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- Mannheim Study of Children at Risk (8)
- longitudinal study (8)
- Längsschnittstudie (7)
- Mannheimer Risikokinderstudie (6)
- Gene-environment interaction (5)
- fMRI (5)
- DRD4 (4)
- Aggression (3)
- Childhood adversity (3)
- ADHD (2)
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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.
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.
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.
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.
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.
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.
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.
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.
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.
Epigenetic modulations are a hypothesized link between environmental factors and the development of psychiatric disorders. Research has suggested that patients with depression or bipolar disorder exhibit higher methylation levels in the glucocorticoid receptor gene NR3C1. We aimed to investigate whether NR3C1 methylation changes are similarly associated with externalizing disorders such as aggressive behavior and conduct disorder. NR3C1 exon 1F methylation was analyzed in young adults with a lifetime diagnosis of an externalizing disorder (N = 68) or a depressive disorder (N = 27) and healthy controls (N = 124) from the Mannheim Study of Children at Risk. The externalizing disorders group had significantly lower NR3C1 methylation levels than the lifetime depressive disorder group (p = 0.009) and healthy controls (p = 0.001) This report of lower methylation levels in NR3C1 in externalizing disorders may indicate a mechanism through which the differential development of externalizing disorders as opposed to depressive disorders might occur.