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Internalizing and externalizing problems that emerge during adolescence differentially increase boys’ and girls’ risk for developing psychiatric disorders. It is not clear, however, whether there are sex differences in the intrinsic functional architecture of the brain that underlie changes in the severity of internalizing and externalizing problems in adolescents. Using resting-state fMRI data and self-reports of behavioral problems obtained from 128 adolescents (73 females; 9–14 years old) at two timepoints, we conducted multivoxel pattern analysis to identify resting-state functional connectivity markers at baseline that predict changes in the severity of internalizing and externalizing problems in boys and girls 2 years later. We found sex-differentiated involvement of the default mode network in changes in internalizing and externalizing problems. Whereas changes in internalizing problems were associated with the dorsal medial subsystem in boys and with the medial temporal subsystem in girls, changes in externalizing problems were predicted by hyperconnectivity between core nodes of the DMN and frontoparietal network in boys and hypoconnectivity between the DMN and affective networks in girls. Our results suggest that different neural mechanisms predict changes in internalizing and externalizing problems in adolescent boys and girls and offer insights concerning mechanisms that underlie sex differences in the expression of psychopathology in adolescence.

Background Psychosocial stressors characterized by social threat, such as interpersonal loss and social rejection, are associated with depression in adolescents. Few studies, however, have examined whether social threat affects fronto-cingulate-limbic systems implicated in adolescent depression. Methods We assessed lifetime stressor severity across several domains using the Stress and Adversity Inventory (STRAIN) in 57 depressed adolescents (16.15 ± 1.32 years, 34 females), and examined whether the severity of social threat and non-social threat stressors was associated with gray matter volumes (GMVs) in the anterior cingulate cortex (ACC), amygdala, hippocampus, and nucleus accumbens (NAcc). We also examined how lifetime social threat severity and GMVs in these regions related to depressive symptoms at baseline and over 9 months. Results General stressor severity was related to greater depression severity at baseline and over 9 months. Moreover, greater severity of social threat (but not non-social threat) stressors was associated with smaller bilateral amygdala and NAcc GMVs, and smaller bilateral surface areas of caudal and rostral ACC (all pFDR ⩽ 0.048). However, neither social threat nor non-social threat stressor severity was related to hippocampal GMVs (all pFDR ⩾ 0.318). All fronto-cingulate-limbic structures that were associated with the severity of social threat were negatively associated with greater depression severity over 9 months (all pFDR ⩽ 0.014). Post-hoc analyses suggested that gray matter morphometry of bilateral amygdala, NAcc, and rostral and caudal ACC mediated the association between social threat and depression severity in adolescents over 9 months (all pFDR < 0.048). Conclusions Social threat specifically affects fronto-cingulate-limbic pathways that contribute to the maintenance of depression in adolescents.

Background Efforts to develop neuroimaging-based biomarkers in major depressive disorder (MDD), at the individual level, have been limited to date. As diagnostic criteria are currently symptom-based, MDD is conceptualized as a disorder rather than a disease with a known etiology; further, neural measures are often confounded by medication status and heterogeneous symptom states. Methods We describe a consortium to quantify neuroanatomical and neurofunctional heterogeneity via the dimensions of novel multivariate coordinate system (COORDINATE-MDD). Utilizing imaging harmonization and machine learning methods in a large cohort of medication-free, deeply phenotyped MDD participants, patterns of brain alteration are defined in replicable and neurobiologically-based dimensions and offer the potential to predict treatment response at the individual level. International datasets are being shared from multi-ethnic community populations, first episode and recurrent MDD, which are medication-free, in a current depressive episode with prospective longitudinal treatment outcomes and in remission. Neuroimaging data consist of de-identified, individual, structural MRI and resting-state functional MRI with additional positron emission tomography (PET) data at specific sites. State-of-the-art analytic methods include automated image processing for extraction of anatomical and functional imaging variables, statistical harmonization of imaging variables to account for site and scanner variations, and semi-supervised machine learning methods that identify dominant patterns associated with MDD from neural structure and function in healthy participants. Results We are applying an iterative process by defining the neural dimensions that characterise deeply phenotyped samples and then testing the dimensions in novel samples to assess specificity and reliability. Crucially, we aim to use machine learning methods to identify novel predictors of treatment response based on prospective longitudinal treatment outcome data, and we can externally validate the dimensions in fully independent sites. Conclusion We describe the consortium, imaging protocols and analytics using preliminary results. Our findings thus far demonstrate how datasets across many sites can be harmonized and constructively pooled to enable execution of this large-scale project.

Emerging evidence suggests that obesity impacts brain physiology at multiple levels. Here we aimed to clarify the relationship between obesity and brain structure using structural MRI (n = 6420) and genetic data (n = 3907) from the ENIGMA Major Depressive Disorder (MDD) working group. Obesity (BMI > 30) was significantly associated with cortical and subcortical abnormalities in both mass-univariate and multivariate pattern recognition analyses independent of MDD diagnosis. The most pronounced effects were found for associations between obesity and lower temporo-frontal cortical thickness (maximum Cohen´s d (left fusiform gyrus) = −0.33). The observed regional distribution and effect size of cortical thickness reductions in obesity revealed considerable similarities with corresponding patterns of lower cortical thickness in previously published studies of neuropsychiatric disorders. A higher polygenic risk score for obesity significantly correlated with lower occipital surface area. In addition, a significant age-by-obesity interaction on cortical thickness emerged driven by lower thickness in older participants. Our findings suggest a neurobiological interaction between obesity and brain structure under physiological and pathological brain conditions.

Researchers have begun to examine the psychological toll of the ongoing global COVID-19 pandemic. Data are now emerging indicating that there may be long-term adverse effects of the pandemic on new mothers and on children born during this period. In a longitudinal study of maternal mental health and child emotional development during the pandemic, we conducted online assessments of a cohort of women at two time points: when they were pregnant at the beginning of the surge of the pandemic in the United States (baseline,N= 725), and approximately 1 year postpartum (follow-up,N= 296), examining prenatal and postnatal maternal mental health, prenatal pandemic-related stress, and infant temperament. Pandemic-related stress at baseline was associated with concurrent depressive symptoms and infant negative affect at follow-up. Baseline maternal depressive symptoms were associated with follow-up depressive symptoms, which in turn were also associated with infant negative affect. Pandemic-related stress during pregnancy may have enduring effects on infant temperament. These findings have important implications for our understanding of the emotional development of children who werein uteroduring the COVID-19 pandemic.

Background Suicidal ideation (SI) typically emerges during adolescence but is challenging to predict. Given the potentially lethal consequences of SI, it is important to identify neurobiological and psychosocial variables explaining the severity of SI in adolescents. Methods In 106 participants (59 female) recruited from the community, we assessed psychosocial characteristics and obtained resting-state fMRI data in early adolescence (baseline: aged 9-13 years). Across 250 brain regions, we assessed local graph theory-based properties of interconnectedness: local efficiency, eigenvector centrality, nodal degree, within-module z-score, and participation coefficient. Four years later (follow-up: ages 13-19 years), participants self-reported their SI severity. We used least absolute shrinkage and selection operator (LASSO) regressions to identify a linear combination of psychosocial and brain-based variables that best explain the severity of SI symptoms at follow-up. Nested-cross-validation yielded model performance statistics for all LASSO models. Results A combination of psychosocial and brain-based variables explained subsequent severity of SI (R2 = .55); the strongest was internalizing and externalizing symptom severity at follow-up. Follow-up LASSO regressions of psychosocial-only and brain-based-only variables indicated that psychosocial-only variables explained 55% of the variance in SI severity; in contrast, brain-based-only variables performed worse than the null model. Conclusions A linear combination of baseline and follow-up psychosocial variables best explained the severity of SI. Follow-up analyses indicated that graph theory resting-state metrics did not increase the prediction of the severity of SI in adolescents. Attending to internalizing and externalizing symptoms is important in early adolescence; resting-state connectivity properties other than local graph theory metrics might yield a stronger prediction of the severity of SI.

The COVID-19 pandemic is a unique period of stress, uncertainty, and adversity that will have significant implications for adolescent mental health. Nevertheless, stress and adversity related to COVID-19 may be more consequential for some adolescents’ mental health than for others. We examined whether heart rate variability (HRV) indicated differential susceptibility to mental health difficulties associated with COVID-19 stress and COVID-19 family adversity. Approximately 4 years prior to the pandemic, we assessed resting HRV and HRV reactivity to a well-validated stress paradigm in 87 adolescents. During the pandemic, these adolescents (ages 13–19) reported on their health-related stress and concerns about COVID-19, family adversity related to COVID-19, and their recent emotional problems. The association between COVID-19 stress and emotional problems was significantly stronger for adolescents who previously exhibited higher resting HRV or higher HRV reactivity. For adolescents who exhibited lower resting HRV or HRV augmentation, COVID-19 stress was not associated with emotional problems. Conversely, lower resting HRV indicated vulnerability to the effect of COVID-19 family adversity on emotional problems. Different patterns of parasympathetic functioning may reflect differential susceptibility to the effects of COVID-19 stress versus vulnerability to the effects of COVID-19 family adversity on mental health during the pandemic.

BACKGROUND: Given the high prevalence of depressive symptoms reported by adolescents and associated risk of experiencing psychiatric disorders as adults, differentiating the trajectories of the symptoms related to negative valence at an individual level could be crucial in gaining a better understanding of their effects later in life. METHODS: A longitudinal deep learning framework is presented, identifying self-reported and behavioral measurements that detect the depressive symptoms associated with the Negative Valence System domain of the NIMH Research Domain Criteria (RDoC). RESULTS: Applied to the annual records of 621 participants (age range: 12 to 17 years) of the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA), the deep learning framework identifies predictors of negative valence symptoms, which include lower extraversion, poorer sleep quality, impaired executive control function and factors related to substance use. LIMITATIONS: The results rely mainly on self-reported measures and do not provide information about the underlying neural correlates. Also, a larger sample is required to understand the role of sex and other demographics related to the risk of experiencing symptoms of negative valence. CONCLUSIONS: These results provide new information about predictors of negative valence symptoms in individuals during adolescence that could be critical in understanding the development of depression and identifying targets for intervention. Importantly, findings can inform preventive and treatment approaches for depression in adolescents, focusing on a unique predictor set of modifiable modulators to include factors such as sleep hygiene training, cognitive-emotional therapy enhancing coping and controllability experience and/or substance use interventions.

Background Suicidal behaviours are a major source of mortality and morbidity among adolescents. Given the maturational changes that occur in cortical and subcortical structures during adolescence, we tested whether atypical brain structural measurements were associated with a history of suicide attempt. Methods We assessed 3 groups of adolescents (n = 92; 79% female, mean age 15.9 years, range 11.6-18.1 years): patients with a depressive disorder and a history of suicide attempt (n = 28); patient controls, who had a depressive disorder but no history of suicide attempt (n = 34); and healthy controls (n = 30). We derived regional cortical thickness and surface area, and subcortical volumes, from T1-weighted anatomic MRI scans acquired at 3 T. Results We found significant group differences in surface area in the prefrontal, temporal and parietal regions, as well as in the volume of several subcortical nuclei (pFDR ≤ 0.05), but not in cortical thickness. Post hoc analyses indicated that morphological alterations primarily differentiated patients with a history of suicide attempt from healthy controls, but not from patient controls. However, patients with a history of suicide attempt exhibited positive correlations between age and cortical thickness in the temporal cortices and right insula, and between age and right putamen volume (i.e., thicker regional cortex and larger subcortical volumes with age). These correlations were negative in both patient controls and healthy controls (i.e., thinner regional cortex and smaller subcortical volumes). Limitations Sample sizes, cross-sectional findings and psychiatric heterogeneity were limitations of this study. Conclusion Macroscopic structural differences in several brain regions differentiated adolescents with a history of suicide attempt from healthy controls, but not from patient controls. However, adolescents with a history of suicide attempt may present with atypical maturation of specific cortical and subcortical regions that might contribute to the risk of suicidal behaviour.

BackgroundPregnant women may be especially susceptible to negative events (i.e. adversity) related to the coronavirus disease 2019 (COVID-19) pandemic and negative affective responses to these events (i.e. stress). We examined the latent structure of stress and adversity related to the COVID-19 pandemic among pregnant women, potential antecedents of COVID-19-related stress and adversity in this population, and associations with prenatal depressive symptoms.MethodWe surveyed 725 pregnant women residing in the San Francisco Bay Area in March−May 2020, 343 of whom provided addresses that were geocoded and matched by census tract to measures of community-level risk. We compared their self-reported depressive symptoms to women matched on demographic factors and history of mental health difficulties who were pregnant prior to the pandemic.ResultsWomen who were pregnant during the pandemic were nearly twice as likely to have possible depression than were matched women who were pregnant prior to the pandemic. Individual- and community-level factors tied to socioeconomic inequality were associated with latent factors of COVID-19-related stress and adversity. Beyond objective adversity, subjective stress responses were strongly associated with depressive symptoms during the pandemic.ConclusionsHighlighting the role of subjective responses in vulnerability to prenatal depression and factors that influence susceptibility to COVID-19-related stress, these findings inform the allocation of resources to support recovery from this pandemic and future disease outbreaks. In addition to policies that mitigate disruptions to the environment due to the pandemic, treatments that focus on cognitions about the self and the environment may help to alleviate depressive symptoms in pregnant women.

Background Maternal depression is prevalent during and following pregnancy and is related to adverse outcomes in offspring. Perinatal depression is associated with risk for difficulties in offspring; however, the mechanisms underlying this association are not clear. We examined whether maternal prenatal and postnatal depressive symptoms were associated with infant white matter organization and with behavioral problems in toddlerhood. Methods 37 mother–infant dyads (20 male; ages 5.95–7.66 months) participated in this study. We conducted diffusion MRI with infants during natural sleep. Mothers reported on their prenatal and postnatal depressive symptoms at six months postpartum. We calculated fractional anisotropy (FA), radial, axial, and mean diffusivity, and assessed offspring behavioral problems at age 18 months. Results Prenatal depressive symptoms were associated with FA of the corpus callosum; postnatal depressive symptoms were not associated with FA of limbic tracts or corpus callosum segmentations. Higher levels of prenatal depressive symptoms were associated with higher FA and lower radial diffusivity of the corpus callosum genu; FA of this region was positively associated with behavioral problems at age 18 months. Limitations This study had a small sample size; therefore, findings should be replicated. Further, we used retrospective reports of maternal prenatal depression, but validated them in this study. Conclusions Depressive symptoms during pregnancy may affect infant corpus callosum development and, in turn, offspring behaviors. These findings suggest that early maternal stress accelerates infant neurodevelopment in a manner that may increase risk for behavioral problems. Thus, efforts to reduce maternal prenatal depression should be a public health priority.

BACKGROUND: Objective biomarkers of cognitive vulnerabilities related to suicidal ideation (SI) may assist in early prevention in adolescents. Previously, we found that smaller gray matter volumes (GMVs) of the dorsal striatum prospectively predicted implicit SI, measured using a computerized implicit association test (IAT) assessing associations between “self” and “death,” in a community sample of adolescents. Here, we sought to replicate these findings in an independent sample of depressed adolescents. METHODS: 53 depressed adolescents who varied in severity of suicidal thoughts and behaviors completed high-resolution structural MRI. Caudate, putamen, and nucleus accumbens GMVs were estimated using FreeSurfer 6.0. Robust linear regressions were used to examine associations between striatal GMVs and implicit and explicit SI, covarying for sex, age, total intracranial volume, medication use, and depression severity. Significance was determined using Bonferroni correction. Finally, LASSO regression was used to identify which striatal GMV contributed most to prediction of SI. RESULTS: Smaller bilateral caudate and right nucleus accumbens GMVs were associated with stronger IAT scores (all ps

BackgroundMajor depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in MDD patients, and whether this process is associated with clinical characteristics in a large multi-center international dataset.MethodsWe performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 29 samples worldwide. Normative brain aging was estimated by predicting chronological age (10-75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 1,147 male and 1,386 female controls from the ENIGMA MDD working group. The learned model parameters were applied to 1,089 male controls and 1,167 depressed males, and 1,326 female controls and 2,044 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted “brain age” and chronological age was calculated to indicate brain predicted age difference (brain-PAD).FindingsOn average, MDD patients showed a higher brain-PAD of +0.90 (SE 0.21) years (Cohen’s d=0.12, 95% CI 0.06-0.17) compared to controls. Relative to controls, first-episode and currently depressed patients showed higher brain-PAD (+1.2 [0.3] years), and the largest effect was observed in those with late-onset depression (+1.7 [0.7] years). In addition, higher brain-PAD was associated with higher self-reported depressive symptomatology (b=0.05, p=0.004).InterpretationThis highly powered collaborative effort showed subtle patterns of abnormal structural brain aging in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the predictive value of these brain-PAD estimates.FundingThis work was supported, in part, by NIH grants U54 EB020403 and R01 MH116147.

PURPOSE OF REVIEW: In this review we provide an overview of definitions and determinants of resilience in the context of neuroimaging research in Major Depressive Disorder (MDD). We summarize emerging literature on functional neuroimaging biomarkers of resilience in MDD and discuss their clinical relevance and implications for future research. RECENT FINDINGS: Resilience in MDD is characterized by dissociable profiles of activation and functional connectivity within brain networks involved in cognitive control, emotion regulation, and reward processing. Increased activation of frontal cortical brain regions implicated in cognitive appraisal and emotion regulation is a common characteristic of resilient individuals at high risk for MDD and of individuals with MDD with a favorable illness course. Furthermore, significant associations between fronto-striato-limbic functional connectivity and both positively-interpreted stressful life events in resilient high-risk individuals and a favorable response to first-line treatments in depressed individuals suggest that neuro-compensatory changes and experience-dependent plasticity underlie resilience in MDD. SUMMARY: Emerging research has identified putative functional neuroimaging biomarkers of resilience in MDD. A continued focus on identifying neurobiological underpinnings of resilience, in the context of dynamic environmental and developmental influences on MDD, will advance our understanding of resilience in this disorder and improve approaches to prevention and treatment.

Objective Early life stress (ELS) is associated with increased risk for the development of major depressive disorder (MDD) in adulthood; however, the degree to which ELS is associated with an early onset of MDD (ie, during childhood or adolescence) is not known. In this meta-analysis, we estimated the associations between ELS and the risk for onset of MDD before age 18 years. In addition, we examined the associations between eight specific forms of ELS (ie, sexual abuse, physical abuse, poverty, physical illness/injury, death of a family member, domestic violence, natural disaster, and emotional abuse) and risk for youth-onset MDD. Method We conducted a systematic search in scientific databases for studies that assessed both ELS and the presence or absence of MDD before age 18 years. We identified 62 journal articles with a total of 44,066 unique participants. We assessed study quality using the Newcastle−Ottawa Scale. When heterogeneous effect sizes were detected, we tested whether demographic and/or methodological factors moderated the association between ELS and MDD. Results Using a random-effects meta-analysis, we found that individuals who experienced ELS were more likely to develop MDD before the age of 18 years than were individuals without a history of ELS (odds ratio = 2.50; 95% confidence interval 2.08, 3.00). Separate meta-analyses revealed a range of associations with MDD: whereas some types of ELS (eg, poverty) were not associated with MDD, other types (eg, emotional abuse) were associated more strongly with MDD than was ELS considered more broadly. Conclusion These findings provide important evidence that the adverse effect of ELS on MDD risk manifests early in development, prior to adulthood, and varies by type of ELS.

Altered regulation of diurnal cortisol has been associated with both dimensional symptoms and clinical diagnoses of attention deficit-hyperactivity disorder (ADHD). Indeed, a recent meta-analysis suggests that lower diurnal cortisol output may be a biomarker of attention deficit-hyperactivity disorder (ADHD); importantly, however, the influence of psychiatric comorbidities on this association has not been characterized. Approximately two-thirds of children with ADHD have at least one co-occurring neuropsychiatric condition, and altered HPA-axis function has been implicated in many of these conditions. Using dimensional measures of psychopathology, we examined whether comorbid symptoms influence the association of ADHD symptoms with daily cortisol output.138 adolescents (ages 11-15 years) completed measures of symptoms of psychopathology and provided saliva samples over two days. We analyzed whether ADHD symptoms were related to morning, afternoon, and evening cortisol, the cortisol awakening response (CAR) and cumulative daily cortisol (area under the curve with respect to ground [AUCg]) while accounting for symptoms of three psychiatric disorders that are commonly comorbid with ADHD: conduct disorder (CD), anxiety, and depression. In sensitivity analyses, we included symptoms of oppositional defiant disorder (ODD) in place of CD symptoms.After controlling for symptoms of CD, anxiety, and depression, ADHD symptoms were associated significantly with higher cumulative diurnal cortisol (AUCg), morning cortisol, and afternoon cortisol. Symptoms of CD, anxiety and depression were not associated significantly with any cortisol metrics; however, in sensitivity analyses, ODD symptoms were associated with lower AUCg and morning cortisol.Our findings highlight the distinct influence of ADHD and externalizing symptoms on cortisol output. Further work is needed to examine the specificity of altered HPA-axis activity as a biomarker of ADHD and to elucidate whether symptoms of ADHD differ in their association with diurnal cortisol as a function of their severity.

Background Mental disorders are currently the greatest global health burden. The coronavirus diseases 2019 (COVID-19) pandemic is having an adverse impact on people's mental health, particularly in vulnerable populations, such as refugees. Aims The present study was designed to examine the association between COVID-19 and changes in mental health in Syrian refugees in Turkey. Method We conducted a two-wave panel survey of a representative sample of 302 of the estimated 500 000 Syrian refugees (ages 18 and older) living under humanitarian support in Istanbul (first wave between 9 and 15 July 2020 and the follow-up between 11 and 14 September 2020). We administered seven items from the CoRonavIruS Health Impact Survey in addition to one-context specific item about life changes because of COVID-19, and measures of depression (10-item Center for Epidemiologic Study Depression Scale, CESD-10), anxiety (6-item State-Trait Anxiety Inventory, STAI-6) and perceived stress (Perceived Stress Scale, PSS-4). Results A factor analysis yielded three COVID-19 factors, labelled ‘social relationships’, ‘stress’ and ‘hope.’ We conducted a series of cross-lag panel analyses to test associations between the COVID-19 factors and mental health. We found associations between all COVID-19 factors and CESD-10, between COVID-19 ‘stress’ and STAI-6, and between COVID-19 ‘stress’ and COVID-19 ‘hope’ and PSS-4. Conclusions Our measures of life changes because of the COVID-19 pandemic are associated with changes in the mental health of Syrian refugees living in Istanbul. It is therefore important that they are provided with services to reduce what may be particularly debilitating consequences of COVID-19.

Depression is a chronic and debilitating condition that often emerges during adolescence, a period of significant brain maturation. Few studies, however, have examined how mechanisms of neuroplasticity, including myelination, are affected by adolescent-onset depression. Here, we used multimodal MR imaging to characterize myelin, indexed by R1, in white matter tracts previously associated with depression and compare 48 adolescents with lifetime depression (45 with current depression, 3 remitted) and 35 healthy controls in R1. Compared to healthy controls, R1 was higher in adolescents with lifetime depression in the uncinate fasciculus and corpus callosum genu (all βs > 0.42; all ps 0.86; all ps 0.82; all ps 0.32). While fractional anisotropy (FA), a commonly examined measure of white matter organization based on diffusion-weighted MRI, in the left uncinate was positively associated with lifetime depression in our sample (β = 0.56; p = 0.016), we found no evidence of sex-specific effects of depression in FA. Our results suggest that R1 is more sensitive to sex-specific effects of depression than FA, particularly in female adolescents. Given evidence that myelin inhibits synapse formation and reduces brain plasticity, our findings implicate experience-driven regional myelination as a mechanism underlying depression during periods of significant neural maturation such as adolescence.

OBJECTIVE: Exposure to high levels of fine particle air pollution (PM(2.5)) is associated with adolescent pathophysiology. It is unclear, however, if PM(2.5) is associated with physiology within psychosocial contexts, such as social stress, and whether some adolescents are particularly vulnerable to PM(2.5) -related adverse effects. This study examined the association between PM(2.5) and autonomic reactivity to social stress in adolescents and tested whether symptoms of anxiety and depression moderated this association. METHODS: Adolescents from Northern California (n=144) participated in a modified Trier Social Stress Test (TSST) while providing high-frequency heart rate variability (HRV) and skin conductance level (SCL) data. PM(2.5) data were recorded from CalEnviroScreen. Adolescents reported on their own symptoms of anxiety and depression using the Youth Self-Report, which has been used in prior studies and has good psychometric properties (Cronbach’s alpha in this sample was 0.86). RESULTS: Adolescents residing in neighborhoods characterized by higher concentrations of PM(2.5) demonstrated greater autonomic reactivity (i.e., indexed by lower HRV and higher SCL) (β=.27; b=0.44, p=.001, 95% CI [0.19, 0.68]) in response to social stress; this association was not accounted for by socioeconomic factors. In addition, adolescents who reported more severe anxiety and depression symptoms showed the strongest association between PM(2.5) and autonomic reactivity to social stress (β=.53; b=0.86, p

Background Dysfunctional reward processing is a core feature of major depressive disorder. While there is growing knowledge of reward processing in adolescent depression, researchers have ignored neural mechanisms of resilience to depression. Here, we examine neural correlates of reward processing that characterize resilience and risk in adolescents at risk for depression, facilitating the development of effective intervention approaches that strengthen resilience to psychopathology in at-risk youth. Methods 50 adolescent females were followed through age 18: 32 at-risk adolescents who either did (remitted-depressed; n = 15) or did not (resilient; n = 17) experience a depressive episode, and 18 low-risk healthy controls. Participants completed clinical assessments at 18-month intervals and an fMRI reward-processing task in late adolescence. We conducted predictive modeling with a priori reward regions of interest (ROIs). Results At-risk resilient and remitted-depressed adolescents exhibited less striatal activation than did controls during anticipation of reward. Resilient adolescents exhibited greater activation than did remitted-depressed adolescents in the middle frontal gyrus during reward anticipation, and less activation in the superior frontal gyrus and cuneus during processing of reward outcome. Using predictive modeling, ventral anterior cingulate cortex and putamen activation during reward processing distinguished resilient from remitted-depressed adolescents with 83% accuracy. Limitations The relatively small sample size of only females and the fact that fMRI data were obtained at one time point in late adolescence are limitations. Conclusions Distinct patterns of neural activation in reward circuitry appear to be markers of risk and resilience that may be targets for prevention and treatment approaches aimed at strengthening adaptive reward processing in at-risk adolescents.

The nature and consequences of threat in the caregiving environment have been widely studied and discussed. The construct of psychosocial neglect, however, has received less attention. In this paper, we advance a novel framework for examining the nature and consequences of neglect, which we posit can be represented as variations along a continuum from severe psychosocial neglect to environmental enrichment. Recognizing that caregiving is multi-dimensional, we conceptualize enriching input from caregivers as falling along two dimensions. Specifically, we propose that caregivers vary in their provision of emotional and cognitive input, and that the effects of this input on child development are moderated by caregiver sensitivity. Further, we present preliminary data indicating that emotional and cognitive input are separable. Conceptualizing the caregiving environment along these two dimensions advances the field in terms of (1) characterizing variation in early life experience; (2) understanding predictors of child developmental outcomes; and (3) identifying optimal targets for interventions to improve the well-being of children.

Background Suicidal ideation (SI) is an important predictor of suicide attempt, yet SI is difficult to predict. Given that SI begins in adolescence when brain networks are maturing, it is important to understand associations between network functioning and changes in severity of SI. Methods Thirty-three depressed adolescents were administered the Columbia-Suicide Severity Rating Scale to assess SI and completed resting-state fMRI at baseline (T1) and 6 months later (T2). We computed coherence in the executive control (ECN), default mode (DMN), salience (SN), and non-relevant noise networks and then examined the association between changes in brain network coherence and changes in SI severity from T1 to T2. Results A greater reduction in severity of SI was associated with a stronger increase in SN coherence from T1 to T2. There were no associations between the other networks and SI. Limitations We cannot generalize our findings to more psychiatrically diverse samples. More time-points are necessary to understand the trajectory of SI and SN coherence change. Conclusions Our finding that reductions in SI are associated with increases in SN coherence extends previous cross-sectional results documenting a negative association between SI severity and SN coherence. The SN is involved in coordinating activation of ECN and DMN in response to salient information. Given this regulatory role of the SN, the association between SN coherence and SI suggests that adolescents with reduced SN coherence might more easily engage in harmful thoughts. Thus, the SN may be particularly relevant as a target for treatment applications in depressed adolescents.

Animal models of stress and related conditions, including depression, have shown that elevated peripheral levels of inflammatory cytokines have downstream consequences on glutamate (Glu) in the brain. Although studies in human adults with depression have reported evidence of higher inflammation but lower Glu in the anterior cingulate cortex (ACC), the extent to which peripheral inflammation contributes to glutamatergic abnormalities in adolescents with depression is not well-understood. It is also unclear whether antioxidants, such as ascorbate (Asc), may buffer against the effects of inflammation on Glu metabolism. Fifty-five depressed adolescents were recruited in the present cross-sectional study and provided blood samples, from which we assayed pro-inflammatory cytokines, and underwent a short-TE proton magnetic spectroscopy scan at 3T, from which we estimated Glu and Asc in the dorsal ACC. In the 31 adolescents with usable cytokine and Glu data, we found that IL-6 was significantly positively associated with dorsal ACC Glu (β = 0.466 ± 0.199, p = 0.029). Of the 16 participants who had usable Asc data, we found that at higher levels of dorsal ACC Asc, there was a negative association between IL-6 and Glu (interaction effect: β = −0.906 ± 0.433, p = 0.034). Importantly, these results remained significant when controlling for age, gender, percentage of gray matter in the dorsal ACC voxel, BMI, and medication (antidepressant and anti-inflammatory) usage. While preliminary, our results underscore the importance of examining both immune and neural contributors to depression and highlight the potential role of anti-inflammatory compounds in mitigating the adverse effects of inflammation (e.g., glutamatergic neuroexcitotoxicity). Future studies that experimentally manipulate levels of inflammation, and of ascorbate, and that characterize these effects on cortical glutamate concentrations and subsequent behavior in animals and in humans are needed.

Childhood adversity and anxiety have been associated with increased risk for internalizing disorders later in life and with a range of brain structural abnormalities. However, few studies have examined the link between harsh parenting practices and brain anatomy, outside of severe maltreatment or psychopathology. Moreover, to our knowledge, there has been no research on parenting and subclinical anxiety symptoms which remain persistent over time during childhood (i.e., between 2.5 and 9 years old). Here, we examined data in 94 youth, divided into four cells based on their levels of coercive parenting (high / low) and of anxiety (high / low) between 2.5 and 9 years old. Anatomical images were analyzed using voxel-based morphometry (VBM) and FreeSurfer. Smaller gray matter volumes in the prefrontal cortex regions and in the amygdala were observed in youth with high versus low levels of harsh parenting over time. In addition, we observed significant interaction effects between parenting practices and subclinical anxiety symptoms in rostral anterior cingulate cortical thickness and in amygdala volume. These youth should be followed further in time to identify which youth will or will not go on to develop an anxiety disorder, and to understand factors associated with the development of sustained anxiety psychopathology.

Social anxiety disorder (SAD) is commonly diagnosed during adolescence and is associated with psychological stress reactivity and heightened physiological arousal. No study, however, has systematically examined which aspects of autonomic nervous system function mediate likely links between stress sensitivity and social anxiety symptoms in adolescents. Here, we assessed 163 adolescents (90 females; 12.29 ± 1.39 years) with respect to life stress and social anxiety symptoms, and measured respiratory sinus arrhythmia (RSA) and skin conductance levels (SCL) during a psychosocial stress paradigm. We operationalized stress sensitivity as the residual variance in subjective stress severity after accounting for objective severity and changes in autonomic regulation using standardized change scores in RSA and SCL. In females only, stress sensitivity and social anxiety symptoms were significantly correlated with each other (p < .001) and with autonomic regulation during both reactivity and recovery (all ps < 0.04). Further, sympathetic nervous system dominance during recovery specifically mediated associations between stress sensitivity and social anxiety symptoms (B = 1.06, 95% CI: 0.02–2.64). In contrast, in males, stress sensitivity, autonomic regulation during reactivity or recovery, and social anxiety symptoms were not significantly associated (all ps > 0.1). We interpret these results in the context of psychobiological models of SAD and discuss implications for interventions targeting autonomic processes.

Suicidal ideation (SI) and non-suicidal self-injury (NSSI) are two distinct yet often co-occurring risk factors for suicide deaths in adolescents. Elucidating the neurobiological patterns that specifically characterize SI and NSSI in adolescents is needed to inform the use of these markers in intervention studies and to develop brain-based treatment targets. Here, we clinically assessed 70 adolescents—49 adolescents with depression and 21 healthy controls—to determine SI and NSSI history. Twenty-eight of the depressed adolescents had a history of SI and 29 had a history of NSSI (20 overlapping). All participants underwent a resting-state fMRI scan. We compared groups in network coherence of subdivisions of the central executive network (CEN), default mode network (DMN), and salience network (SN). We also examined group differences in between-network connectivity and explored brain-behavior correlations. Depressed adolescents with SI and with NSSI had lower coherence in the ventral DMN compared to those without SI or NSSI, respectively, and healthy controls (all ps ps ps ps

Emerging evidence suggests that obesity impacts brain physiology at multiple levels. Here we aimed to clarify the relationship between obesity and brain structure using structural MRI (n = 6420) and genetic data (n = 3907) from the ENIGMA Major Depressive Disorder (MDD) working group. Obesity (BMI > 30) was significantly associated with cortical and subcortical abnormalities in both mass-univariate and multivariate pattern recognition analyses independent of MDD diagnosis. The most pronounced effects were found for associations between obesity and lower temporo-frontal cortical thickness (maximum Cohen´s d (left fusiform gyrus) = −0.33). The observed regional distribution and effect size of cortical thickness reductions in obesity revealed considerable similarities with corresponding patterns of lower cortical thickness in previously published studies of neuropsychiatric disorders. A higher polygenic risk score for obesity significantly correlated with lower occipital surface area. In addition, a significant age-by-obesity interaction on cortical thickness emerged driven by lower thickness in older participants. Our findings suggest a neurobiological interaction between obesity and brain structure under physiological and pathological brain conditions.

Background Adolescence is a period of high risk for the onset of depression, characterized by variability in symptoms, severity, and course. During adolescence, the neurocircuitry implicated in depression continues to mature, suggesting that it is an important period for intervention. Reflecting the recent emergence of 'precision mental health' - a person-centered approach to identifying, preventing, and treating psychopathology - researchers have begun to document associations between heterogeneity in features of depression and individual differences in brain circuitry, most frequently in resting-state functional connectivity (RSFC). Methods In this review, we present emerging work examining pre- and post-treatment measures of network connectivity in depressed adolescents; these studies reveal potential intervention-specific neural markers of treatment efficacy. We also review findings from studies examining associations between network connectivity and both types of depressive symptoms and response to treatment in adults, and indicate how this work can be extended to depressed adolescents. Finally, we offer recommendations for research that we believe will advance the science of precision mental health of adolescence. Results Nascent studies suggest that linking RSFC-based pathophysiological variation with effects of different types of treatment and changes in mood following specific interventions will strengthen predictions of prognosis and treatment response. Studies with larger sample sizes and direct comparisons of treatments are required to determine whether RSFC patterns are reliable neuromarkers of treatment response for depressed adolescents. Although we are not yet at the point of using RSFC to guide clinical decision-making, findings from research examining the stability and reliability of RSFC point to a favorable future for network-based clinical phenotyping. Conclusions Delineating the correspondence between specific clinical characteristics of depression (e.g., symptoms, severity, and treatment response) and patterns of network-based connectivity will facilitate the development of more tailored and effective approaches to the assessment, prevention, and treatment of depression in adolescents.

It has been difficult to find robust brain structural correlates of the overall severity of major depressive disorder (MDD). We hypothesized that specific symptoms may better reveal correlates and investigated this for the severity of insomnia, both a key symptom and a modifiable major risk factor of MDD. Cortical thickness, surface area and subcortical volumes were assessed from T1-weighted brain magnetic resonance imaging (MRI) scans of 1053 MDD patients (age range 13-79 years) from 15 cohorts within the ENIGMA MDD Working Group. Insomnia severity was measured by summing the insomnia items of the Hamilton Depression Rating Scale (HDRS). Symptom specificity was evaluated with correlates of overall depression severity. Disease specificity was evaluated in two independent samples comprising 2108 healthy controls, and in 260 clinical controls with bipolar disorder. Results showed that MDD patients with more severe insomnia had a smaller cortical surface area, mostly driven by the right insula, left inferior frontal gyrus pars triangularis, left frontal pole, right superior parietal cortex, right medial orbitofrontal cortex, and right supramarginal gyrus. Associations were specific for insomnia severity, and were not found for overall depression severity. Associations were also specific to MDD; healthy controls and clinical controls showed differential insomnia severity association profiles. The findings indicate that MDD patients with more severe insomnia show smaller surfaces in several frontoparietal cortical areas. While explained variance remains small, symptom-specific associations could bring us closer to clues on underlying biological phenomena of MDD.

Attachment security may be a mechanism by which exposure to early life adversity affects subsequent generations. We used a prospective cohort design to examine this possibility in a convenience sample of 124 women (age = 23–45 years, M = 32.32 [SD = 4.83] years; 57.3% White, 22.6% Asian) who provided self-reports of attachment style during pregnancy using the Attachment Style Questionnaire, of whom 96 (age = 28–50 years, M = 36.67 [SD = 4.90] years; 60.4% White, 19.8% Asian) were reassessed when their child was preschool-age (M = 4.38 [SD = 1.29] years). Women self-reported on their own childhood maltreatment severity and their child’s current emotional and behavioral problems using the Childhood Trauma Questionnaire and the Child Behavior Checklist for ages 1.5–5, respectively. Maternal childhood maltreatment severity was associated with less secure, and more avoidant and anxious attachment. Mediation analyses revealed further that less secure maternal attachment, but not avoidant or anxious attachment, mediated the associations between maternal childhood maltreatment and offspring emotional and behavioral problems. These findings suggest that improving maternal attachment security, which can be identified even prior to the child’s birth, is an important target to consider for intervention efforts aimed at minimizing adverse intergenerational effects of early life adversity.

Suicide is the second leading cause of death among adolescents. While clinicians and researchers have begun to recognize the importance of considering multidimensional factors in understanding risk for suicidal thoughts and behaviors (STBs) during this developmental period, the role of puberty has been largely ignored. In this review, we contend that the hormonal events that occur during puberty have significant effects on the organization and development of brain systems implicated in the regulation of social stressors, including amygdala, hippocampus, striatum, medial prefrontal cortex, orbitofrontal cortex, and anterior cingulate cortex. Guided by previous experimental work in adults, we also propose that the influence of pubertal hormones and social stressors on neural systems related to risk for STBs is especially critical to consider in adolescents with a neurobiological sensitivity to hormonal changes. Furthermore, facets of the pubertal transition, such as pubertal timing, warrant deeper investigation and may help us gain a more comprehensive understanding of sex differences in the neurobiological and psychosocial mechanisms underlying adolescent STBs. Ultimately, advancing our understanding of the pubertal processes that contribute to suicide risk will improve early detection and facilitate the development of more effective, sex-specific, psychiatric interventions for adolescents.

Background Over 320 million individuals are living with Major Depressive Disorder (MDD), a leading cause of disability worldwide. Thus, there is a crucial need to identify processes that contribute to the maintenance of depressive episodes. Difficulty removing negative information from working memory (WM) is posited to exacerbate affective, cognitive, and biological dysregulation in Major Depressive Disorder (MDD), but this has not yet been tested empirically. Methods In this study we examined whether training depressed individuals to remove negative information from WM (RNI training) would reduce symptoms of depression and levels of rumination, and would be associated with attenuated biological responsivity to stress. Individuals diagnosed with MDD were randomly assigned to complete Real-RNI training or Sham-RNI training for six days. Results Across conditions, participants exhibited significant improvements from pre- to post-training in removing negative information from WM, symptoms of depression, and rumination. Furthermore, participants in the Real-RNI condition showed a more attenuated pattern of cortisol and respiratory sinus arrhythmia (RSA) responses to stress than did participants in the Sham-RNI training condition. Limitations We did not assess the long-term effects of training. It will be important for future research to examine whether the documented training-related effects persist across time. Conclusions This study is the first to examine the effects of RNI training on clinical symptoms and biological responses to stress in MDD, and it provides experimental evidence that training individuals with depression to remove negative information from WM can help to modulate the heightened biological responses to stress seen in depression.

A key objective in the field of translational psychiatry over the past few decades has been to identify the brain correlates of major depressive disorder (MDD). Identifying measurable indicators of brain processes associated with MDD could facilitate the detection of individuals at risk, and the development of novel treatments, the monitoring of treatment effects, and predicting who might benefit most from treatments that target specific brain mechanisms. However, despite intensive neuroimaging research towards this effort, underpowered studies and a lack of reproducible findings have hindered progress. Here, we discuss the work of the ENIGMA Major Depressive Disorder (MDD) Consortium, which was established to address issues of poor replication, unreliable results, and overestimation of effect sizes in previous studies. The ENIGMA MDD Consortium currently includes data from 45 MDD study cohorts from 14 countries across six continents. The primary aim of ENIGMA MDD is to identify structural and functional brain alterations associated with MDD that can be reliably detected and replicated across cohorts worldwide. A secondary goal is to investigate how demographic, genetic, clinical, psychological, and environmental factors affect these associations. In this review, we summarize findings of the ENIGMA MDD disease working group to date and discuss future directions. We also highlight the challenges and benefits of large-scale data sharing for mental health research. ENIGMA MDD work is supported by NIH grants U54 EB020403 (Thompson), R01 MH116147 (Thompson), and R01 MH117601 (Jahanshad & Schmaal). LS was supported by an NHMRC Career Development Fellowship (1140764). AFFDIS cohort: this study was funded by the University Medical Center Goettingen (UMG Startfoerderung) and the research team is supported by German Federal Ministry of Education and Research (Bundesministerium fuer Bildung und Forschung, BMBF: 01 ZX 1507, “PreNeSt - e:Med”). Barcelona cohort: MJP is funded by the Ministerio de Ciencia e Innovación of the Spanish Government and by the Instituto de Salud Carlos III through a ‘Miguel Servet’ research contract (CP16–0020); National Research Plan (Plan Estatal de I + D + I 2016–2019); and co-financed by the European Regional Development Fund (ERDF). BRC DeCC cohort: CHYF is supported by NIHR BRC. Calgary cohort: supported by Canadian Institutes for Health Research, Branch Out Neurological Foundation. Cardiff cohort: supported by the Medical Research Council (grant G 1100629) and the National Center for Mental Health (NCMH), funded by Health Research Wales (HS/14/20). CLING cohort: this study was partially supported by the Deutsche Forschungsgemeinschaft (DFG) via grants to OG (GR1950/5–1 and GR1950/10–1). CODE cohort: Henrik Walter is supported by a grant of the Deutsche Forschungsgemeinschaft (WA 1539/4–1). The CODE cohort was collected from studies funded by Lundbeck and the German Research Foundation (WA 1539/4–1, SCHN 1205/3–1, SCHR443/11–1). DIP-Groningen cohort: this study was supported by the Gratama Foundation, the Netherlands (2012/35 to NG). Edinburgh cohort: The research leading to these results was supported by IMAGEMEND, which received funding from the European Community’s Seventh Framework Programme (FP7/2007–2013) under grant agreement no. 602450. This paper reflects only the author’s views and the European Union is not liable for any use that may be made of the information contained therein. This work was also supported by a Wellcome Trust Strategic Award 104036/Z/14/Z. FOR2107-Marburg cohort: funded by the German Research Foundation (DFG, grant FOR2107 KR 3822/7–2 to AK; FOR2107 KI 588/14–2 to TK and FOR2107 JA 1890/7–2 to AJ). Houston cohorts: supported in part by NIMH grant R01 085667 and the Dunn Research Foundation. JCS is supported by the Pat Rutherford, Jr. Endowed Chair in Psychiatry. IMH Study cohort: supported by funding from NHG (SIG/15012) and NMRC CISSP (2018). Melbourne cohort: funded by National Health and Medical Research Council of Australia (NHMRC) Project Grants 1064643 (Principal Investigator BJH) and 1024570 (Principal Investigator CGD). Minnesota cohort: the study was funded by the National Institute of Mental Health (K23MH090421; Dr. Cullen) and Biotechnology Research Center (P41 RR008079; Center for Magnetic Resonance Research), the National Alliance for Research on Schizophrenia and Depression, the University of Minnesota Graduate School, and the Minnesota Medical Foundation. This work was carried out in part using computing resources at the University of Minnesota Supercomputing Institute. Münster cohort: funded by the German Research Foundation (DFG, grant FOR2107 DA1151/5–1 and DA1151/5–2 to UD; SFB-TRR58, Projects C09 and Z02 to UD) and the Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Münster (grant Dan3/012/17 to UD). NESDA cohort: The infrastructure for the NESDA study (www.nesda.nl) is funded through the Geestkracht program of the Netherlands Organisation for Health Research and Development (Zon-Mw, grant number 10–000–1002) and is supported by participating universities (VU University Medical Center, GGZ inGeest, Arkin, Leiden University Medical Center, GGZ Rivierduinen, University Medical Center Groningen) and mental health care organizations, see www.nesda.nl. Pharmo cohort: supported by ERA-NET PRIOMEDCHILD FP 6 (EU) grant 11.32050.26. PSYABM-NORMENT: supported by the Research Council of Norway (project number 229135). The South East Norway Health Authority Research Funding (project number 2015052). The Department of Psychology, University of Oslo, Norway. San Francisco cohort: supported by NIH/NCCIH 1R61AT009864–01A1. NIMH R01MH085734. SHIP and SHIP-trend cohorts: SHIP is part of the Community Medicine Research net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the Ministry of Cultural Affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. MRI scans in SHIP and SHIP-TREND have been supported by a joint grant from Siemens Healthineers, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. Stanford cohorts: this work was supported by NIH grant R37 MH101495. The BiDirect Study was supported by grants from the German Federal Ministry of Education and Research (BMBF; grants FKZ-01ER0816 and FKZ-01ER1506). MDS is partially supported by an award funded by the Phyllis and Jerome Lyle Rappaport Foundation. TCH is supported by NIMH grant 5K01MH117442. EJWVS, JL, and TFB are supported by European Research Council grant no. ERC-ADG-2014–671084 INSOMNIA. TFB is supported by a VU University Amsterdam University Research Fellowship 2016–2017. JL is supported by a VU University Amsterdam University Research Fellowship 2017–2018.

Major depressive disorder (MDD) is characterized by biased information processing that leads to difficulties regulating negative affect, which includes difficulty decreasing negative affect as well as maladaptively increasing negative affect via cognitive processes. To examine the underlying neural correlates, we scanned depressed and never-depressed adults as they completed a cognitive reappraisal task which required decreasing negative affect while viewing a negative image (down-regulation) and increasing negative affect while viewing a neutral image (emotion generation). Compared to control participants, MDD participants had less recruitment of the dorsal anterior cingulate (dACC) and supplementary motor area (SMA) during early phases of down-regulation, the latter associated with poorer negative affect regulation. Further, MDD participants exhibited greater recruitment of the right middle temporal gyrus (MTG) during emotion generation, which was associated with lower negative affect. Dysregulated negative affect in MDD may be due to impairments in efficiently activating the dACC and SMA to meet regulation demands, and maladaptive generation of negative affect that characterizes individuals with MDD may be counteracted by compensatory activation in the MTG. Elucidating neural mechanisms that underlie the generation of negative affect in the absence of external stimuli is an important extension of previous work examining dysfunctional emotional processes in MDD.

Despite the high prevalence and substantial costs of early life stress (ELS), the mechanisms through which ELS confers risk for psychopathology are poorly understood, particularly among youth who are in an earlier stage of the transition through puberty. We sought to advance our understanding of the link between ELS and psychopathology by testing whether rumination mediates the relation between ELS and symptoms of psychopathology in youth in the early stages of puberty, and whether sex moderates this mediation. We assessed levels of ELS, both brooding and reflection subtypes of rumination, and internalizing and externalizing symptoms in 170 youth in the early stages of puberty (56% girls) ages 9–13 years. Brooding, but not reflection, mediated the relation between ELS and both internalizing and externalizing symptoms. Importantly, however, sex moderated the relation among ELS, brooding, and symptoms. Specifically, brooding mediated the relation between ELS and both internalizing and externalizing symptoms for girls, but not for boys. Findings support the formulation that brooding is a mechanism linking ELS to multiple forms of behavioral and emotional problems exclusively in girls in the early stages of puberty.

Researchers are becoming increasingly interested in linking specific forms of early life stress (ELS) to specific neurobiological markers, including alterations in the morphology of stress-sensitive brain regions. We used a person-centered, multi-informant approach to investigate the associations of specific constellations of ELS with hippocampal and amygdala volume in a community sample of 211 9- to 13-year-old early adolescents. Further, we compared this approach to a cumulative risk model of ELS, in which ELS was quantified by the total number of stressors reported. Using latent class analysis, we identified three classes of ELS (labeled typical/low, family instability, and direct victimization) that were distinguished by experiences of family instability and victimization. Adolescents in the direct victimization class had significantly smaller hippocampal volume than did adolescents in the typical/low class; ELS classes were not significantly associated with amygdala volume. The cumulative risk model of ELS had a poorer fit than did the person-centered model; moreover, cumulative ELS was not significantly associated with hippocampal or amygdala volume. Our results underscore the utility of taking a person-centered approach to identify alterations in stress-sensitive brain regions based on constellations of ELS, and suggest victimization is specifically associated with hippocampal hypotrophy observed in early adolescence.

Early life stress (ELS) is a significant risk factor for the emergence of internalizing problems in adolescence. Beginning in adolescence, females are twice as likely as males to experience internalizing disorders. The present study was designed to examine sex differences in the association between ELS and internalizing problems in early pubertal adolescents, and whether and how corticolimbic function and connectivity may underlie these associations. Fifty-nine early pubertal males and 78 early pubertal females, ages 9–13 years (all Tanner Stage 3 or below) underwent functional magnetic resonance imaging as they performed an emotion label task that robustly interrogates corticolimbic function. Participants were also interviewed about their experience of ELS. Females exhibited a positive association between ELS and internalizing problems, whereas males exhibited no such association. Whole-brain and amygdala region of interest analyses indicated that whereas females exhibited a positive association between ELS and the ventrolateral prefrontal cortex during implicit emotion regulation, males showed no such association. Activation in these regions was positively associated with internalizing problems in females but not males; however, activation in these regions did not mediate the association between ELS and internalizing problems. Finally, both boys and girls exhibited an association between ELS and increased negative connectivity between the right ventrolateral prefrontal cortex and bilateral amygdala. Using a carefully characterized sample of early pubertal adolescents, the current study highlights important sex differences in the development of corticolimbic circuitry during a critical period of brain development. These sex differences may play a significant role in subsequent risk for internalizing problems.

Background Although approximately half of adults diagnosed with a depressive or anxiety disorder exhibit their simultaneous co-occurrence, traditional research has centered on single-target diagnoses, overlooking comorbidities within samples. In this article, we review and extend the literature that directly investigates co-occurring depression and anxiety, with the goal of shifting the focus from co-occurring diagnoses to symptom dimensions. Methods First, we review studies that have directly compared psychobiological features (neural, neuroendocrine, autonomic) across depression, anxiety, and their co-occurrence, defined either categorically or dimensionally. Second, we analyze adults’ diurnal cortisol secretion to examine the independent and interactive relations of continuously-assessed depressive and anxiety symptoms to neuroendocrine function. Results Previous findings on the psychobiology of diagnostic co-occurrence are mixed. While nascent, evidence from dimensionally focused studies suggests that co-occurring levels of depressive and anxiety symptoms can interact with one another, as reflected in a distinct psychobiological profile for individuals with high levels of both symptom dimensions. Results of our analyses support this formulation: we found that depressive and anxiety symptom dimensions interacted consistently in their relation to the measures of diurnal cortisol. Limitations The illustrative sample was relatively small and included only women; future research should examine generalizability of these findings. Conclusions A dimensional approach to investigating the psychobiology of co-occurring depression and anxiety affords both conceptual and practical advantages. Simultaneously assessing depressive and anxiety symptom dimensions can efficiently capture their unique, shared, and interactive features, thereby identifying targets for intervention across a wide range of symptom presentations.

Background Researchers have documented that child maltreatment is associated with adverse long-term consequences for mental health, including increased risk for depression. Attempts to conduct meta-analyses of the association between different forms of child maltreatment and depressive symptomatology in adulthood, however, have been limited by the wide range of definitions of child maltreatment in the literature. Objective We sought to meta-analyze a single, widely-used dimensional measure of child maltreatment, the Childhood Trauma Questionnaire, with respect to depression diagnosis and symptom scores. Participants and setting 192 unique samples consisting of 68,830 individuals. Methods We explored the association between total scores and scores from specific forms of child maltreatment (i.e., emotional abuse, physical abuse, sexual abuse, emotional neglect, and physical neglect) and depression using a random-effects meta-analysis. Results We found that higher child maltreatment scores were associated with a diagnosis of depression (g = 1.07; 95 % CI, 0.95–1.19) and with higher depression symptom scores (Z = .35; 95 % CI, .32–.38). Moreover, although each type of child maltreatment was positively associated with depression diagnosis and scores, there was variability in the size of the effects, with emotional abuse and emotional neglect demonstrating the strongest associations. Conclusions These analyses provide important evidence of the link between child maltreatment and depression, and highlight the particularly larger association with emotional maltreatment in childhood.

The stress response system is disrupted in individuals with major depressive disorder (MDD) as well as in those at elevated risk for developing MDD. We examined whether DNA methylation (DNAm) levels of CpG sites within HPA-axis genes predict the onset of MDD. Seventy-seven girls, approximately half (n = 37) of whom were at familial risk for MDD, were followed longitudinally. Saliva samples were taken in adolescence (M age = 13.06 years [SD = 1.52]) when participants had no current or past MDD diagnosis. Diagnostic interviews were administered approximately every 18 months until the first onset of MDD or early adulthood (M age of last follow-up = 19.23 years [SD = 2.69]). We quantified DNAm in saliva samples using the Illumina EPIC chip and examined CpG sites within six key HPA-axis genes (NR3C1, NR3C2, CRH, CRHR1, CRHR2, FKBP5) alongside 59 genotypes for tagging SNPs capturing cis genetic variability. DNAm levels within CpG sites in NR3C1, CRH, CRHR1, and CRHR2 were associated with risk for MDD across adolescence and young adulthood. To rule out the possibility that findings were merely due to the contribution of genetic variability, we re-analyzed the data controlling for cis genetic variation within these candidate genes. Importantly, methylation levels in these CpG sites continued to significantly predict the onset of MDD, suggesting that variation in the epigenome, independent of proximal genetic variants, prospectively predicts the onset of MDD. These findings suggest that variation in the HPA axis at the level of the methylome may predict the development of MDD.

Altres ajuts: The ENIGMA-Major Depressive Disorder working group gratefully acknowledges support from the NIH Big Data to Knowledge (BD2K) award (U54 EB020403 to PMT) and NIH grant R01 MH116147 (PMT). LS is supported by an NHMRC MRFF Career Development Fellowship (APP1140764). We wish to acknowledge the patients and control subjects that have particiaped int the study. We thank Rosa Schirmer, Elke Schreiter, Reinhold Borschke and Ines Eidner for image acquisition and data preparation, and Anna Oliynyk for quality checks. We thank Dorothee P. Auer and F. Holsboer for initiation of the RUD study. We wish to acknowledge the patients and control subjects that have particiaped int the study. We thank Rosa Schirmer, Elke Schreiter, Reinhold Borschke and Ines Eidner for image acquisition and data preparation, and Anna Oliynyk for quality checks. We thank Dorothee P. Auer and F. Holsboer for initiation of the RUD study. NESDA: The infrastructure for the NESDA study (www.nesda.nl) is funded through the Geestkracht program of the Netherlands Organisation for Health Research and Development (Zon-Mw, grant number 10-000-1002) and is supported by participating universities (VU University Medical Center, GGZ inGeest, Arkin, Leiden University Medical Center, GGZ Rivierduinen, University Medical Center Groningen) and mental health care organizations, see www.nesda.nl. M-JvT was supported by a VENI grant (NWO grant number 016.156.077). UCSF: This work was supported by the Brain and Behavior Research Foundation (formerly NARSAD) to TTY; the National Institute of Mental Health (R01MH085734 to TTY; K01MH117442 to TCH) and by the American Foundation for Suicide Prevention (PDF-1-064-13) to TCH. Stanford: This work was supported by NIMH Grants R01MH59259 and R37101495 to IHG. MS is partially supported by an award funded by the Phyllis and Jerome Lyle Rappaport Foundation. Muenster: This work was funded by the German Research Foundation (SFB-TRR58, Projects C09 and Z02 to UD) and the Interdisciplinary Center for Clinical Research (IZKF) of the medical faculty of Münster (grant Dan3/012/17 to UD). Marburg: This work was funded by the German Research Foundation (DFG, grant FOR2107 DA1151/5-1 and DA1151/5-2 to UD; KI 588/ 14-1, KI 588/14-2 to TK; KR 3822/7-1, KR 3822/7-2 to AK; JA 1890/ 7-1, JA 1890/7-2 to AJ). IMH-MDD: This work was supported by the National Healthcare Group Research Grant (SIG/15012) awarded to KS. Barcelona: This study was funded by two grants of the Fondo de Investigación Sanitaria from the Instituto de Salud Carlos III, by the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM). The author is funded through 'Miguel Servet' research contract (CP16-0020), co-financed by the European Regional Development Fund (ERDF) (2016-2019). QTIM: We thank the twins and singleton siblings who gave generously of their time to participate in the QTIM study. We also thank the many research assistants, radiographers, and IT support staff for data acquisition and DNA sample preparation. This study was funded by White matter disturbances in major depressive disorder: a coordinated analysis across 20 international. . . 1521 the National Institute of Child Health & Human Development (RO1 HD050735); National Institute of Biomedical Imaging and Bioengineering (Award 1U54EB020403-01, Subaward 56929223); National Health and Medical Research Council, Australia (Project Grants 496682, 1009064). NIH ENIGMA-BD2K U54 EB020403 (Thompson); R01 MH117601 (Jahanshad/Schmaal). Magdeburg: M.L. and M.W. are funded by SFB 779. Bipolar Family Study: This study has received funding from the European Community's Seventh Framework Programme (FP7/2007-2013). This paper reflects only the author's views and the European Union is not liable for any use that may be made of the information contained therein. This work was also supported by a Wellcome Trust Strategic Award (104036/Z/14/Z). Minnesota Adolescent Depression Study: The study was funded by the National Institute of Mental Health (K23MH090421), the National Alliance for Research on Schizophrenia and Depression, the University of Minnesota Graduate School, the Minnesota Medical Foundation, and the Biotechnology Research Center (P41 RR008079 to the Center for Magnetic Resonance Research), University of Minnesota, and the Deborah E. Powell Center for Women's Health Seed Grant, University of Minnesota. Dublin: This study was supported by Science Foundation Ireland through a Stokes Professorhip grant to TF. MPIP: The MPIP Sample comprises patients included in the Recurrent Unipolar Depression (RUD) Case-Control study at the clinic of the Max Planck Institute of Psychiatry, Munich, German. The RUD study was supported by GlaxoSmithKline. Alterations in white matter (WM) microstructure have been implicated in the pathophysiology of major depressive disorder (MDD). However, previous findings have been inconsistent, partially due to low statistical power and the heterogeneity of depression. In the largest multi-site study to date, we examined WM anisotropy and diffusivity in 1305 MDD patients and 1602 healthy controls (age range 12-88 years) from 20 samples worldwide, which included both adults and adolescents, within the MDD Working Group of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) consortium. Processing of diffusion tensor imaging (DTI) data and statistical analyses were harmonized across sites and effects were meta-analyzed across studies. We observed subtle, but widespread, lower fractional anisotropy (FA) in adult MDD patients compared with controls in 16 out of 25 WM tracts of interest (Cohen's d between 0.12 and 0.26). The largest differences were observed in the corpus callosum and corona radiata. Widespread higher radial diffusivity (RD) was also observed (all Cohen's d between 0.12 and 0.18). Findings appeared to be driven by patients with recurrent MDD and an adult age of onset of depression. White matter microstructural differences in a smaller sample of adolescent MDD patients and controls did not survive correction for multiple testing. In this coordinated and harmonized multisite DTI study, we showed subtle, but widespread differences in WM microstructure in adult MDD, which may suggest structural disconnectivity in MDD.

Objective: Asymmetry is a subtle but pervasive aspect of the human brain, and it may be altered in several psychiatric conditions. MRI studies have shown subtle differences of brain anatomy between people with major depressive disorder and healthy control subjects, but few studies have specifically examined brain anatomical asymmetry in relation to this disorder, and results from those studies have remained inconclusive. At the functional level, some electroencephalography studies have indicated left fronto-cortical hypoactivity and right parietal hypoactivity in depressive disorders, so aspects of lateralized anatomy may also be affected. The authors used pooled individual-level data from data sets collected around the world to investigate differences in laterality in measures of cortical thickness, cortical surface area, and subcortical volume between individuals with major depression and healthy control subjects.Methods: The authors investigated differences in the laterality of thickness and surface area measures of 34 cerebral cortical regions in 2,256 individuals with major depression and 3,504 control subjects from 31 separate data sets, and they investigated volume asymmetries of eight subcortical structures in 2,540 individuals with major depression and 4,230 control subjects from 32 data sets. T-1-weighted MRI data were processedwith a single protocol using FreeSurfer and the Desikan-Killiany atlas. The large sample size provided 80% power to detect effects of the order of Cohen's d=0.1.Results: The largest effect size (Cohen's d) of major depression diagnosis was 0.085 for the thickness asymmetry of the superior temporal cortex, which was not significant after adjustment for multiple testing. Asymmetry measures were not significantly associated with medication use, acute compared with remitted status, first episode compared with recurrent status, or age at onset.Conclusions: Altered brain macro-anatomical asymmetry may be of little relevance to major depression etiology in most cases.

Atypical regulation of the hypothalamic-pituitary-adrenal (HPA) axis is a putative mechanism underlying the association between exposure to early life stress (ELS) and the subsequent development of mental and physical health difficulties. Recent research indicates that puberty is a period of HPA-axis plasticity during which the effects of exposure to ELS on cortisol regulation may change. In particular, increases in the sex hormones that drive pubertal maturation, including dehydroepiandrosterone (DHEA) and testosterone, may be implicated in pubertal recalibration of cortisol regulation. In the current study, we examined the associations among levels of objectively-rated threat-related ELS and salivary waking cortisol, DHEA, and testosterone in a sample of 178 adolescents (55% female) who were in early puberty at baseline (Tanner stages 1-3; mean Tanner stage[SD]=1.93[0.64]; mean age[SD]=11.42[1.04]) and were followed up approximately two years later (mean Tanner stage[SD]=3.46[0.86]; mean age[SD]=13.38[1.06]). Using multi-level modeling, we disaggregated the effects of between-individual levels and within-individual increases in pubertal stage and sex hormones on change in cortisol. Controlling for between-individual differences in average pubertal stage, the association between levels of cortisol and DHEA was more strongly positive among adolescents who evidenced greater within-individual increases in pubertal stage across time. Both higher average levels and greater within-individual increases in DHEA and testosterone were associated with increases in cortisol across time, indicating positive coupling of developmental changes in these hormones; however, coupling was attenuated in adolescents who were exposed to more severe threat-related ELS prior to puberty. These findings advance our understanding of the development of the HPA-axis and its association with childhood environmental risk during puberty.

Early life adversity and insecure attachment style are known risk factors for perinatal depression. The biological pathways linking these experiences, however, have not yet been elucidated. We hypothesized that overlap in patterns of DNA methylation in association with each of these phenomena could identify genes and pathways of importance. Specifically, we wished to distinguish between allostatic-load and role-transition hypotheses of perinatal depression. We conducted a large-scale analysis of methylation patterns across 5 × 106 individual CG dinucleotides in 54 women participating in a longitudinal prospective study of perinatal depression, using clustering-based criteria for significance to control for multiple comparisons. We identified 1580 regions in which methylation density was associated with childhood adversity, 3 in which methylation density was associated with insecure attachment style, and 6 in which methylation density was associated with perinatal depression. Shorter telomeres were observed in association with childhood trauma but not with perinatal depression or attachment insecurity. A detailed analysis of methylation density in the oxytocin receptor gene revealed similar patterns of DNA methylation in association with perinatal depression and with insecure attachment style, while childhood trauma was associated with a distinct methylation pattern in this gene. Clinically, attachment style was strongly associated with depression only in pregnancy and the early postpartum, whereas the association of childhood adversity with depression was time-invariant. We concluded that the broad DNA methylation signature and reduced telomere length associated with childhood adversity could indicate increased allostatic load across multiple body systems, whereas perinatal depression and attachment insecurity may be narrower phenotypes with more limited DNA methylation signatures outside the CNS, and no apparent association with telomere length or, by extension, allostatic load. In contrast, the finding of matching DNA methylation patterns within the oxytocin receptor gene for perinatal depression and attachment insecurity is consistent with the theory that the perinatal period is a time of activation of existing attachment schemas for the purpose of structuring the mother–child relationship, and that such activation may occur in part through specific patterns of methylation of the oxytocin receptor gene.

Objective Several studies have found associations between a diagnosis or symptoms of major depressive disorder and markers of cellular aging and dysfunction. These investigations, however, are predominantly cross-sectional and focus on adults. In the present study, we used a prospective longitudinal design to test the cross-sectional association between depressive symptoms in adolescents and telomere length (TL) as well as mitochondrial DNA copy number (mtDNA-cn). Method A total of 121 adolescents (mean age = 11.38 years, SD = 1.03; 39% male adolescents and 61% female adolescents) were followed for approximately 2 years. At baseline and follow-up, participants provided saliva for DNA extraction, from which measures of TL and mtDNA-cn were obtained. Depressive symptoms were obtained via the Children’s Depression Inventory. Results There was no association between depressive symptoms and markers of cellular aging at baseline; however, depressive symptoms at baseline predicted higher rates of telomere erosion (β = −0.201, p = .016) and greater increases in mtDNA-cn (β = 0.190, p = .012) over the follow-up period. Markers of cellular aging at baseline did not predict subsequent changes in depressive symptoms. Furthermore, including the number of stressful life events did not alter these patterns of findings. Conclusion These results indicate that depressive symptoms precede changes in cellular aging and dysfunction, rather than the reverse.

Early life stress (ELS) is a risk factor for the development of depression in adolescence; the mediating neurobiological mechanisms, however, are unknown. In this study, we examined in early pubertal youth the associations among ELS, cortisol stress responsivity, and white matter microstructure of the uncinate fasciculus and the fornix, two key frontolimbic tracts; we also tested whether and how these variables predicted depressive symptoms in later puberty. A total of 208 participants (117 females; M age = 11.37 years; M Tanner stage = 2.03) provided data across two or more assessment modalities: ELS; salivary cortisol levels during a psychosocial stress task; diffusion magnetic resonance imaging; and depressive symptoms. In early puberty there were significant associations between higher ELS and decreased cortisol production, and between decreased cortisol production and increased fractional anisotropy in the uncinate fasciculus. Further, increased fractional anisotropy in the uncinate fasciculus predicted higher depressive symptoms in later puberty, above and beyond earlier symptoms. In post hoc analyses, we found that sex moderated several additional associations. We discuss these findings within a broader conceptual model linking ELS, emotion dysregulation, and depression across the transition through puberty, and contend that brain circuits implicated in the control of hypothalamic–pituitary–adrenal axis function should be a focus of continued research.

Research with community samples suggests that non-affective features of families, such as the amount of time parents and adolescents spend together, affect depressive symptoms in adolescents. It is possible, however, that spending time with parents not only protects against the onset of depressive symptoms, but also reduces symptoms in adolescents who are already depressed. The current study was designed to test this formulation while also examining whether affective dimensions of family functioning – specifically parental warmth – accounted for or moderated observed associations. Finally, we tested the reverse direction of the associations, examining whether greater severity of depression in adolescents results in parents spending less time with them. Forty-one adolescents (ages 14 to 17 years) who met criteria for a current major depressive episode participated in the present study with one parent. Once each month for six time points, dyads completed reports of depressive symptoms and the amount of time parents and adolescents spent with each other. Participants also completed measures of parental warmth. Results of lagged multilevel modeling indicated that spending more time with a parent predicted fewer depressive symptoms in adolescents at the following assessment relative to their mean; in contrast, greater severity of depressive symptoms did not predict spending less time with a parent at the following assessment. In contrast, parental warmth did not account for or moderate the association between time together and depressive symptoms. These results suggest that non-affective dimensions of family life, specifically spending more time with parents, have beneficial effects on depressive symptoms in adolescents diagnosed with depression.

BACKGROUND: Major Depressive Disorder (MDD) is characterized by aberrant resting-state functional connectivity (FC) in anterior cingulate regions (e.g., subgenual anterior cingulate [sgACC]) and by negative emotional functioning that is inflexible or resistant to change. METHODS: MDD (N=33) and control (CTL; N=31) adults completed a resting-state scan, followed by a smartphone-based Experience Sampling Methodology (ESM) protocol surveying 10 positive and negative emotions 5 times per day for 21 days. We used multilevel modeling to assess moment-to-moment emotional inflexibility (i.e., strong temporal connections between emotions). We examined group differences in whole-brain FC analysis of bilateral sgACC, and then examined associations between emotional experiences and the extracted FC values within each group. RESULTS: As predicted, MDDs had inflexibility in sadness and avoidance (p