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Emotion regulation deficits are characteristic of youth depression and are underpinned by altered frontoamygdalar function. However, the causal dynamics of frontoamygdalar pathways in depression and how these dynamics relate to treatment prognosis remain unexplored. This study aimed to assess frontoamygdalar effective connectivity during cognitive reappraisal in youths with depression and to test whether pathway dynamics are predictive of individual response to combined cognitive behavioral therapy plus treatment with fluoxetine or placebo. One hundred seven young people with moderate to severe depression and 94 healthy control participants completed a functional magnetic resonance imaging cognitive reappraisal task. After the task, 87 participants with depression were randomized and received 12 weeks of cognitive behavioral therapy plus either fluoxetine or placebo. Dynamic causal modeling was used to map frontoamygdalar effective connectivity during reappraisal and to assess the predictive capacity of baseline frontoamygdalar effective connectivity on depression diagnosis and posttreatment depression remission. Young people with depression showed weaker inhibitory modulation of ventrolateral prefrontal cortex to amygdala connectivity during reappraisal (0.29 Hz, posterior probability = 1.00). Leave-one-out cross-validation demonstrated that this effect was sufficiently large to predict individual diagnostic status (r = 0.20, p =.003). Posttreatment depression remission was associated with weaker excitatory ventromedial prefrontal cortex to amygdala connectivity (−0.56 Hz, posterior probability = 1.00) during reappraisal at baseline, though this effect did not predict individual remission status (r = −0.02, p =.561). Frontoamygdalar effective connectivity shows promise in identifying youth depression diagnosis, and circuits responsible for negative affect regulation are implicated in responsiveness to first-line depression treatments. [ABSTRACT FROM AUTHOR]

Clinical trials suggest that long-chain omega-3 polyunsaturated fatty acids (n-3 PUFAs) (fish oil) may reduce depressive symptoms in adults with major depressive disorder. Therefore, n-3 PUFAs may be a potential treatment for depression in youth. Participants were 15- to-25 year-old individuals with major depressive disorder who sought care in one of three government-funded mental health services for young people in metropolitan Melbourne, Perth, or Sydney, Australia. Participants were randomly assigned in a double-blind, parallel-arm design to receive either fish oil (840 mg of eicosapentaenoic acid and 560 mg of docosahexaenoic acid) or placebo capsules as adjunct to cognitive behavioral case management. All participants were offered 50-minute cognitive behavioral case management sessions every 2 weeks delivered by qualified therapists (treatment as usual) at the study sites during the intervention period. The primary outcome was change in the interviewer-rated Quick Inventory of Depressive Symptomatology, Adolescent Version, score at 12 weeks. Erythrocyte n-3 PUFA levels were assessed pre-post intervention. A total of 233 young people were randomized to the treatment arms: 115 participants to the n-3 PUFA group and 118 to the placebo group. Mean change from baseline in the Quick Inventory of Depressive Symptomatology score was −5.8 in the n-3 PUFA group and −5.6 in the placebo group (mean difference, 0.2; 95% CI, −1.1 to 1.5; p =.75). Erythrocyte PUFA levels were not associated with depression severity at any time point. The incidence and severity of adverse events were similar in the two groups. This placebo-controlled trial and biomarker analysis found no evidence to support the use of fish oil for treatment in young people with major depressive disorder. [ABSTRACT FROM AUTHOR]

Major depression is a debilitating condition characterised by diverse neurocognitive and behavioural deficits. Nevertheless, our species-typical capacity for depressed mood implies that it serves an adaptive function. Here we apply an interdisciplinary theory of brain function to explain depressed mood and its clinical manifestations. Combining insights from the free-energy principle (FEP) with evolutionary theorising in psychology, we argue that depression reflects an adaptive response to perceived threats of aversive social outcomes (e.g., exclusion) that minimises the likelihood of surprising interpersonal exchanges (i.e., those with unpredictable outcomes). We suggest that psychopathology typically arises from ineffectual attempts to alleviate interpersonal difficulties and/or hyper-reactive neurobiological responses to social stress (i.e., uncertainty), which often stems from early experience that social uncertainty is difficult to resolve. [ABSTRACT FROM AUTHOR]

Investigating how brain development during adolescence and early adulthood underlies guilt- and shame-proneness may be important for understanding risk processes for mental disorders. The aim of this study was to investigate the neurodevelopmental correlates of interpersonal guilt- and shame-proneness in healthy adolescents and young adults using structural magnetic resonance imaging (sMRI). Sixty participants (age range: 15–25) completed sMRI and self-report measures of interpersonal guilt- and shame-proneness. Independent of interpersonal guilt, higher levels of shame-proneness were associated with thinner posterior cingulate cortex (PCC) thickness and smaller amygdala volume. Higher levels of shame-proneness were also associated with attenuated age-related reductions in thickness of lateral orbitofrontal cortex (lOFC). Our findings highlight the complexities in understanding brain–behavior relationships during the adolescent/young adult period. Results were consistent with growing evidence that accelerated cortical thinning during adolescence may be associated with superior socioemotional functioning. Further research is required to understand the implications of these findings for mental disorders characterized by higher levels of guilt and shame. [ABSTRACT FROM AUTHOR]

Background: Studies of depressed patients have demonstrated increased amygdala activation to negative affective stimuli. In this study, we used a paradigm that employed personally relevant social stimuli, which are known to strongly activate the amygdala, to test whether the amygdala demonstrated aberrant activity in depressed participants as they responded to stimuli with positive valence. Methods: Nineteen patients with major depressive disorder, aged 15 to 24 years, were matched with 20 healthy control participants. They completed a novel functional magnetic resonance imaging task in which they received social feedback from people who they believed had evaluated them. Voxelwise statistical parametric maps of brain response to positive social feedback and to a control feedback condition were compared to test the hypothesis that differences in neural response between depressed and control participants would arise in the amygdala. Results: Depressed participants showed increased neural response to the positive- versus control-feedback condition in the amygdala (p < .05, corrected). An exploratory analysis showed that depressed participants responded to faces from both feedback conditions with increased activity in regions subserving social appraisal (ventrolateral prefrontal cortex and inferior parietal cortex) and affective processing (pregenual anterior cingulate cortex and anterior insular cortex; p < .001, uncorrected). Conclusions: Depressed patients responded to positive social feedback with increased amygdala activation, demonstrating that amygdala hyperresponsivity in depression is not restricted to negatively-valenced stimuli. The heightened sensitivity of depressed participants to social evaluation may help explain symptoms of depression such as social withdrawal. [Copyright &y& Elsevier]

Abstract: Adolescent development is accompanied by the emergence of a population-wide increase in vulnerability to depression that is maintained through adulthood. We provide a model for understanding how this vulnerability to depression arises, and why depression is so often precipitated by social rejection or loss of status during this phase. There is substantial remodeling and maturation of the dopaminergic reward system and the prefrontal cortex during adolescence, that coincides with the adolescent entering the complex world of adult peer and romantic relationships, where the rewards that can be obtained (feelings such as belonging, romantic love, status and agency) are abstract and temporally distant from the proximal context. Development of the prefrontal cortex makes it possible to pursue such complex and distal rewards, which are, however, tenuous and more readily frustrated than more immediate rewards. We hypothesize that when these distant rewards are frustrated they suppress the reward system, and that when such suppression is extensive and occurs for long enough, the clinical picture that results is one of depression. [Copyright &y& Elsevier]

• Social anxiety disorder (SAD) has been linked to impaired fear regulation. • We investigated threat and safety reversal learning in young patients with SAD. • People with SAD showed unimpaired reversal learning across all measured domains. • Overall, higher social anxiety symptoms predicted more safety reversal learning. Social anxiety disorder (SAD) has been linked to maladaptive forms of fear regulation, including flexibly distinguishing between learned threat and safety signals. Few studies have examined this in young, unmedicated SAD patients, including its neural basis. We aimed to characterize the neural, subjective, and autonomic correlates of reversal learning in patients with SAD and compare them to matched patients with major depressive disorder and to healthy control participants. All participants completed a threat-safety reversal learning task during functional magnetic resonance imaging. Successful threat-safety updating was associated with significant activation of primary regions of interest (anterior cingulate, insula and ventromedial prefrontal cortex), however, no significant differences were observed between them, consistent with subjective reports of task-evoked anxiety and affect. Contrary to expectations, we did not observe threat and safety reversal learning to be significantly impaired in young people with SAD. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) often emerges during adolescence with detrimental effects on development as well as lifetime consequences. Identifying neurobiological markers that are associated with the onset or course of this disorder in childhood and adolescence is important for early recognition and intervention and, potentially, for the prevention of illness onset. In this systematic review, 68 longitudinal neuroimaging studies, from 34 unique samples, that examined the association of neuroimaging markers with onset or changes in paediatric depression published up to 1 February 2019 were examined. These studies employed different imaging modalities at baseline; structural magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), functional MRI (fMRI) or electroencephalography (EEG). Most consistent evidence across studies was found for blunted reward-related (striatal) activity (fMRI and EEG) as a potential biological marker for both MDD onset and course. With regard to structural brain measures, the results were highly inconsistent, likely caused by insufficient power to detect complex mediating effects of genetic and environmental factors in small sample sizes. Overall, there were a limited number of samples, and confounding factors such as sex and pubertal development were often not considered, whereas these factors are likely to be relevant especially in this age range. [ABSTRACT FROM AUTHOR]

The self-concept – the set of beliefs that a person has about themselves – shows significant development from adolescence to early adulthood, in parallel with brain development over the same period. We sought to investigate how age-related changes in self-appraisal processes corresponded with brain network segregation and integration in healthy adolescents and young adults. We scanned 88 participants (46 female), aged from 15 to 25 years, as they performed a self-appraisal task. We first examined their patterns of activation to self-appraisal, and replicated prior reports of reduced dorsomedial prefrontal cortex activation with older age, with similar reductions in precuneus, right anterior insula/operculum, and a region extending from thalamus to striatum. We used independent component analysis to identify distinct anterior and posterior components of the default mode network (DMN), which were associated with the self-appraisal and rest-fixation parts of the task, respectively. Increasing age was associated with reduced functional connectivity between the two components. Finally, analyses of task-evoked interactions between pairs of nodes within the DMN identified a subnetwork that demonstrated reduced connectivity with increasing age. Decreased network integration within the DMN appears to be an important higher-order maturational process supporting the emerging adult self. [ABSTRACT FROM AUTHOR]

This systematic review aimed to provide a comprehensive summary of the current literature on the neurobiological underpinnings of the experience of the negative moral emotions: shame, embarrassment and guilt. PsycINFO, PubMed and MEDLINE were used to identify existing studies. Twenty-one functional and structural magnetic resonance imaging and positron emission tomography studies were reviewed. Although studies differed considerably in methodology, their findings highlight both shared and distinct patterns of brain structure/function associated with these emotions. Shame was more likely to be associated with activity in the dorsolateral prefrontal cortex, posterior cingulate cortex and sensorimotor cortex; embarrassment was more likely to be associated with activity in the ventrolateral prefrontal cortex and amygdala; guilt was more likely to be associated with activity in ventral anterior cingulate cortex, posterior temporal regions and the precuneus. Although results point to some common and some distinct neural underpinnings of these emotions, further research is required to replicate findings. [ABSTRACT FROM AUTHOR]

Safety learning creates associations between conditional stimuli and the absence of threat. Studies of human fear conditioning have accumulated evidence for the neural signatures of safety over various paradigms, aligning on several common brain systems. While these systems are often interpreted as underlying safety learning in a generic sense, they may instead reflect the expression of learned safety, pertaining to processes of fear inhibition, positive affect, and memory. Animal models strongly suggest these can be separable from neural circuits implicated in the conditioning process itself (or safety acquisition). While acquisition-expression distinctions are ubiquitous in behavioural science, this lens has not been applied to safety learning, which remains a novel area in the field. In this mini-review, we overview findings from prevalent safety paradigms in humans, and synthesise these with insights from animal models to propose that the neurobiology of safety learning be conceptualised along an acquisition-expression model, with the aim of stimulating richer brain-based characterisations of this important process. [ABSTRACT FROM AUTHOR]

Neuroimaging studies of suicidal behavior have so far been conducted in small samples, prone to biases and false-positive associations, yielding inconsistent results. The ENIGMA-MDD Working Group aims to address the issues of poor replicability and comparability by coordinating harmonized analyses across neuroimaging studies of major depressive disorder and related phenotypes, including suicidal behavior. Here, we pooled data from 18 international cohorts with neuroimaging and clinical measurements in 18,925 participants (12,477 healthy control subjects and 6448 people with depression, of whom 694 had attempted suicide). We compared regional cortical thickness and surface area and measures of subcortical, lateral ventricular, and intracranial volumes between suicide attempters, clinical control subjects (nonattempters with depression), and healthy control subjects. We identified 25 regions of interest with statistically significant (false discovery rate <.05) differences between groups. Post hoc examinations identified neuroimaging markers associated with suicide attempt including smaller volumes of the left and right thalamus and the right pallidum and lower surface area of the left inferior parietal lobe. This study addresses the lack of replicability and consistency in several previously published neuroimaging studies of suicide attempt and further demonstrates the need for well-powered samples and collaborative efforts. Our results highlight the potential involvement of the thalamus, a structure viewed historically as a passive gateway in the brain, and the pallidum, a region linked to reward response and positive affect. Future functional and connectivity studies of suicidal behaviors may focus on understanding how these regions relate to the neurobiological mechanisms of suicide attempt risk. [ABSTRACT FROM AUTHOR]

Deficient safety learning has been implicated in the pathogenesis of anxiety disorders. Despite increased translational interest, there has been limited research on the basis of safety learning in humans. Here, we examined safety learning in seventy-three healthy participants via a modified Pavlovian conditioned inhibition paradigm, featuring a conditioned threat stimulus that was reinforced alone (A+), but not when combined with a second stimulus (the conditioned inhibitor, AX-). During a test phase, X and a control safety cue (C) were combined with a second threat stimulus to assess their inhibition of threat responses, measured via skin conductance (SCRs) and US-expectancy ratings. Both stimuli exhibited conditioned inhibition, but X suppressed ratings by a greater magnitude than C. Trait anxiety also predicted increased US-expectancy ratings of X. These findings suggest that a Pavlovian inhibitor accrues greater safety value than a merely unreinforced safety signal. Conditioned inhibition paradigms may have utility in the ongoing study of safety learning and its relevance to anxious psychopathology. • Safety learning was compared between a conditioned inhibitor and a conventional CS-. • Both inhibited threat responses at test, but the inhibitor showed greater suppression of US-expectancy ratings. • The inhibitor was easily re-learned as threatening when subsequently reinforced, contrary to conventional theory. • US-expectancy to the conditioned inhibitor was associated with higher trait anxiety. [ABSTRACT FROM AUTHOR]