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Objective: Subclinical or subthreshold depressive symptoms (StD) are frequent in adolescence and are related to suicidality and onset of depression in adulthood, however, their neurobiology is poorly understood. We examined the relationship between StD and subcortical grey matter structures in unmedicated adolescents with no history of axis I diagnosis., Methods: 277 youths from Chicago aged 14 years participated, undergoing a structural MRI scan and completing the Revised Children's Anxiety and Depression Scale (RCADS). Blood samples provided a composite of five pro-inflammatory cytokines. Regions of interest (ROI) for vertex-based surface analysis were the left and right amygdala, hippocampus, thalamus, caudate, nucleus accumbens, pallidum and putamen. Covariates were age, pubertal status, socioeconomic disadvantage and intracranial volume. Males and females were analysed separately., Results: StD had positive associations (outward shape) with subcortical morphology in the right amygdala and left hippocampus in females, and the bilateral putamen and the left caudate, hippocampus and thalamus in males. However, we also found negative associations with StD (inward contractions) in the hippocampus in females and the caudate in males. Pro-inflammatory cytokines did not mediate the relationship between StD and outward morphology or volume., Conclusion: This is one of the first studies to examine subcortical morphology of basal ganglia and thalamic regions related to StD in adolescents, and the first study to report mostly positive associations between StD, volume and outward morphology in youths. These findings could reflect intact neurogenesis or resilience to depression, however longitudinal research is needed to further understand the neurobiology of StD in adolescents., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Low socioeconomic status (SES) is associated with a higher probability of multiple exposures (e.g., neighborhood violence, poor nutrition, housing instability, air pollution, and insensitive caregiving) known to affect structural development of subcortical brain regions that subserve threat and reward processing, however, few studies have examined the relationship between SES and such subcortical structures in adolescents. We examined SES variations in volume and surface morphometry of subcortical regions. The sample comprised 256 youth in eighth grade (mean age = 13.9 years), in whom high dimensional deformation mapping of structural 3T magnetic resonance imaging scans was performed. Vertex-wise linear regression analyses examined associations between income to poverty ratio and surfaces of the hippocampus, amygdala, thalamus, caudate, putamen, nucleus accumbens and pallidum, with the covariates age, pubertal status, and intracranial volume. Given sex differences in pubertal development and subcortical maturation at this age, the analyses were stratified by sex. Among males, who at this age average an earlier pubertal stage than females, the relationship between SES and local shape variation in subcortical regions was almost entirely positive. For females, the relationship between SES and local shape variation was negative. Racial identity was associated with SES in our sample, however supplementary analyses indicated that most of the associations between SES and subcortical structure were independent of it. Although these cross-sectional results are not definitive, they are consistent with a scenario where low SES delays structural maturation of subcortical regions involved with threat and reward processing. Future longitudinal studies are needed to test this hypothesis., (© 2019 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)

The importance of the amygdala as a salience detector and in emotional learning is now well accepted. The mechanisms that regulate and inhibit the amygdala, however, are less well understood. This review provides evidence from imaging and lesion studies to support the role of the ventromedial prefrontal cortex (vmPFC) as a moderator and inhibitor of the amygdala. The dual inhibition model centres on the broadly defined ventromedial prefrontal cortex (vmPFC) and the distinct role of two of its subcomponents, the rostral anterior cingulate cortex and orbitofrontal cortex. The dual inhibition model posits that these two regions, along with their associated inhibitory pathways, must interact for adequate inhibitory control of the amygdala and emotional regulation. Following a description of the model's experimental support, it is then proposed as a neuropsychological mechanism for post-traumatic stress disorder (PTSD). Flashbacks, as a defining feature of PTSD, are described in terms of a subcortical orienting network. Finally, there is a discussion of how a neuropsychological understanding of post-traumatic stress disorder (PTSD) might inform a clinician's approach to treatment and how the dual inhibition model might have a more general application to understanding emotional dysregulation.

Background: Sex differences in emotion processing may play a role in women's increased risk for Major Depressive Disorder (MDD). However, studies of sex differences in brain mechanisms involved in emotion processing in MDD (or interactions of sex and diagnosis) are sparse., Methods: We conducted an event-related fMRI study examining the interactive and distinct effects of sex and MDD on neural activity during a facial emotion perception task. To minimize effects of current affective state and cumulative disease burden, we studied participants with remitted MDD (rMDD) who were early in the course of the illness. In total, 88 individuals aged 18-23 participated, including 48 with rMDD (32 female) and 40 healthy controls (HC; 25 female)., Results: fMRI revealed an interaction between sex and diagnosis for sad and neutral facial expressions in the superior frontal gyrus and left middle temporal gyrus. Results also revealed an interaction of sex with diagnosis in the amygdala., Limitations: Data was from two sites, which might increase variability, but it also increases power to examine sex by diagnosis interactions., Conclusions: This study demonstrates the importance of taking sex differences into account when examining potential trait (or scar) mechanisms that could be useful in identifying individuals at-risk for MDD as well as for evaluating potential therapeutic innovations., (Copyright © 2017 Elsevier B.V. All rights reserved.)

We present neuroimaging markers of the remitted state of major depressive disorder (rMDD) during facial emotion perception in 84 individuals during fMRI. Participants comprised 47 individuals (aged 18-23) diagnosed with rMDD and 37 healthy controls (HCs). Participants classified emotional faces or animals (control condition) in the Facial Emotion Perception Test (FEPT) during fMRI. Behavioural performance on the FEPT did not differ significantly between groups. During fMRI, both groups demonstrated significant blood oxygen level-dependent (BOLD) activity in bilateral inferior frontal gyri for the faces minus animals (F-A) contrast. The rMDD group additionally showed BOLD activity during F-A in numerous regions, including the bilateral paracingulate gyri, middle temporal gyri and right amygdala. The rMDD group exhibited significantly greater activity than the HC group in regions including the bilateral middle temporal gyri and left superior frontal gyrus. Although the rMDD group did not manifest the behavioural performance deficits on facial emotion recognition tasks that have been observed in actively depressed individuals, the rMDD group nevertheless showed increased BOLD activity compared with never-depressed controls during F-A in multiple posterior brain regions, suggesting that persistent effects of illness or possible trait vulnerabilities may distinguish individuals with rMDD from never-depressed controls., (© The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.)

Background: Recent meta-analyses of resting-state networks in major depressive disorder (MDD) implicate network disruptions underlying cognitive and affective features of illness. Heterogeneity of findings to date may stem from the relative lack of data parsing clinical features of MDD such as phase of illness and the burden of multiple episodes., Method: Resting-state functional magnetic resonance imaging data were collected from 17 active MDD and 34 remitted MDD patients, and 26 healthy controls (HCs) across two sites. Participants were medication-free and further subdivided into those with single v. multiple episodes to examine disease burden. Seed-based connectivity using the posterior cingulate cortex (PCC) seed to probe the default mode network as well as the amygdala and subgenual anterior cingulate cortex (sgACC) seeds to probe the salience network (SN) were conducted., Results: Young adults with remitted MDD demonstrated hyperconnectivity of the left PCC to the left inferior frontal gyrus and of the left sgACC to the right ventromedial prefrontal cortex (PFC) and left hippocampus compared with HCs. Episode-independent effects were observed between the left PCC and the right dorsolateral PFC, as well as between the left amygdala and right insula and caudate, whereas the burden of multiple episodes was associated with hypoconnectivity of the left PCC to multiple cognitive control regions as well as hypoconnectivity of the amygdala to large portions of the SN., Conclusions: This is the first study of a homogeneous sample of unmedicated young adults with a history of adolescent-onset MDD illustrating brain-based episodic features of illness.

Objective: Functional connectivity MRI (fcMRI) studies of individuals currently diagnosed with major depressive disorder (MDD) document hyperconnectivities within the default mode network (DMN) and between the DMN and salience networks (SN) with regions of the cognitive control network (CCN). Studies of individuals in the remitted state are needed to address whether effects derive from trait, and not state or chronic burden features of MDD., Method: fcMRI data from two 3.0 Tesla GE scanners were collected from 30 unmedicated (47% medication naïve) youth (aged 18-23, modal depressive episodes = 1, mean age of onset = 16.2, SD = 2.6) with remitted MDD (rMDD; modal years well = 4) and compared with data from 23 healthy controls (HCs) using four bilateral seeds in the DMN and SN (posterior cingulate cortex (PCC), subgenual anterior cingulate (sgACC), and amygdala), followed by voxel-based comparisons of the whole brain., Results: Compared to HCs, rMDD youth exhibited hyperconnectivities from both PCC and sgACC seeds with lateral, parietal, and frontal regions of the CCN, extending to the dorsal medial wall. A factor analysis reduced extracted data and a PCC factor was inversely correlated with rumination among rMDD youth. Two factors from the sgACC hyperconnectivity clusters were related to performance in cognitive control on a Go/NoGo task, one positively and one inversely., Conclusions: Findings document hyperconnectivities of the DMN and SN with the CCN (BA 8/10), which were related to rumination and sustained attention. Given these cognitive markers are known predictors of response and relapse, hyperconnectivities may increase relapse risk or represent compensatory mechanisms.