A Data-Driven Latent Variable Approach to Validating the Research Domain Criteria Framework.

Despite the widespread use of the Research Domain Criteria (RDoC) framework in psychiatry and neuroscience, recent studies suggest that the RDoC is insufficiently specific or excessively broad relative to the underlying brain circuitry it seeks to elucidate. To address these concerns of the RDoC framework, our study employed a latent variable approach, specifically utilizing bifactor analysis. We examined a total of 84 whole-brain task-based fMRI (tfMRI) activation maps from 19 studies with a total of 6,192 participants. Within this set of 84 maps, a curated subset of 37 maps with a balanced representation of RDoC domains constituted the training set of our analysis, and the remaining held-out maps formed the internal validation set. External validation was performed with 36 peak coordinate activation maps from Neurosynth, using terms of RDoC constructs as seeds for topic meta-analysis. Our results indicate that a bifactor model with a task-general domain and splitting the cognitive systems domain into sub-domains better fits the current corpus of tfMRI data than the current RDoC framework. Our data-driven validation supports revising the RDoC framework to accurately reflect underlying brain circuitry.

Neighborhood disadvantage and parenting predict longitudinal clustering of uncinate fasciculus microstructural integrity and clinical symptomatology in adolescents.

Parenting behaviors and neighborhood environment influence the development of adolescents' brains and behaviors. Simultaneous trajectories of brain and behavior, however, are understudied, especially in these environmental contexts. In this four-wave study spanning 9-18 years of age (N=224 at baseline, N=138 at final assessment) we used longitudinal k-means clustering to identify clusters of participants with distinct trajectories of uncinate fasciculus (UF) fractional anisotropy (FA) and anxiety symptoms; we examined behavioral outcomes and identified environmental factors that predicted cluster membership. We identified three clusters of participants: 1) high UF FA and low symptoms ("low-risk"); 2) low UF FA and high symptoms ("high-risk"); and 3) low UF FA and low symptoms ("resilient"). Adolescents in disadvantaged neighborhoods were more likely to be in the resilient than high-risk cluster if they also experienced maternal warmth. Thus, neighborhood disadvantage may confer neural risk for psychopathology that can be buffered by maternal warmth, highlighting the importance of considering multiple environmental influences in understanding emotional and neural development in youth.

A Comparison of Quantitative R1 and Cortical Thickness in Identifying Age, Lifespan Dynamics, and Disease States of the Human Cortex.

Brain development and aging are complex processes that unfold in multiple brain regions simultaneously. Recently, models of brain age prediction have aroused great interest, as these models can potentially help to understand neurological diseases and elucidate basic neurobiological mechanisms. We test whether quantitative magnetic resonance imaging can contribute to such age prediction models. Using R1, the longitudinal rate of relaxation, we explore lifespan dynamics in cortical gray matter. We compare R1 with cortical thickness, a well-established biomarker of brain development and aging. Using 160 healthy individuals (6-81 years old), we found that R1 and cortical thickness predicted age similarly, but the regions contributing to the prediction differed. Next, we characterized R1 development and aging dynamics. Compared with anterior regions, in posterior regions we found an earlier R1 peak but a steeper postpeak decline. We replicate these findings: firstly, we tested a subset (N = 10) of the original dataset for whom we had additional scans at a lower resolution; and second, we verified the results on an independent dataset (N = 34). Finally, we compared the age prediction models on a subset of 10 patients with multiple sclerosis. The patients are predicted older than their chronological age using R1 but not with cortical thickness.

Accelerated DNA methylation age in adolescent girls: associations with elevated diurnal cortisol and reduced hippocampal volume.

Numerous studies have linked exposure to stress to adverse health outcomes through the effects of cortisol, a product of the stress response system, on cellular aging processes. Accelerated DNA methylation age is a promising epigenetic marker associated with stress and disease risk that may constitute a link from stress response to changes in neural structures. Specifically, elevated glucocorticoid signaling likely contributes to accelerating DNA methylation age, which may signify a maladaptive stress-related cascade that leads to hippocampal atrophy. We examined the relations among diurnal cortisol levels, DNA methylation age and hippocampal volume in a longitudinal study of 46 adolescent girls. We computed area under the curve from two daily cortisol collection periods, and calculated DNA methylation age using previously established methods based on a set of CpG sites associated with chronological age. We computed a residual score by partialling out chronological age; higher discrepancies reflect relatively accelerated DNA methylation age. We assessed hippocampal volume via T1-weighted images and automated volumetric segmentation. We found that greater diurnal cortisol production was associated with accelerated DNA methylation age, which in turn was associated with reduced left hippocampal volume. Finally, accelerated DNA methylation age significantly mediated the association between diurnal cortisol and left hippocampal volume. Thus, accelerated DNA methylation age may be an epigenetic marker linking hypothalamic-pituitary-adrenal axis dysregulation with neural structure. If these findings are replicated, the current study provides a method for advancing our understanding of mechanisms by which glucocorticoid signaling is associated with cellular aging and brain development.

Common and distinct patterns of grey-matter volume alteration in major depression and bipolar disorder: evidence from voxel-based meta-analysis.

Finding robust brain substrates of mood disorders is an important target for research. The degree to which major depression (MDD) and bipolar disorder (BD) are associated with common and/or distinct patterns of volumetric changes is nevertheless unclear. Furthermore, the extant literature is heterogeneous with respect to the nature of these changes. We report a meta-analysis of voxel-based morphometry (VBM) studies in MDD and BD. We identified studies published up to January 2015 that compared grey matter in MDD (50 data sets including 4101 individuals) and BD (36 data sets including 2407 individuals) using whole-brain VBM. We used statistical maps from the studies included where available and reported peak coordinates otherwise. Group comparisons and conjunction analyses identified regions in which the disorders showed common and distinct patterns of volumetric alteration. Both disorders were associated with lower grey-matter volume relative to healthy individuals in a number of areas. Conjunction analysis showed smaller volumes in both disorders in clusters in the dorsomedial and ventromedial prefrontal cortex, including the anterior cingulate cortex and bilateral insula. Group comparisons indicated that findings of smaller grey-matter volumes relative to controls in the right dorsolateral prefrontal cortex and left hippocampus, along with cerebellar, temporal and parietal regions were more substantial in major depression. These results suggest that MDD and BD are characterised by both common and distinct patterns of grey-matter volume changes. This combination of differences and similarities has the potential to inform the development of diagnostic biomarkers for these conditions.

Telomere length and cortisol reactivity in children of depressed mothers.

A growing body of research demonstrates that individuals diagnosed with major depressive disorder (MDD) are characterized by shortened telomere length, which has been posited to underlie the association between depression and increased instances of medical illness. The temporal nature of the relation between MDD and shortened telomere length, however, is not clear. Importantly, both MDD and telomere length have been associated independently with high levels of stress, implicating dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and anomalous levels of cortisol secretion in this relation. Despite these associations, no study has assessed telomere length or its relation with HPA-axis activity in individuals at risk for depression, before the onset of disorder. In the present study, we assessed cortisol levels in response to a laboratory stressor and telomere length in 97 healthy young daughters of mothers either with recurrent episodes of depression (i.e., daughters at familial risk for depression) or with no history of psychopathology. We found that daughters of depressed mothers had shorter telomeres than did daughters of never-depressed mothers and, further, that shorter telomeres were associated with greater cortisol reactivity to stress. This study is the first to demonstrate that children at familial risk of developing MDD are characterized by accelerated biological aging, operationalized as shortened telomere length, before they had experienced an onset of depression; this may predispose them to develop not only MDD but also other age-related medical illnesses. It is critical, therefore, that we attempt to identify and distinguish genetic and environmental mechanisms that contribute to telomere shortening.

A profile approach to impulsivity in bipolar disorder: the key role of strong emotions.

OBJECTIVE: Bipolar disorder has been associated with elevated impulsivity - a complex construct subsuming multiple facets. We aimed to compare specific facets of impulsivity in bipolar disorder, including those related to key psychological correlates of the illness: reward sensitivity and strong emotion. METHOD: Ninety-one individuals diagnosed with bipolar I disorder (inter-episode period) and 80 controls completed several well-validated impulsivity measures, including those relevant to reward (Fun-seeking subscale of the Behavioral Activation System scale) and emotion (Positive Urgency and Negative Urgency scales). RESULTS: Bipolar participants reported higher impulsivity scores than did controls on all of the impulsivity measures, except the Fun-seeking subscale of the Behavioral Activation System scale. Positive Urgency - a measure assessing the tendency to act impulsively when experiencing strong positive emotion - yielded the largest group differences: F(1,170) = 78.69, P < 0.001, partial η(2)  = 0.316. Positive Urgency was also associated with poorer psychosocial functioning in the bipolar group: ΔR(2)  = 0.24, b = -0.45, P < 0.001. CONCLUSION: Individuals with bipolar I disorder appear to be at particular risk of behaving impulsively when experiencing strong positive emotions. Findings provide an important first step toward developing a more refined understanding of impulsivity in bipolar disorder with the potential to inform targeted interventions.

Behavioral activation system moderates self-referent processing following recovery from depression.

BACKGROUND: Previous research has implicated the behavioral activation system (BAS) in depression. The relationship of BAS functioning to aspects of cognitive vulnerability to depression, however, is not known. Method The present study investigated associations among level of BAS functioning and the encoding and recall of positive and negative self-referent information in currently non-depressed participants with a history of recurrent major depression (recovered; RMD) and in never-depressed control participants (CTL). Participants completed self-report measures of levels of BAS and behavioral inhibition system (BIS) functioning. Following a negative mood induction, participants were presented with a series of positive and negative adjectives; they indicated which words described them and later recalled as many of the words as they were able. RESULTS: The relationship of BAS functioning to self-referent processing was dependent on participant group. Although lower BAS reward responsivity was associated with the endorsement and recall of fewer positive words across groups, the magnitude of these associations was stronger, and was only significant, within the RMD group. Furthermore, only for RMD participants was lower BAS reward responsivity associated with the endorsement of more negative words. These effects were not accounted for by depressive or anxiety symptoms, current mood, or level of BIS functioning. CONCLUSIONS: These results indicate that BAS functioning may be distinctively linked to negatively biased self-referent processing, one facet of cognitive vulnerability to depression, in individuals with a history of major depressive disorder. Enhancing BAS functioning may be important in buffering cognitive vulnerability to depression.

Pubertal stage and brain anatomy in girls.

Studies of puberty have focused primarily on changes in hormones and on observable physical bodily characteristics. Little is known, however, about the nature of the relation between pubertal status and brain physiology. This is particularly important given findings that have linked the onset of puberty with both changes in cognitive functioning and increases in the incidence of depression and anxiety. The present study examined relations between pubertal stage, as assessed by Tanner staging, and brain anatomy in a sample of 54 girls aged 9-15 years. Brain morphometric analysis was conducted using high-resolution magnetic resonance imaging (MRI). The hippocampus and amygdala were manually traced on MRI scans in all participants. Stepwise regression analyses were conducted with total intracranial volume (ICV), age, and pubertal status as the predictor variables and hippocampus and amygdala volumes as outcome variables. Pubertal status was significantly associated with left amygdala volume, after controlling for both age and ICV. In addition, puberty was related to right hippocampus and amygdala volumes, after controlling for ICV. In contrast, no significant associations were found between age and hippocampal and amygdala volumes after controlling for pubertal status and ICV. These findings highlight the importance of the relation between pubertal status and morphometry of the hippocampus and amygdala, and of limbic and subcortical structures that have been implicated in emotional and social behaviors.

Investigating neural primacy in Major Depressive Disorder: multivariate Granger causality analysis of resting-state fMRI time-series data.

Major Depressive Disorder (MDD) has been conceptualized as a neural network-level disease. Few studies of the neural bases of depression, however, have used analytical techniques that are capable of testing network-level hypotheses of neural dysfunction in this disorder. Moreover, of those that have, fewer still have attempted to determine the directionality of influence within functionally abnormal networks of structures. We used multivariate GC analysis, a technique that estimates the extent to which preceding neural activity in one or more seed regions predicts subsequent activity in target brain regions, to analyze blood-oxygen-level-dependent (BOLD) data collected during eyes-closed rest from depressed and never-depressed persons. We found that activation in the hippocampus predicted subsequent increases in ventral anterior cingulate cortex (vACC) activity in depression, and that activity in the medial prefrontal cortex and vACC were mutually reinforcing in MDD. Hippocampal and vACC activation in depressed participants predicted subsequent decreases in dorsal cortical activity. This study shows that, on a moment-by-moment basis, there is increased excitatory activity among limbic and paralimbic structures, as well as increased inhibition in the activity of dorsal cortical structures, by limbic structures in depression; these aberrant patterns of effective connectivity implicate disturbances in the mesostriatal dopamine system in depression. These findings advance the neural theory of depression by detailing specific patterns of limbic excitation in MDD, by making explicit the primary role of limbic inhibition of dorsal cortex in the cortico-limbic relation posited to underlie depression, and by presenting an integrated neurofunctional account of altered dopamine function in this disorder.

Specificity of cognitive biases in patients with current depression and remitted depression and in patients with asthma.

BACKGROUND: Previous studies have demonstrated a specific cognitive bias for sad stimuli in currently depressed patients; little is known, however, about whether this bias persists after recovery from the depressive episode. Depression is frequently observed in patients with asthma and is associated with a worse course of the disease. Given these high rates of co-morbidity, we could expect to observe a similar bias towards sad stimuli in patients with asthma. METHOD: We therefore examined cognitive biases in memory and attention in 20 currently and 20 formerly depressed participants, 20 never-depressed patients diagnosed with asthma, and 20 healthy control participants. All participants completed three cognitive tasks: the self-referential encoding and incidental recall task, the emotion face dot-probe task and the emotional Stroop task. RESULTS: Compared with healthy participants, currently and formerly depressed participants, but not patients with asthma, exhibited specific biases for sad stimuli. CONCLUSIONS: These results suggest that cognitive biases are evident in depression even after recovery from an acute episode but are not found in never-depressed patients with asthma.

Amygdala volume in major depressive disorder: a meta-analysis of magnetic resonance imaging studies.

Major depressive disorder has been associated with volumetric abnormality in the amygdala. In this meta-analysis we examine results from magnetic resonance imaging volumetry studies of the amygdala in depression in order to assess both the nature of the relationship between depression and amygdala volume as well as the influence of extraexperimental factors that may account for significant variability in reported findings. We searched PubMed and ISI Web of Knowledge databases for articles published from 1985 to 2008 that used the wildcard terms 'Depress*' and 'Amygdal*' in the title, keywords or abstract. From the 13 studies that met inclusion criteria for our meta-analysis, we calculated aggregate effect size and heterogeneity estimates from amygdala volumetric data; we then used meta-regression to determine whether variability in specific extraexperimental factors accounted for variability in findings. The lack of a reliable difference in amygdala volume between depressed and never-depressed individuals was accounted for by a positive correlation between amygdala volume differences and the proportion of medicated depressed persons in study samples: whereas the aggregate effect size calculated from studies that included only medicated individuals indicated that amygdala volume was significantly increased in depressed relative to healthy persons, studies with only unmedicated depressed individuals showed a reliable decrease in amygdala volume in depression. These findings are consistent with a formulation in which an antidepressant-mediated increase in levels of brain-derived neurotrophic factor promotes neurogenesis and protects against glucocorticoid toxicity in the amygdala in medicated but not in unmedicated depression.

Panic attacks and psychopathology among youth.

OBJECTIVE: To determine the association between panic attacks and mental disorders among youth in the community. METHOD: Data were drawn from the Methods for the Epidemiology of Child and Adolescent Mental Disorders study (n = 1285), a community-based sample of youth aged 9-17. Multiple logistic regression analyses were used to determine the association between panic attacks and the range of mental disorders, diagnosed with the Diagnostic Interview Schedule for Children 2.3. RESULTS: Panic attacks were prevalent among 3.3% of the sample. Panic attacks were associated with an increased likelihood of any anxiety disorders [OR = 4.6 (2.5, 8.5)] and any affective disorder [OR = 5.8 (2.8, 11.7)], as well as social phobia [OR = 2.3 (1.0, 5.4)], specific phobia [OR = 3.4 (1.1, 10.1)], agoraphobia [OR = 2.9 (1.1, 7.6)], generalized anxiety disorder [OR = 4.8 (1.9, 12.1)], separation anxiety disorder [OR = 3.1 (1.3, 7.7)], major depression [OR = 3.6 (1.6, 8.3)], dysthymia [OR = 6.7 (2.9, 15.5)], and hypomania [OR = 26.1 (5.5, 124.1)]. CONCLUSION: These data are consistent with, and extend, previous clinical findings by showing that panic attacks are associated with increased likelihood of a range of affective and anxiety disorders, but not substance use disorders, among youth in the community. The use of longitudinal study designs in future investigations may be useful in increasing our understanding of the mechanisms underlying these associations.

Natural course of adolescent major depressive disorder in a community sample: predictors of recurrence in young adults.

OBJECTIVE: The primary purpose was to identify factors related to the recurrence of major depressive disorder during young adulthood (19-23 years of age) in a community sample of formerly depressed adolescents. METHOD: A total of 274 participants with adolescent-onset major depressive disorder were assessed twice during adolescence and again after their 24th birthday. Lifetime psychiatric information was obtained from their first-degree relatives. Adolescent predictor variables included demographic characteristics, psychosocial variables, characteristics of adolescent major depressive disorder, comorbidity, family history of major depressive disorder and nonmood disorder, and antisocial and borderline personality disorder symptoms. RESULTS: Low levels of excessive emotional reliance, a single episode of major depressive disorder in adolescence, low proportion of family members with recurrent major depressive disorder, low levels of antisocial and borderline personality disorder symptoms, and a positive attributional style (males only) independently predicted which formerly depressed adolescents would remain free of future psychopathology. Female gender, multiple major depressive disorder episodes in adolescence, higher proportion of family members with recurrent major depressive disorder, elevated borderline personality disorder symptoms, and conflict with parents (females only) independently predicted recurrent major depressive disorder. Comorbid anxiety and substance use disorders in adolescence and elevated antisocial personality disorder symptoms independently distinguished adolescents who developed recurrent major depressive disorder comorbid with nonmood disorder from those who developed pure major depressive disorder. CONCLUSIONS: Formerly depressed adolescents with the risk factors identified in this study are at elevated risk for recurrence of major depressive disorder during young adulthood and therefore warrant continued monitoring and preventive or prophylactic treatment.

Risk for psychopathology in the children of depressed mothers: a developmental model for understanding mechanisms of transmission.

A large body of literature documents the adverse effects of maternal depression on the functioning and development of offspring. Although investigators have identified factors associated with risk for abnormal development and psychopathology in the children, little attention has been paid to the mechanisms explaining the transmission of risk from the mothers to the children. Moreover, no existing model both guides understanding of the various processes' interrelatedness and considers the role of development in explicating the manifestation of risk in the children. This article proposes a developmentally sensitive, integrative model for understanding children's risk in relation to maternal depression. Four mechanisms through which risk might be transmitted are evaluated: (a) heritability of depression; (b) innate dysfunctional neuroregulatory mechanisms; (c) exposure to negative maternal cognitions, behaviors, and affect; and (d) the stressful context of the children's lives. Three factors that might moderate this risk are considered: (a) the father's health and involvement with the child, (b) the course and timing of the mother's depression, and (c) characteristics of the child. Relevant issues are discussed, and promising directions for future research are suggested.

First onset versus recurrence of depression: differential processes of psychosocial risk.

Differential risk factors for the onset of depression were prospectively examined in a community-based sample of adolescents (N = 1,709), some of whom had a history of major depressive disorder (MDD; n = 286) and some of whom did not (n = 1,423). From the theories of J. Teasdale (1983, 1988) and R. Post (1992) concerning the etiology of initial versus recurrent episodes of depression, the authors hypothesized that (a) dysphoric mood and dysfunctional thinking styles would be correlated more highly among those with a previous history of MDD than among those without a history of MDD; (b) dysphoric mood or symptoms and dysfunctional thinking would be a stronger predictor of onset of recurrent episodes (n = 43) than of first onsets (n = 70); and (c) major life stress would be a stronger predictor of first onsets of MDD than of recurrent episodes. The results provide support for the 3 hypotheses and suggest that distinct processes are involved in the onset of first and recurrent episodes of MDD.

Gender differences in correlates of depressive symptoms in adolescents.

PURPOSE: To determine: (a) what demographic and psychosocial factors are associated with elevated levels of depressive symptoms in adolescence; (b) whether girls and boys show different profiles of correlates and probable risk factors for depressive symptoms; and (c) what the implications are of these results for future research directions and policy decisions. METHODS: Using a nationally representative sample of adolescent school students in Grades 5-12, the Commonwealth Fund Adolescent Health Survey assessed depressive symptoms as well as a number of variables posited to be risk factors and correlates of depression. RESULTS: Depressive symptoms were found to differ by gender, age, socioeconomic status, and ethnicity. In addition, life stress, social support, and coping were associated with depressive symptoms. Importantly, stress and social support appear to be particularly salient aspects of depression among girls. Both physical and sexual abuse were strongly linked with depression for both boys and girls, with sexual abuse having a stronger impact among boys. Finally, high levels of depressive symptoms were associated with increased use of both mental and physical health care resources among boys and girls. CONCLUSIONS: The correlates of depression in this adolescent sample closely resemble those seen in adult samples, including demographic and psychosocial variables. Some psychosocial variables, such as stress and social support, may have a greater impact on depressive symptoms for girls than for boys. Results of this study also have important implications for the health care system, given that higher levels of depressive symptoms were found to be associated with greater utilization of physical health care resources.

Ethnic differences in the association between pubertal status and symptoms of depression in adolescent girls.

PURPOSE: To examine the importance of chronologic age versus pubertal status in predicting adolescent girls' depressive symptoms in different ethnic groups. METHODS: A national probability sample was used to obtain a representative cohort of 3216 adolescents, 5th through 8th grades. Subjects completed a questionnaire, which included a modified version of the Children's Depression Inventory (CDI) and an assessment of timing of menarche. RESULTS: Among Caucasians, post-menarcheal adolescent girls had higher depression scores than did same-aged pre-menarcheal girls. Boys and pre-menarcheal girls had similar depression scores in most age groups. Among African-Americans and Hispanics, there were no menarche-associated differences in depressive symptoms. CONCLUSION: In early adolescence pubertal status is a better predictor of depressive symptoms than chronological age in Caucasian, but not African-American or Hispanic girls.

Consequences of depression during adolescence: marital status and marital functioning in early adulthood.

In previous studies, depression has been associated with both marital status and marital distress. Unfortunately, given the cross-sectional design of most of this research, the temporal nature of these associations is unclear. The authors examined the marital functioning of young adults as a function of whether they received psychiatric diagnoses of major depressive disorder or nonaffective psychiatric disorder during adolescence. Depression during adolescence was found to predict higher rates of marriage among younger women and subsequent marital dissatisfaction. This pattern of results appears to be specific to depression: The presence during adolescence of a nonaffective psychiatric disorder was unrelated to subsequent marital functioning. These findings highlight the potentially adverse consequences of depression in adolescence and underscore the importance of prevention and early treatment efforts.

Gender differences in anxiety disorders and anxiety symptoms in adolescents.

Gender differences in anxiety were examined in a large sample of adolescents that included 1,079 who had never met criteria for any disorder, 95 who had recovered from an anxiety disorder, and 47 who had a current anxiety disorder. Participants were examined on a wide array of psychosocial measures. There was a preponderance of females among current and recovered anxiety disorder cases, but not among those who had never experienced an anxiety disorder. The female preponderance emerges early in life, and retrospective data indicate that at age 6, females are already twice as likely to have experienced an anxiety disorder than are males. Psychosocial variables that were correlated with both anxiety and gender were identified. Statistically controlling for these variables did not eliminate the gender differences in prevalence or anxiety symptom means.