Christine Macare

Gently restless: association of ADHD-like traits with response inhibition and interference control

Abstract Impairment of inhibition-related functions is one of the most pronounced cognitive deficits found in attention-deficit/hyperactivity disorder (ADHD). Compelling evidence from studies of unaffected relatives of patients with ADHD and of ADHD-like traits in healthy subjects suggest the continuous distribution of ADHD symptoms in the population. A more subtle inhibitory deficit can also be found in healthy relatives of patients and in subjects with high ADHD-like traits. Here, we examined the relationship between inhibitory performance and ADHD-like traits, for the first time, in a large sample of healthy adults by applying multiple, widely used tests of inhibition-related functions. ADHD-like traits, in general, were independently predicted by Stroop interference score and, at trend level, by go/no-go commission error rate while controlling for socio-demographic factors, verbal intelligence and neuroticism. Additionally, higher inattentive traits were related to worse Stroop performance at trend level, and higher hyperactive/impulsive traits were significantly associated with more go/no-go commission errors. ADHD-like traits were strongly related to neuroticism. The study shows that individual differences in ADHD-like traits are related to variance in fundamental inhibition-related functions over and above effects of negative affect regulation, but the relationships tend to be small. The results suggest the quasi-dimensionality of ADHD and raise further questions about the relationship between genetic factors and the deficit of inhibition-related functions in the ADHD spectrum.

Neural basis of reward anticipation and its genetic determinants

Significance We characterize in humans a coordinated network of brain activity describing neurobehavioral correlates of reward anticipation. The network involves nodes in striatal and cortical brain regions, which are preferentially associated with distinct externalizing behaviors—hyperactivity and alcohol consumption—suggesting that the heterogeneity of reward-related behaviors might be accounted for by different association patterns of nodes and their connecting links. In a genome-wide association study of the striatal node with subsequent functional validation in Drosophila, we identify molecular genetic mechanisms involving vacuolar protein sorting-associated protein 4A (VPS4A) in dopamine regulation, reward anticipation, and hyperactivity. Our approach might facilitate the identification of causal neural mechanisms, important for the identification of previously unidentified targets and the establishment of neurobehaviorally informed end points for clinical trials. Dysfunctional reward processing is implicated in various mental disorders, including attention deficit hyperactivity disorder (ADHD) and addictions. Such impairments might involve different components of the reward process, including brain activity during reward anticipation. We examined brain nodes engaged by reward anticipation in 1,544 adolescents and identified a network containing a core striatal node and cortical nodes facilitating outcome prediction and response preparation. Distinct nodes and functional connections were preferentially associated with either adolescent hyperactivity or alcohol consumption, thus conveying specificity of reward processing to clinically relevant behavior. We observed associations between the striatal node, hyperactivity, and the vacuolar protein sorting-associated protein 4A (VPS4A) gene in humans, and the causal role of Vps4 for hyperactivity was validated in Drosophila. Our data provide a neurobehavioral model explaining the heterogeneity of reward-related behaviors and generate a hypothesis accounting for their enduring nature.

Hypothalamic-pituitary-adrenal (HPA) axis functioning as predictor of antidepressant response–Meta-analysis

Objective Although antidepressants are effective, around 50% of depressed patients are non‐responsive. At the same time, some patients show alterations in the hypothalamic‐pituitary‐adrenal (HPA) axis. Due to interactions with central monoaminergic systems, these may profit less from antidepressants. Method To determine whether non‐responders and responders differed in pre‐treatment HPA axis functioning, the Cochrane Library, EMBASE, MEDLINE, and PsycINFO were searched. Studies using patients with depression being treated with antidepressants, and including both a pre‐treatment HPA and a post‐treatment response measure were included. Standardised mean differences were calculated for meta‐analysis. Results Thirty‐nine studies were included. Non‐responders and responders did not differ in pre‐treatment corticotropin‐releasing hormone or adrenocorticotropic hormone. Meta‐regression showed non‐responders had comparably higher pre‐treatment cortisol in studies measuring cortisol non‐invasively, not reporting sample storage, failing to control for age, and excluding patients with comorbidities. Conclusions Only studies with a specific methodological profile seem to be able to show that the more marked depressed patients’ alterations in the HPA axis, the less likely they are to profit from antidepressants. Highlights39 studies investigated HPA functioning as a predictor of antidepressant response.Non‐responders did not differ from responders in pre‐treatment CRH and ACTH.Non‐responders had higher cortisol in studies with a specific methodological profile.

Methylation of OPRL1 mediates the effect of psychosocial stress on binge drinking in adolescents

BACKGROUND Nociceptin is a key regulator linking environmental stress and alcohol drinking. In a genome-wide methylation analysis, we recently identified an association of a methylated region in the OPRL1 gene with alcohol-use disorders. METHODS Here, we investigate the biological basis of this observation by analysing psychosocial stressors, methylation of the OPRL1 gene, brain response during reward anticipation and alcohol drinking in 660 fourteen-year-old adolescents of the IMAGEN study. We validate our findings in marchigian sardinian (msP) alcohol-preferring rats that are genetically selected for increased alcohol drinking and stress sensitivity. RESULTS We found that low methylation levels in intron 1 of OPRL1 are associated with higher psychosocial stress and higher frequency of binge drinking, an effect mediated by OPRL1 methylation. In individuals with low methylation of OPRL1, frequency of binge drinking is associated with stronger BOLD response in the ventral striatum during reward anticipation. In msP rats, we found that stress results in increased alcohol intake and decreased methylation of OPRL1 in the nucleus accumbens. CONCLUSIONS Our findings describe an epigenetic mechanism that helps to explain how psychosocial stress influences risky alcohol consumption and reward processing, thus contributing to the elucidation of biological mechanisms underlying risk for substance abuse.

A neurobiological pathway to smoking in adolescence: TTC12-ANKK1-DRD2 variants and reward response

The TTC12-ANKK1-DRD2 gene-cluster has been implicated in adult smoking. Here, we investigated the contribution of individual genes in the TTC12-ANKK1-DRD2 cluster in smoking and their association with smoking-associated reward processing in adolescence. A meta-analysis of TTC12-ANKK1-DRD2 variants and self-reported smoking behaviours was performed in four European adolescent cohorts (N = 14,084). The minor G-allele of rs2236709, mapping TTC12, was associated with self-reported smoking (p = 5.0 × 10−4) and higher plasma cotinine levels (p = 7.0 × 10−5). This risk allele was linked to an increased ventral-striatal blood-oxygen level-dependent (BOLD) response during reward anticipation (n = 1,263) and with higher DRD2 gene expression in the striatum (p = 0.013), but not with TTC12 or ANKK gene expression. These data suggest a role for the TTC12-ANKK1-DRD2 gene-cluster in adolescent smoking behaviours, provide evidence for the involvement of DRD2 in the early stages of addiction and support the notion that genetically-driven inter-individual differences in dopaminergic transmission mediate reward sensitivity and risk to smoking.