped for five dopamine gene variants. Results: Smoking initiation was related to allelic variation in the dopamine D-4 receptor gene (DRD4), whereas smoking continuation and dependence showed association with the dopamine D-2 receptor gene (DRD2). Adolescents with the seven-repeat allele of the common DRD4 exon 3 polymorphism had rates of ever smoking that were significantly higher than in those with other genotypes. Once smoking started, carriers of the T allele of a single nucleotide polymorphism of DRD2 (rs4648317) reported higher rates of current smoking and scored higher on nicotine dependence than their allelic counterparts. Among current smokers, intention to quit was significantly lower in adolescents homozygous for the 10-repeat allele of the common dopamine transporter 3 untranslated region polymorphism. Conclusions: Our results provide preliminary evidence of genetic influences on different stages of smoking and suggest the importance of specific dopamine genes in smoking progression in adolescence.
Conduct disorder (CD) causes high financial and social costs, not only in affected families but across society, with only moderately effective treatments so far. There is consensus that CD is likely caused by the convergence of many different factors, including genetic and adverse environmental factors. There is ample evidence of gene-environment interactions in the etiology of CD on a behavioral level regarding genetically sensitive designs and candidate gene-driven approaches, most prominently and consistently represented by MAOA. However, conclusive indications of causal GxE patterns are largely lacking. Inconsistent findings, lack of replication and methodological limitations remain a major challenge. Likewise, research addressing the identification of affected brain pathways which reflect plausible biological mechanisms underlying GxE is still very sparse. Future research will have to take multilevel approaches into account, which combine genetic, environmental, epigenetic, personality, neural and hormone perspectives. A better understanding of relevant GxE patterns in the etiology of CD might enable researchers to design customized treatment options (e.g. biofeedback interventions) for specific subgroups of patients.
Frühkindliche Regulationsstörungen: Vorläufer von Verhaltensstörungen des späteren Kindesalters?
(2003)
Die Entwicklung von Kindern, die in ihrer frühen Kindheit erhöhten Belastungen ausgesetzt waren, zeichnet sich durch eine grosse Variabilität aus. Welche Kinder besonders gefährdet sind und welchen es gelingt, Entwicklungsrisiken zu überwinden, wird anhand von Daten der Mannheimer Risikokinderstudie aufgezeigt. Dabei handelt es sich um eine prospektive Längsschnittstudie an einer Kohorte von 362 Kindern, die in ihrer Entwicklung von der Geburt bis ins Schulalter begleitet werden. Die Ergebnisse bis zum Alter von acht Jahren machen deutlich, dass die Entwicklungsprognose von sehr kleinen Frühgeborenen und von Kindern postnatal depressiver Mütter davon abhängt, wie die frühe Beziehung zwischen Mutter und Risikokind gelingt. Sie unterstreichen damit die besondere Bedeutung der frühen Mutter-Kind-Interaktion in der Entwicklung von Risikokindern.
To examine whether the dopamine receptor D4 gene (DRD4) exon III VNTR moderates the risk of infants with regulatory disorders for developing attention-deficit/hyperactivity disorder (ADHD) later in childhood. In a prospective longitudinal study of children at risk for later psychopathology, 300 participants were assessed for regulatory problems in infancy, DRD4 genotype, and ADHD symptoms and diagnoses from childhood to adolescence. To examine a potential moderating effect on ADHD measures, linear and logistic regressions were computed. Models were fit for the main effects of the DRD4 genotype (presence or absence of the 7r allele) and regulatory problems (presence or absence), with the addition of the interaction term. All models were controlled for sex, family adversity, and obstetric risk status. In children without the DRD4-7r allele, a history of regulatory problems in infancy was unrelated to later ADHD. But in children with regulatory problems in infancy, the additional presence of the DRD4-7r allele increased the risk for ADHD in childhood. The DRD4 genotype seems to moderate the association between regulatory problems in infancy and later ADHD. A replication study is needed before further conclusions can be drawn, however.
We assessed intra-individual variability of response times (RT) and single-trial P3 amplitudes following targets in healthy adults during a Flanker/NO-GO task. RT variability and variability of the neural responses coupled at the faster frequencies examined (0.07-0.17 Hz) at Pz, the target-P3 maxima, despite non-significant associations for overall variability (standard deviation, SD). Frequency-specific patterns of variability in the single-trial P3 may help to understand the neurophysiology of RT variability and its explanatory models of attention allocation deficits beyond intra-individual variability summary indices such as SD.
Background: Depressed mood is prevalent during pregnancy, with accumulating evidence suggesting an impact on developmental outcome in the offspring. However, the long-term effects of prenatal maternal depression regarding internalizing psychopathology in the offspring are as yet unclear. Results: In n=85 young adults exposed to prenatal maternal depressed mood, no significantly higher risk for a diagnosis of depressive disorder was observed. However, they reported significantly lower levels of depressive symptoms. This association was especially pronounced when prenatal maternal depressed mood was present during the first trimester of pregnancy and when maternal mood was depressed pre- as well as postnatally. At an uncorrected level only, prenatal maternal depressed mood was associated with decreased amygdala volume. Limitations: Prenatal maternal depressed mood was not assessed during pregnancy, but shortly after childbirth. No diagnoses of maternal clinical depression during pregnancy were available. Conclusions: Self-reported depressive symptoms do not imply increased, but rather decreased symptom levels in young adults who were exposed to prenatal maternal depressed mood. A long-term perspective may be important when considering consequences of prenatal risk factors.
The present study aimed to clarify the functional role of genes in the dopamine and serotonin systems by examining whether polymorphisms in these genes are related to adolescent externalizing behavior either alone or in interaction with each other. Participants were selected from an ongoing prospective study of the outcome of early risk factors. At age 15 years, 298 adolescents (144 males, 154 females) completed the Youth Self Report, 296 primary caregivers the Child Behavior Checklist and 253 teachers the Teacher Report Form. DNA was genotyped for the DRD4 exon III VNTR and the 5-HTTLPR polymorphisms. Results revealed that individuals with the DRD4 7r allele reported significantly more externalizing behavior than carriers of other variants. In addition, a significant interaction emerged, indicating that adolescents carrying two copies of the 5-HTTLPR short allele and the DRD4 7r variant scored highest on aggressive and/or delinquent behavior compared to other genotypes. This result suggests an effect of 5-HTTLPR on externalizing behavior in the presence of DRD4 7r but no effect in its absence.
Converging evidence emphasizes the role of an interaction between monoamine oxidase A (MAOA) genotype, environmental adversity, and sex in the pathophysiology of aggression. The present study aimed to clarify the impact of this interaction on neural activity in aggression-related brain systems. Functional magnetic resonance imaging was performed in 125 healthy adults from a high-risk community sample followed since birth. DNA was genotyped for the MAOA-VNTR (variable number of tandem repeats). Exposure to childhood life stress (CLS) between the ages of 4 and 11 years was assessed using a standardized parent interview, aggression by the Youth/Young Adult Self-Report between the ages of 15 and 25 years, and the VIRA-R (Vragenlijst Instrumentele En Reactieve Agressie) at the age of 15 years. Significant interactions were obtained between MAOA genotype, CLS, and sex relating to amygdala, hippocampus, and anterior cingulate cortex (ACC) response, respectively. Activity in the amygdala and hippocampus during emotional face-matching increased with the level of CLS in male MAOA-L, while decreasing in male MAOA-H, with the reverse pattern present in females. Findings in the opposite direction in the ACC during a flanker NoGo task suggested that increased emotional activity coincided with decreased inhibitory control. Moreover, increasing amygdala activity was associated with higher Y(A)SR aggression in male MAOA-L and female MAOA-H carriers. Likewise, a significant association between amygdala activity and reactive aggression was detected in female MAOA-H carriers. The results point to a moderating role of sex in the MAOAx CLS interaction for intermediate phenotypes of emotional and inhibitory processing, suggesting a possible mechanism in conferring susceptibility to violence-related disorders.
Entwicklung von Risikokindern im Schulalter : die langfristigen Folgen frühkindlicher Belastungen
(2000)
Background: Several studies have reported higher smoking rates among adolescents with externalizing disorders (attention-deficit hyperactivity disorder and conduct disorder) as compared to healthy controls. Objective: To follow the association between childhood externalizing disorders and smoking during development, to determine the type of problems most strongly related to later tobacco use, and to control for the influence of covarying factors. Methods: Participants were from a longitudinal study of a birth cohort of 384 children born with different perinatal and psychosocial risks. Standardized assessments of behavioral disorders between 2 and 11 years and of tobacco use at age 15 were obtained. Results: 15-year-olds with externalizing disorders between 2 and 11 years reported higher tobacco use than those without a history of disorder. This association could be followed back into early childhood and held up even after controlling for covariates. Conclusions: The findings suggest that childhood externalizing disorders may represent an independent risk factor for elevated tobacco use in adolescence
IMPORTANCE: There is accumulating evidence relating maternal smoking during pregnancy to attention-deficit/hyperactivity disorder (ADHD) without elucidating specific mechanisms. Research investigating the neurobiological underpinnings of this disorder has implicated deficits during response inhibition. Attempts to uncover the effect of prenatal exposure to nicotine on inhibitory control may thus be of high clinical importance.
MAIN OUTCOMES AND MEASURES: Functional magnetic resonance imaging response, morphometric data, lifetime ADHD symptoms, and novelty seeking.
RESULTS: Participants prenatally exposed to nicotine exhibited a weaker response in the anterior cingulate cortex (t(168) = 4.46; peak Montreal Neurological Institute [MNI] coordinates x = -2, y = 20, z = 30; familywise error [FWE]-corrected P = .003), the right inferior frontal gyrus (t(168) = 3.65; peak MNI coordinates x = 44, y = 38, z = 12; FWE-corrected P = .04), the left inferior frontal gyrus (t(168) = 4.09; peak MNI coordinates x = -38, y = 36, z = 8; FWE-corrected P = .009), and the supramarginal gyrus (t(168) = 5.03; peak MNI coordinates x = 64, y = -28, z = 22; FWE-corrected P = .02) during the processing of the NoGo compared to neutral stimuli, while presenting a decreased volume in the right inferior frontal gyrus. These findings were obtained irrespective of the adjustment of confounders, ADHD symptoms, and novelty seeking. There was an inverse relationship between inferior frontal gyrus activity and ADHD symptoms and between anterior cingulate cortex activity and novelty seeking.
CONCLUSIONS AND RELEVANCE: These findings point to a functional involvement of prenatal exposure to tobacco smoke in neural alterations similar to ADHD, which underlines the importance of smoking prevention treatments.
Cognitive or executive control is a critical mental ability, an important marker of mental illness, and among the most heritable of neurocognitive traits. Two candidate genes, catechol-O-methyltransferase (COMT) and DRD4, which both have a roles in the regulation of cortical dopamine, have been consistently associated with cognitive control. Here, we predicted that individuals with the COMT Met/Met allele would show improved response execution and inhibition as indexed by event-related potentials in a Go/NoGo task, while individuals with the DRD4 7-repeat allele would show impaired brain activity. We used independent component analysis (ICA) to separate brain source processes contributing to high-density EEG scalp signals recorded during the task. As expected, individuals with the DRD4 7-repeat polymorphism had reduced parietal P3 source and scalp responses to response (Go) compared to those without the 7-repeat. Contrary to our expectation, the COMT homozygous Met allele was associated with a smaller frontal P3 source and scalp response to response-inhibition (NoGo) stimuli, suggesting that while more dopamine in frontal cortical areas has advantages in some tasks, it may also compromise response inhibition function. An interaction effect emerged for P3 source responses to Go stimuli. These were reduced in those with both the 7-repeat DRD4 allele and either the COMT Val/Val or the Met/Met homozygous polymorphisms but not in those with the heterozygous Val/Met polymorphism. This epistatic interaction between DRD4 and COMT replicates findings that too little or too much dopamine impairs cognitive control. The anatomic and functional separated maximally independent cortical EEG sources proved more informative than scalp channel measures for genetic studies of brain function and thus better elucidate the complex mechanisms in psychiatric illness.
There is converging evidence suggesting a particular susceptibility to the addictive properties of nicotine among adolescents. The aim of the current study was to prospectively ascertain the relationship between age at first cigarette and initial smoking experiences, and to examine the combined effects of these characteristics of adolescent smoking behavior on adult smoking. It was hypothesized that the association between earlier age at first cigarette and later development of nicotine dependence may, at least in part, be attributable to differences in experiencing pleasurable early smoking sensations. Data were drawn from the participants of the Mannheim Study of Children at Risk, an ongoing epidemiological cohort study from birth to adulthood. Structured interviews at age 15, 19 and 22 years were conducted to assess the age at first cigarette, early smoking experiences and current smoking behavior in 213 young adults. In addition, the participants completed the Fagerstrom Test for Nicotine Dependence. Adolescents who smoked their first cigarette at an earlier age reported more pleasurable sensations from the cigarette, and they were more likely to be regular smokers at age 22. The age at first cigarette also predicted the number of cigarettes smoked and dependence at age 22. Thus, both the age of first cigarette and the pleasure experienced from the cigarette independently predicted aspects of smoking at age 22.
Objective: We investigated in a high-risk sample the differential impact of biological and psychosocial risk factors on antisocial behaviour pathways. Method: One hundred and thirty-eight boys and 155 girls born at differing degrees of obstetric and psychosocial risk were examined from birth until adolescence. Childhood temperament was assessed by a highly-structured parent-interview and standardized behavioural observations, adolescent temperament was measured by self-report. Neurodevelopmental variables were assessed by age-specific developmental tests. Emotional and behaviour problems were measured at the ages of 8 and 15 by the Achenbach scales. Results: In both genders, psychosocial adversity and early self-control temperament were strongly associated with early-onset persistent (EOP) antisocial behaviour. Psychosocial adversity and more severe externalizing problems differentiated the EOP from childhood-limited (CL) pathway. In girls, adolescent-onset (AO) antisocial behaviour was strongly associated with novelty seeking at 15 years. Conclusion: Our findings emphasize the need for early support and intervention in psychosocially disadvantaged families.