It has not yet been determined if the commonly reported cannabis–psychosis association is limited to individuals with pre-existing genetic risk for psychotic disorders.

We examined whether the relationship between polygenic risk score for schizophrenia (PRS-Sz) and psychotic-like experiences (PLEs), as measured by the Community Assessment of Psychic Experiences-42 (CAPE-42) questionnaire, is mediated or moderated by lifetime cannabis use at 16 years of age in 1740 of the individuals of the European IMAGEN cohort. Secondary analysis examined the relationships between lifetime cannabis use, PRS-Sz and the various sub-scales of the CAPE-42. Sensitivity analyses including covariates, including a PRS for cannabis use, were conducted and results were replicated using data from 1223 individuals in the Dutch Utrecht cannabis cohort.

PRS-Sz significantly predicted cannabis use (p = 0.027) and PLE (p = 0.004) in the IMAGEN cohort. In the full model, considering PRS-Sz and covariates, cannabis use was also significantly associated with PLE in IMAGEN (p = 0.007). Results remained consistent in the Utrecht cohort and through sensitivity analyses. Nevertheless, there was no evidence of a mediation or moderation effects.

These results suggest that cannabis use remains a risk factor for PLEs, over and above genetic vulnerability for schizophrenia. This research does not support the notion that the cannabis–psychosis link is limited to individuals who are genetically predisposed to psychosis and suggests a need for research focusing on cannabis-related processes in psychosis that cannot be explained by genetic vulnerability.

Sex-related differences in psychopathology are known phenomena, with externalizing and internalizing symptoms typically more common in boys and girls, respectively. However, the neural correlates of these sex-by-psychopathology interactions are underinvestigated, particularly in adolescence.

Participants were 14 years of age and part of the IMAGEN study, a large (N = 1526) community-based sample. To test for sex-by-psychopathology interactions in structural grey matter volume (GMV), we used whole-brain, voxel-wise neuroimaging analyses based on robust non-parametric methods. Psychopathological symptom data were derived from the Strengths and Difficulties Questionnaire (SDQ).

We found a sex-by-hyperactivity/inattention interaction in four brain clusters: right temporoparietal-opercular region (p < 0.01, Cohen's d = −0.24), bilateral anterior and mid-cingulum (p < 0.05, Cohen's d = −0.18), right cerebellum and fusiform (p < 0.05, Cohen's d = −0.20) and left frontal superior and middle gyri (p < 0.05, Cohen's d = −0.26). Higher symptoms of hyperactivity/inattention were associated with lower GMV in all four brain clusters in boys, and with higher GMV in the temporoparietal-opercular and cerebellar-fusiform clusters in girls.

Using a large, sex-balanced and community-based sample, our study lends support to the idea that externalizing symptoms of hyperactivity/inattention may be associated with different neural structures in male and female adolescents. The brain regions we report have been associated with a myriad of important cognitive functions, in particular, attention, cognitive and motor control, and timing, that are potentially relevant to understand the behavioural manifestations of hyperactive and inattentive symptoms. This study highlights the importance of considering sex in our efforts to uncover mechanisms underlying psychopathology during adolescence.

Tobacco smoking remains one of the leading causes of preventable illness and death and is heritable with complex underpinnings. Converging evidence suggests a contribution of the polygenic risk for smoking to the use of tobacco and other substances. Yet, the underlying brain mechanisms between the genetic risk and tobacco smoking remain poorly understood.

Genomic, neuroimaging, and self-report data were acquired from a large cohort of adolescents from the IMAGEN study (a European multicenter study). Polygenic risk scores (PGRS) for smoking were calculated based on a genome-wide association study meta-analysis conducted by the Tobacco and Genetics Consortium. We examined the interrelationships among the genetic risk for smoking initiation, brain structure, and the number of occasions of tobacco use.

A higher smoking PGRS was significantly associated with both an increased number of occasions of tobacco use and smaller cortical volume of the right orbitofrontal cortex (OFC). Furthermore, reduced cortical volume within this cluster correlated with greater tobacco use. A subsequent path analysis suggested that the cortical volume within this cluster partially mediated the association between the genetic risk for smoking and the number of occasions of tobacco use.

Our data provide the first evidence for the involvement of the OFC in the relationship between smoking PGRS and tobacco use. Future studies of the molecular mechanisms underlying tobacco smoking should consider the mediation effect of the related neural structure.

In alcoholism, one relevant mechanism contributing to relapse is the exposure to stimuli that are associated with alcohol intake. Such conditioned cues can elicit conditioned responses like alcohol craving and consumption. In the last decade, considerable progress has been made in identifying basic neuronal mechanisms that underlie cue-induced alcohol craving.

We explored whether functional brain activation during exposure to alcohol-associated stimuli is related to the prospective relapse risk in detoxified alcohol-dependent patients.

46 alcohol-dependent and 46 healthy volunteers participated in a fMRI study using a cue reactivity paradigm, in which visual alcohol-related and control stimuli were presented. Patients were followed for 3 months. Afterwards data was analysed regarding the subsequent relapse, resulting in 16 abstainers and 30 relapsers.

Alcohol-related versus neutral stimuli activated a frontocortical-limbic network including inferior, medial and middle frontal gyrus as well as putamen in the group of patients relative to healthy controls. Moreover, abstainers showed a stronger activation in orbitofrontal cortex as well as midbrain during the presentation of alcohol-related cues whereas relapsers revealed a stronger activation of cingulate gyrus.

This study suggests that cue-induced activation of orbitofrontal cortex and dopaminergic innervated midbrain is negatively associated with the prospective relapse risk in alcohol-dependent patients. This could indicate a more pronounced and conscious processing of alcohol cues which might serve as a warning signal and a behavioural controlling function. In contrast, prospective relapsers showed a stronger activation of cingulate gyrus, a region involved in the attribution of motivational value.

Although neuroimaging studies suggest brain regional abnormalities in depressive disorders, it remains unclear whether abnormalities are present at illness onset or reflect disease progression.

We hypothesized that cerebral variations were present in adolescents with subthreshold depression known to be at high risk for later full-blown depression.

We examined brain structural and diffusion-weighted magnetic resonance images of adolescents with subthreshold depression.

The participants were extracted from the European IMAGEN study cohort of healthy adolescents recruited at age 14. Subthreshold depression was defined as a distinct period of abnormally depressed or irritable mood, or loss of interest, plus two or more depressive symptoms but without diagnosis of Major Depressive Episode. Comparisons were performed between adolescents meeting these criteria and control adolescents within the T1-weighted imaging modality (118 and 475 adolescents respectively) using voxel-based morphometry and the diffusion tensor imaging modality (89 ad 422 adolescents respectively) using tract-based spatial statistics. Whole brain analyses were performed with a statistical threshold set to p< 0.05 corrected for multiple comparisons.

Compared with controls, adolescents with subthreshold depression had smaller gray matter volume in caudate nuclei, medial frontal and cingulate cortices; smaller white matter volume in anterior limb of internal capsules, left forceps minor and right cingulum; and lower fractional anisotropy and higher radial diffusivity in the genu of corpus callosum.

The findings suggest that adolescents with subthreshold depression have volumetric and microstructural gray and white matter changes in the emotion regulation frontal-striatal-limbic network.

Dysfunctional behavioural and neural processing of reward has been found in currently depressed individuals. However, little is known about altered reward processing in remitted depressed individuals.

A total of 23 medication-free individuals with remitted major depressive disorder (rMDD) and 23 matched healthy controls (HCs) performed a reward task during functional magnetic resonance imaging. We also investigated reward dependence, novelty seeking and harm avoidance using the Tridimensional Personality Questionnaire and their association with neural responses of reward processing.

Compared to HCs, individuals with rMDD exhibited enhanced responses to reward-predicting cues in the hippocampus, amygdala and superior frontal gyrus. When reward was delivered, rMDD subjects did not significantly differ from HCs. In both groups neural activity during reward anticipation was negatively correlated with harm avoidance.

Our results show that rMDD is characterized by hyperactivation in fronto-limbic regions during reward anticipation. Alterations in neural activation during reward processing might reflect an increased effort in remitted depressed individuals to allocate neural activity for executive and evaluative processes during anticipatory reward processing.

Resilience is the capacity of individuals to resist mental disorders despite exposure to stress. Little is known about its neural underpinnings. The putative variation of white-matter microstructure with resilience in adolescence, a critical period for brain maturation and onset of high-prevalence mental disorders, has not been assessed by diffusion tensor imaging (DTI). Lower fractional anisotropy (FA) though, has been reported in the corpus callosum (CC), the brain's largest white-matter structure, in psychiatric and stress-related conditions. We hypothesized that higher FA in the CC would characterize stress-resilient adolescents.

Three groups of adolescents recruited from the community were compared: resilient with low risk of mental disorder despite high exposure to lifetime stress (n = 55), at-risk of mental disorder exposed to the same level of stress (n = 68), and controls (n = 123). Personality was assessed by the NEO-Five Factor Inventory (NEO-FFI). Voxelwise statistics of DTI values in CC were obtained using tract-based spatial statistics. Regional projections were identified by probabilistic tractography.

Higher FA values were detected in the anterior CC of resilient compared to both non-resilient and control adolescents. FA values varied according to resilience capacity. Seed regional changes in anterior CC projected onto anterior cingulate and frontal cortex. Neuroticism and three other NEO-FFI factor scores differentiated non-resilient participants from the other two groups.

High FA was detected in resilient adolescents in an anterior CC region projecting to frontal areas subserving cognitive resources. Psychiatric risk was associated with personality characteristics. Resilience in adolescence may be related to white-matter microstructure.

Enhanced acquisition and delayed extinction of fear conditioning are viewed as major determinants of anxiety disorders, which are often characterized by a dysfunctional hypothalamic–pituitary–adrenal (HPA) axis.

In this study we employed cued fear conditioning in two independent samples of healthy subjects (sample 1: n=60, sample 2: n=52). Two graphical shapes served as conditioned stimuli and painful electrical stimulation as the unconditioned stimulus. In addition, guided by findings from published animal studies on HPA axis-related genes in fear conditioning, we examined variants of the glucocorticoid receptor and corticotropin-releasing hormone receptor 1 genes.

Variation in these genes showed enhanced amygdala activation during the acquisition and reduced prefrontal activation during the extinction of fear as well as altered amygdala–prefrontal connectivity.

This is the first demonstration of the involvement of genes related to the HPA axis in human fear conditioning.

The experience of uncontrollability and helplessness in the face of stressful life events is regarded as an important determinant in the development and maintenance of depression. The inability to successfully deal with stressors might be linked to dysfunctional prefrontal functioning. We assessed cognitive, behavioural and physiological effects of stressor uncontrollability in depressed and healthy individuals. In addition, relationships between altered cortical processing and cognitive vulnerability traits of depression were analysed.

A total of 26 unmedicated depressed patients and 24 matched healthy controls were tested in an expanded forewarned reaction (S1–S2) paradigm. In a factorial design, stressor controllability varied across three consecutive conditions: (a) control, (b) loss of control and (c) restitution of control. Throughout the experiment, error rates, ratings of controllability, arousal, emotional valence and helplessness were assessed together with the post-imperative negative variation (PINV) of the electroencephalogram.

Depressed participants showed an enhanced frontal PINV as an electrophysiological index of altered information processing during both loss of control and restitution of control. They also felt more helpless than controls. Furthermore, frontal PINV magnitudes were associated with habitual rumination in the depressed subsample.

These findings indicate that depressed patients are more susceptible to stressor uncontrollability than healthy subjects. Moreover, the experience of uncontrollability seems to bias subsequent information processing in a situation where control is objectively re-established. Alterations in prefrontal functioning appear to contribute to this vulnerability and are also linked to trait markers of depression.

El objetivo de este estudio era desarrollar nuevas claves estandarizadas asociadas al alcohol y evaluar sus efectos sobre la activación cerebral con resonancia magnética nuclear funcional (RMNf). Se presentaron imágenes de bebidas alcohólicas y neutrales e imágenes neutrales afectivamente a 44 alcohólicos abstinentes y 37 sujetos de control sanos emparejados por la edad. Evaluamos la respuesta de conductancia de la piel, y la activación y la valencia provocadas. Los alcohólicos y los sujetos de control no difirieron en la activación, la valencia o la respuesta de conductancia de la piel evocadas por los estímulos asociados con el alcohol y los neutrales afectivamente, mientras que los alcohólicos evaluaron las bebidas no alcohólicas como más desagradables y activadoras, comparado con los sujetos de control. En el estudio piloto de RMNf, se presentaron imágenes relacionadas con el alcohol y abstractas a seis alcohólicos abstinentes, e indujeron una activación significativa de las áreas cerebrales asociadas con los procesos emocionales visuales, como el giro fusiforme, partes del sistema de recompensa del cerebro (ganglios basales y giro orbitofrontal) y otras regiones cerebrales en las cortezas frontal y parietal asociadas con la red de atención. Estas observaciones indican que se pueden utilizar imágenes estandarizadas de bebidas alcohólicas para evaluar los circuitos cerebrales implicados en el procesamiento y la evaluación de las claves de alcohol.