Collaborative meta-analysis finds no evidence of a strong interaction between stress and 5-HTTLPR genotype contributing to the development of depression

The hypothesis that the S allele of the 5-HTTLPR serotonin transporter promoter region is associated with increased risk of depression, but only in individuals exposed to stressful situations, has generated much interest, research, and controversy since first proposed in 2003. Multiple meta-analyses combining results from heterogeneous analyses have not settled the issue. To determine the magnitude of the interaction and the conditions under which it might be observed, we performed new analyses on 31 datasets containing 38 802 European-ancestry subjects genotyped for 5-HTTLPR and assessed for depression and childhood maltreatment or other stressful life events, and meta-analyzed the results. Analyses targeted two stressors (narrow, broad) and two depression outcomes (current, lifetime). All groups that published on this topic prior to the initiation of our study and met the assessment and sample size criteria were invited to participate. Additional groups, identified by consortium members or self-identified in response to our protocol (published prior to the start of analysis1) with qualifying unpublished data were also invited to participate. A uniform data analysis script implementing the protocol was executed by each of the consortium members. Our findings do not support the interaction hypothesis. We found no subgroups or variable definitions for which an interaction between stress and 5-HTTLPR genotype was statistically significant. In contrast, our findings for the main effects of life stressors (strong risk factor) and 5-HTTLPR genotype (no impact on risk) are strikingly consistent across our contributing studies, the original study reporting the interaction, and subsequent meta-analyses. Our conclusion is that if an interaction exists in which the S allele of 5-HTTLPR increases risk of depression only in stressed individuals, then it is not broadly generalizable, but must be of modest effect size and only observable in limited situations

Early Maternal Care and Amygdala Habituation to Emotional Stimuli in Adulthood

Evidence suggests that maternal care constitutes a protective factor for psychopathology which may be conditional on the level of family adversity. Given that psychopathology is frequently linked with social deficits, and the amygdala with social functioning, we investigated the impact of early maternal care on amygdala function under high versus low familial risk for psychopathology. Amygdala activity and habituation during an emotional face-matching paradigm was analyzed in participants of an epidemiological cohort study followed since birth (N=172, 25 years). Early mother-infant interaction was assessed during a standardized nursing and play setting at the age of 3 months. Information on familial risk during the offspring's childhood and on the participants' lifetime psychopathology was obtained with diagnostic interviews. An interaction between maternal stimulation and familial risk was found on amygdala habituation but not on activation, with higher maternal stimulation predicting stronger amygdala habituation in the familial risk group only. Furthermore, amygdala habituation correlated inversely with ADHD diagnoses. The findings underline the long-term importance of early maternal care on the offspring´s socioemotional neurodevelopment and of interventions targeting maternal sensitivity early in life, particularly by increasing maternal interactive behavior in those with familial risk

Positive coping styles and ACC volume - two related mechanisms for conferring resilience?

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

Sex-specific trajectories of ADHD symptoms from adolescence to young adulthood

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

Association of norepinephrine transporter (NET, SLC6A2) genotype with ADHD-related phenotypes: findings of a longitudinal study from birth to adolescence

Variation in the gene encoding for the norepinephrine transporter (NET, SLC6A2) has repeatedly been linked with ADHD, although there is some inconsistency regarding the association with specific genes. The variants for which most consistent association has been found are the NET variants rs3785157 and rs28386840. Here, we tested for their association with ADHD diagnosis and ADHD-related phenotypes during development in a longitudinal German community sample. Children were followed from age 4 to age 15, using diagnostic interviews to assess ADHD. Between the ages of 8 and 15 years, the Child Behavior Checklist (CBCL) was administered to the primary caregivers. The continuous performance task (CPT) was performed at age 15. Controlling for possible confounders, we found that homozygous carriers of the major A allele of the functional promoter variant rs28386840 displayed a higher rate of ADHD lifetime diagnosis. Moreover, homozygous carriers of the minor T allele of rs3785157 were more likely to develop ADHD and showed higher scores on the CBCL externalizing behavior scales. Additionally, we found that individuals heterozygous for rs3785157 made fewer omission errors in the CPT than homozygotes. This is the first longitudinal study to report associations between specific NET variants and ADHD-related phenotypes during the course of development

Impact of prenatal stress on mother-infant dyadic behavior during the still-face paradigm

Abstract 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

Role of CNR1 polymorphisms in moderating the effects of psychosocial adversity on impulsivity in adolescents

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

Ventral striatum and amygdala activity as convergence sites for early adversity and conduct disorder

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

Time course and topography of the motor PINV by <i>DAT1</i> haplotype.

<p><b>Top</b>: The time course of the response-locked motor PINV over the contra- and the ipsilateral motor area is shown. Negativity is up. There were no differences between the genotype groups during response preparation (contingent negative variation, CNV) after the cue (‘A’). Differences selectively affected the post-processing interval. During the button press (vertical dashed line), response selection during the P300 shadows the movement-related potentials. Thus, we calculated the lateralized motor PINV: Time course of the lateralized motor PINV when the potential over the contra- and ipsilateral motor areas is subtracted. This eliminates the symmetrically distributed parts of stimulus-related processing. Negativity is up. The peak immediately preceding the button press, which is related to the cortico-spinal command to muscle contraction, was influenced rather in the opposite direction to the motor PINV. <b>Middle</b>: Topography of the motor PINV: Isopotential line maps of the voltage topography and of the current source density (CSD) are shown, the head is presented in the top view from above, the nose is pointing upwards. Negativity and current sinks are reflected by blue areas, positivity and current sources are illustrated by red areas. Note the contralateral lateralization. <b>Bottom</b>: sLORETA source analysis results illustrating the effects of <i>DAT1</i> polymorphisms on the lateralized motor PINV: Note the stronger centro-parietal activation in Brodman areas 1–4 and 40 for the 6R–10R/6R–10R group, which is missing in the non 6R–10R/6R–10R group (marked by squares and blue arrows). Activation in the premotor area and frontal eye field (BA 6/8) was more bilateral in the non 6R–10R/6R–10R group (red arrows). The blue dipole indicates that RAP-MUSIC yielded a spatial component that showed a localization and orientation which explained the lateralized centro-parietal activation only for the 6R–10R/6R–10R group (details not shown). The crossing red lines were set to a point near the motor cortex hand area in order to illustrate the cortical activation in this area (cf. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0037814#pone-0037814-g004" target="_blank">Figure 4</a>).</p

Dipole and sLORETA source analysis of influences of <i>COMT</i> and <i>DAT1</i> polymorphisms on early visual contingent negative variation (CNV).

<p><b>Left:</b> 4-dipole source model fitted on the early CNV time interval by the genetic algorithm. Equivalent dipole 4 (pink) is symmetric to equivalent dipole 3 (green); both explain the occipito-temporal visual early CNV maxima. Dipoles 1 and 2 pick up additional frontal activity and activity related to the P300/late positive complex. <b>Middle:</b> Dipole moments for the homozygous 6R–10R/Met group (highest occipito-temporal early CNV amplitudes) compared to the homozygous other/Val group (low occipito-temporal early CNV amplitudes). Colours and numbers refer to the dipole model presented on the left, there were no qualitative differences between the groups. The vertical dashed line indicates the time of the imperative stimulus ‘X’, the early CNV time interval following the cue ‘A’ (600–900 ms) is marked in orange. <b>Right:</b> sLORETA source analysis for the same two genetic groups. The dipole locations of the dipole model depicted on the left are indicated. The occipito-temporal activation around Brodman areas 19, 37 (and adjacent areas) was stronger for the homozygous 6R–10R/Met group. The crossing red lines indicate the coordinates x = 0.40, y = −0.63, z = −0.14 (pink dipole).</p