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Objective: Research in adolescent depression has found aberrant intrinsic functional connectivity (iFC) among the ventral striatum (VS) and several brain regions implicated in reward processing. The present study probes this question by taking advantage of the availability of data from a large youth cohort, the IMAGEN Consortium., Methods: iFC data from 303 adolescents (48% of them female) were used to examine associations of VS connectivity at baseline (at age 14) with depressive disorders at baseline and at 2-year (N=250) and 4-year (N=219) follow-ups. Eleven regions of interest, key nodes of the reward system, were used to probe the reward network and calculate the connectivity strength of the VS within this network (VS connectivity rw ). The main analyses assessed associations of VS connectivity rw with depressive disorders, anhedonia, and low mood using logistic regression. Autoregressive models accounting for carryover effects over time were conducted to further evaluate these brain-behavior associations., Results: Higher right VS connectivity rw was associated with higher probability of depressive disorders at baseline (odds ratio=2.65, 95% CI=1.40, 5.05). This finding was confirmed in the autoregressive model, adjusting for carryover effects of the depressive disorders across the three time points. VS connectivity rw was not predictive of depressive disorders at follow-up assessments. Longitudinal associations between VS connectivity rw and anhedonia emerged in the structural equation model: left VS connectivity rw was associated with anhedonia at 2 years (odds ratio=2.20, 95% CI=1.54, 3.14), and right VS connectivity rw was linked to anhedonia at 4 years (odds ratio=1.87, 95% CI=1.09, 3.21). VS connectivity rw did not predict low mood at any time point in the structural equation model., Conclusions: The connectivity strength of the VS within the reward network showed distinct patterns of association with depressive disorders and anhedonia from mid to late adolescence, suggesting that the role of this circuitry in depression changes with age. This study replicates, in an independent sample, the association between the VS and depression previously reported in younger adolescents. The findings suggest a role of VS connectivity rw in anhedonia but not in low mood.

Objective: The dual-pathway model has been proposed to explain the heterogeneity in symptoms of attention deficit hyperactivity disorder (ADHD) by two independent psychological pathways based on distinct brain circuits. The authors sought to test whether the hypothesized cognitive and motivational pathways have separable neural correlates., Methods: In a longitudinal community-based cohort of 1,963 adolescents, the neuroanatomical correlates of ADHD were identified by a voxel-wise association analysis and then validated using an independent clinical sample (99 never-medicated patients with ADHD, 56 medicated patients with ADHD, and 267 healthy control subjects). The cognitive and motivational pathways were assessed by neuropsychological tests of working memory, intrasubject variability, stop-signal reaction time, and delay discounting. The associations were tested between the identified neuroanatomical correlates and both ADHD symptoms 2 years later and the polygenic risk score for ADHD., Results: Gray matter volumes of both a prefrontal cluster and a posterior occipital cluster were negatively associated with inattention. Compared with healthy control subjects, never-medicated patients, but not medicated patients, had significantly lower gray matter volumes in these two clusters. Working memory and intrasubject variability were associated with the posterior occipital cluster, and delay discounting was independently associated with both clusters. The baseline gray matter volume of the posterior occipital cluster predicted the inattention symptoms in a 2-year follow-up and was associated with the genetic risk for ADHD., Conclusions: The dual-pathway model has both shared and separable neuroanatomical correlates, and the shared correlate in the occipital cortex has the potential to serve as an imaging trait marker of ADHD, especially the inattention symptom domain.

Objective: Psychosocial stress is a key risk factor for substance abuse among adolescents. Recently, epigenetic processes such as DNA methylation have emerged as potential mechanisms that could mediate this relationship. The authors conducted a genome-wide methylation analysis to investigate whether differentially methylated regions are associated with psychosocial stress in an adolescent population., Methods: A methylome-wide analysis of differentially methylated regions was used to examine a sample of 1,287 14-year-old adolescents (50.7% of them female) from the European IMAGEN study. The Illumina 450k array was used to assess DNA methylation, pyrosequencing was used for technical replication, and linear regression analyses were used to identify associations with psychosocial stress and substance use (alcohol and tobacco). Findings were replicated by pyrosequencing a test sample of 413 participants from the IMAGEN study., Results: Hypermethylation in the sterile alpha motif/pointed domain containing the ETS transcription factor (SPDEF) gene locus was associated with a greater number of stressful life events in an allele-dependent way. Among individuals with the minor G-allele, SPDEF methylation moderated the association between psychosocial stress and substance abuse. SPDEF methylation interacted with lifetime stress in gray matter volume in the right cuneus, which in turn was associated with the frequency of alcohol and tobacco use. SPDEF was involved in the regulation of trans-genes linked to substance use., Conclusions: Taken together, the study findings describe a novel epigenetic mechanism that helps explain how psychosocial stress exposure influences adolescent substance abuse.

Objective: White matter microstructure alterations have recently been associated with depressive episodes during adolescence, but it is unknown whether they predate depression. The authors investigated whether subthreshold depression in adolescence is associated with white matter microstructure variations and whether they relate to depression outcome., Method: Adolescents with subthreshold depression (N=96) and healthy control subjects (N=336) drawn from a community-based cohort were compared using diffusion tensor imaging and whole brain tract-based spatial statistics (TBSS) at age 14 to assess white matter microstructure. They were followed up at age 16 to assess depression. Probabilistic tractography was used to reconstruct white matter streamlines spreading from the regions identified in the TBSS analysis and along bundles implicated in emotion regulation, the uncinate fasciculus and the cingulum. The authors searched for mediating effects of white matter microstructure on the relationship between baseline subthreshold depression and depression at follow-up, and then explored the specificity of the findings., Results: Lower fractional anisotropy (FA) and higher radial diffusivity were found in the anterior corpus callosum in the adolescents with subthreshold depression. Tractography analysis showed that they also had lower FA in the right cingulum streamlines, along with lower FA and higher mean diffusivity in tracts connecting the corpus callosum to the anterior cingulate cortex. The relation between subthreshold depression at baseline and depression at follow-up was mediated by FA values in the latter tracts, and lower FA values in those tracts distinctively predicted higher individual risk for depression., Conclusions: Early FA variations in tracts projecting from the corpus callosum to the anterior cingulate cortex may denote a higher risk of transition to depression in adolescents.

Objective: The authors sought to explore how conduct, hyperactivity/inattention, and emotional symptoms are associated with neural reactivity to social-emotional stimuli, and the extent to which psychosocial stress modulates these relationships., Method: Participants were community adolescents recruited as part of the European IMAGEN study. Bilateral amygdala regions of interest were used to assess the relationship between the three symptom domains and functional MRI neural reactivity during passive viewing of dynamic angry and neutral facial expressions. Exploratory functional connectivity and whole brain multiple regression approaches were used to analyze how the symptoms and psychosocial stress relate to other brain regions., Results: In response to the social-emotional stimuli, adolescents with high levels of conduct or hyperactivity/inattention symptoms who had also experienced a greater number of stressful life events showed hyperactivity of the amygdala and several regions across the brain. This effect was not observed with emotional symptoms. A cluster in the midcingulate was found to be common to both conduct problems and hyperactivity symptoms. Exploratory functional connectivity analyses suggested that amygdala-precuneus connectivity is associated with hyperactivity/inattention symptoms., Conclusions: The results link hyperactive amygdala responses and regions critical for top-down emotional processing with high levels of psychosocial stress in individuals with greater conduct and hyperactivity/inattention symptoms. This work highlights the importance of studying how psychosocial stress affects functional brain responses to social-emotional stimuli, particularly in adolescents with externalizing symptoms.

Objective: The authors examined whether alterations in the brain's reward network operate as a mechanism across the spectrum of risk for depression. They then tested whether these alterations are specific to anhedonia as compared with low mood and whether they are predictive of depressive outcomes., Method: Functional MRI was used to collect blood-oxygen-level-dependent (BOLD) responses to anticipation of reward in the monetary incentive task in 1,576 adolescents in a community-based sample. Adolescents with current subthreshold depression and clinical depression were compared with matched healthy subjects. In addition, BOLD responses were compared across adolescents with anhedonia, low mood, or both symptoms, cross-sectionally and longitudinally., Results: Activity in the ventral striatum was reduced in participants with subthreshold and clinical depression relative to healthy comparison subjects. Low ventral striatum activation predicted transition to subthreshold or clinical depression in previously healthy adolescents at 2-year follow-up. Brain responses during reward anticipation decreased in a graded manner between healthy adolescents, adolescents with current or future subthreshold depression, and adolescents with current or future clinical depression. Low ventral striatum activity was associated with anhedonia but not low mood; however, the combined presence of both symptoms showed the strongest reductions in the ventral striatum in all analyses., Conclusions: The findings suggest that reduced striatal activation operates as a mechanism across the risk spectrum for depression. It is associated with anhedonia in healthy adolescents and is a behavioral indicator of positive valence systems, consistent with predictions based on the Research Domain Criteria.

Objective: Although euthymic bipolar patients show minimal manic and depressive symptoms, they continue to show impaired emotional regulation and cognitive functioning. Few studies have directly examined the interference of emotional information with cognitive processes and its underlying cerebral mechanisms in euthymic bipolar patients. The authors examined the emotional modulation of cognitive processes and its underlying neural mechanisms in euthymic bipolar patients., Method: Seventeen euthymic bipolar patients and 17 healthy comparison subjects underwent functional magnetic resonance imaging (MRI) while performing an emotional and nonemotional go/nogo task. Neural responses associated with the overall task performance, as well as with the impact of emotional information on the task performance, were assessed., Results: Bipolar disorder patients exhibited increased activity in the temporal cortex, specifically to emotional go/nogo conditions, as well as in the orbitofrontal cortex, the insula, the caudate nuclei, and the dorsal anterior and posterior cingulate cortices when inhibiting emotional stimuli compared with neutral stimuli. Conversely, no global attentional deficits were observed on either a behavioral or neural response level, indicated by similar task performances for all task conditions and similar brain activation patterns when comparing all the go/nogo conditions with the resting state., Conclusions: The present study provides evidence of an altered emotional modulation of cognitive processing in euthymic bipolar patients, indicated by an overactivation in ventral-limbic, temporal, and dorsal brain structures during emotional go/nogo conditions in patients relative to comparison subjects.

Objective: Although the brain areas involved in emotional response and in the recognition of others' emotions have been reported, the neural bases of individual differences in affective style remain to be elucidated. Alexithymia, i.e., impairment of the ability to identify and communicate one's emotional state, influences how emotions are regulated. Alexithymia has been hypothesized to involve anterior cingulate dysfunction. Therefore, the authors searched for differential cerebral regional activation in response to emotional stimuli in subjects with alexithymia., Method: Two groups of eight men each were selected from 437 healthy subjects on the basis of high or low scores on the 20-item Toronto Alexithymia Scale. Using functional magnetic resonance imaging (fMRI), the authors compared the two groups for their regional cerebral activation in response to the presentation of pictures with validated positive or negative arousal capabilities., Results: Men with alexithymia demonstrated less cerebral activation in the left mediofrontal-paracingulate cortex in response to highly negative stimuli and more activation in the anterior cingulate, mediofrontal cortex, and middle frontal gyrus in response to highly positive stimuli than men without alexithymia., Conclusions: These findings provide direct evidence that alexithymia, a personality trait playing a role in affect regulation, is linked with differences in anterior cingulate and mediofrontal activity during emotional stimuli processing.

Objective: The study assessed striatal presynaptic dopamine function in patients with different subtypes of depression., Method: Magnetic resonance imaging and positron emission tomography with [(18)F]fluorodopa ([(18)F]DOPA) were used to compare six depressed patients with marked affective flattening and psychomotor retardation, six depressed patients with marked impulsivity and anxiety, and 10 healthy comparison subjects. Depressed patient groups were matched for severity of depression., Results: [(18)F]DOPA uptake K(i) values in the left caudate were significantly lower in patients with psychomotor retardation than in patients with high impulsivity and in comparison subjects., Conclusions: These results suggest that left caudate dopamine function differs between depressed patients with psychomotor retardation and those with impulsivity and provide direct evidence of a link between dopamine hypofunction and psychomotor retardation in depression.

Objective: The authors' goal was to investigate brain regions involved in the deficiency of working memory control processes in patients with schizophrenia., Method: Regional cerebral blood flow was measured with positron emission tomography in eight men with stabilized schizophrenia and eight healthy men while they were performing a graded random number generation task. Twelve scans were made for each subject. Covariations between randomness of responses and regional activation were analyzed., Results: The pattern of covariation between randomness of responses and activation in the anterior cingulate and superior parietal regions differed between patients and healthy subjects., Conclusions: These results suggest a cinguloparietal dysfunction underlying the impairment of working memory control processes during a random number generation task in patients with schizophrenia.