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Aberrant microstructure of the uncinate fasciculus (UNC), a white matter (WM) tract implicated in emotion regulation, has been hypothesized as a neurobiological mechanism of depression. However, studies testing this hypothesis have yielded inconsistent results. The present meta-analysis consolidates evidence from 44 studies comparing fractional anisotropy (FA) and radial diffusivity (RD), two metrics characterizing WM microstructure, of the UNC in individuals with depression (n = 5016) to healthy individuals (n = 18 425). We conduct meta-regressions to identify demographic and clinical characteristics that contribute to cross-study heterogeneity in UNC findings. UNC FA was reduced in individuals with depression compared to healthy individuals. UNC RD was comparable between individuals with depression and healthy individuals. Comorbid anxiety explained inter-study heterogeneity in UNC findings. Depression is associated with perturbations in UNC microstructure, specifically with respect to UNC FA and not UNC RD. The association between depression and UNC microstructure appears to be moderated by anxiety. Future work should unravel the cellular mechanisms contributing to aberrant UNC microstructure in depression; clarify the relationship between UNC microstructure, depression, and anxiety; and link UNC microstructure to psychological processes, such as emotion regulation.
Irritability, characterized by anger in response to frustration, is normative in childhood. While children typically show a decline in irritability from toddlerhood to school age, elevated irritability throughout childhood may predict later psychopathology. The current study (n = 78) examined associations between trajectories of irritability in early childhood (ages 2–7) and irritability in adolescence (age 12) and tested whether these associations are moderated by parenting behaviors. Results indicate that negative emotion socialization moderated trajectories of irritability – relative to children with low stable irritability, children who exhibited high stable irritability in early childhood and who had parents that exhibited greater negative emotion socialization behaviors had higher irritability in adolescence. Further, negative parental control behavior moderated trajectories of irritability – relative to children with low stable irritability, children who had high decreasing irritability in early childhood and who had parents who exhibited greater negative control behaviors had higher irritability in adolescence. In contrast, positive emotion socialization and control behaviors did not moderate the relations between early childhood irritability and later irritability in adolescence. These results suggest that both irritability in early childhood and negative parenting behaviors may jointly influence irritability in adolescence. The current study underscores the significance of negative parenting behaviors and could inform treatment.
Irritability is a transdiagnostic symptom dimension in developmental psychopathology, closely related to the Research Domain Criteria (RDoC) construct of frustrative nonreward. Consistent with the RDoC framework and calls for transdiagnostic, developmentally-sensitive assessment methods, we report data from a smartphone-based, naturalistic ecological momentary assessment (EMA) study of irritability. We assessed 109 children and adolescents (Mage = 12.55 years; 75.20% male) encompassing several diagnostic groups – disruptive mood dysregulation disorder (DMDD), attention-deficit/hyperactivity disorder (ADHD), anxiety disorders (ANX), healthy volunteers (HV). The participants rated symptoms three times per day for 1 week. Compliance with the EMA protocol was high. As tested using multilevel modeling, EMA ratings of irritability were strongly and consistently associated with in-clinic, gold-standard measures of irritability. Further, EMA ratings of irritability were significantly related to subjective frustration during a laboratory task eliciting frustrative nonreward. Irritability levels exhibited an expected graduated pattern across diagnostic groups, and the different EMA items measuring irritability were significantly associated with one another within all groups, supporting the transdiagnostic phenomenology of irritability. Additional analyses utilized EMA ratings of anxiety as a comparison with respect to convergent validity and transdiagnostic phenomenology. The results support new measurement tools that can be used in future studies of irritability and frustrative nonreward.
While taxonomy segregates anxiety symptoms into diagnoses, patients typically present with multiple diagnoses; this poses major challenges, particularly for youth, where mixed presentation is particularly common. Anxiety comorbidity could reflect multivariate, cross-domain interactions insufficiently emphasized in current taxonomy. We utilize network analytic approaches that model these interactions by characterizing pediatric anxiety as involving distinct, inter-connected, symptom domains. Quantifying this network structure could inform views of pediatric anxiety that shape clinical practice and research.
Participants were 4964 youths (ages 5–17 years) from seven international sites. Participants completed standard symptom inventory assessing severity along distinct domains that follow pediatric anxiety diagnostic categories. We first applied network analytic tools to quantify the anxiety domain network structure. We then examined whether variation in the network structure related to age (3-year longitudinal assessments) and sex, key moderators of pediatric anxiety expression.
The anxiety network featured a highly inter-connected structure; all domains correlated positively but to varying degrees. Anxiety patients and healthy youth differed in severity but demonstrated a comparable network structure. We noted specific sex differences in the network structure; longitudinal data indicated additional structural changes during childhood. Generalized-anxiety and panic symptoms consistently emerged as central domains.
Pediatric anxiety manifests along multiple, inter-connected symptom domains. By quantifying cross-domain associations and related moderation effects, the current study might shape views on the diagnosis, treatment, and study of pediatric anxiety.
Irritability and anxiety frequently co-occur in pediatric populations. Studies separately looking at the neural correlates of these symptoms have identified engagement of similar neural systems – particularly those implicated in emotional processing. Both irritability and anxiety can be considered negative valence emotional states that might relate to emotion dysregulation. However, previous work has not examined the neural responding during the performance of an emotion regulation task as a function of interaction between irritability and anxiety simultaneously.
This fMRI study involved 155 participants (90 with significant psychopathologies and 92 male) who performed the Affective Stroop Task, designed to engage emotion regulation as a function of task demands. The Affective Reactivity Index (ARI) was used to index irritability and the Screen for Child Anxiety Related Emotional Disorders (SCARED) was used to index anxiety.
Levels of irritability, but not anxiety, was positively correlated with responses to visual images within the right rostro-medial prefrontal cortex and left anterior cingulate cortex during view trials. The second region of ventral anterior cingulate cortex showed a condition-by-emotion-by-ARI score-by-SCARED score interaction. Specifically, anxiety level was significantly correlated with a decreased differential BOLD response to negative relative to neutral view trials but only in the presence of relatively high irritability.
Atypical maintenance of emotional stimuli within the rostro-medial prefrontal cortex may exacerbate the difficulties faced by adolescents with irritability. Moreover, increased anxiety combined with significant irritability may disrupt an automatic emotional conflict-based form of emotion regulation that is particularly associated with the ventral anterior cingulate cortex.
Early behaviors that differentiate later biomarkers for psychopathology can guide preventive efforts while also facilitating pathophysiological research. We tested whether error-related negativity (ERN) moderates the link between early behavior and later psychopathology in two early childhood phenotypes: behavioral inhibition and irritability. From ages 2 to 7 years, children (n = 291) were assessed longitudinally for behavioral inhibition (BI) and irritability. Behavioral inhibition was assessed via maternal report and behavioral responses to novelty. Childhood irritability was assessed using the Child Behavior Checklist. At age 12, an electroencephalogram (EEG) was recorded while children performed a flanker task to measure ERN, a neural indicator of error monitoring. Clinical assessments of anxiety and irritability were conducted using questionnaires (i.e., Screen for Child Anxiety Related Disorders and Affective Reactivity Index) and clinical interviews. Error monitoring interacted with early BI and early irritability to predict later psychopathology. Among children with high BI, an enhanced ERN predicted greater social anxiety at age 12. In contrast, children with high childhood irritability and blunted ERN predicted greater irritability at age 12. This converges with previous work and provides novel insight into the specificity of pathways associated with psychopathology.
Irritability and anxiety are two common clinical phenotypes that involve high-arousal negative affect states (anger and fear), and that frequently co-occur. Elucidating how these two forms of emotion dysregulation relate to perturbed neurodevelopment may benefit from alternate phenotyping strategies. One such strategy applies a bifactor latent variable approach that can parse shared versus unique mechanisms of these two phenotypes. Here, we aim to replicate and extend this approach and examine associations with neural structure in a large transdiagnostic sample of youth (N = 331; M = 13.57, SD = 2.69 years old; 45.92% male). FreeSurfer was used to extract cortical thickness, cortical surface area, and subcortical volume. The current findings replicated the bifactor model and demonstrate measurement invariance as a function of youth age and sex. There were no associations of youth's factor scores with cortical thickness, surface area, or subcortical volume. However, we found strong convergent and divergent validity between parent-reported irritability and anxiety factors with clinician-rated symptoms and impairment. A general negative affectivity factor was robustly associated with overall functional impairment across symptom domains. Together, these results support the utility of the bifactor model as an alternative phenotyping strategy for irritability and anxiety, which may aid in the development of targeted treatments.
While emotional dysregulation is a broad construct, the current paper adopts a narrow approach to facilitate translational neuroscience research on pediatric anxiety. The paper first presents data on an adapted version of the antisaccade task and then integrates these data into a research framework. Data on an adapted version of the antisaccade task were collected in 57 youth, including 35 seeking treatment for an anxiety disorder. Associations were examined between performance on the antisaccade task and (a) age, (b) performance on other cognitive-control tasks (i.e., the stop-signal delay and flanker tasks), and (c) level of anxiety symptoms. Better performance on the antisaccade task occurred in older relative to younger subjects and correlated with better performance on the flanker task. Across the 57 youth, higher levels of anxiety correlated with shorter latency for correct antisaccades. These data can be placed within a three-step framework for translational neuroscience research. In the first step, a narrow index of emotion dysregulation is targeted. In the second step, this narrow index is linked to other correlated indicators of the same underlying narrow latent construct. In the third and final step, associations are examined with clinical outcomes and response to treatment.
This study uses novel approaches to examine genetic and environmental influences shared between childhood behavioral inhibition (BI) and symptoms of preadolescent anxiety disorders. Three hundred and fifty-two twin pairs aged 9–13 and their mothers completed questionnaires about BI and anxiety symptoms. Biometrical twin modeling, including a direction-of-causation design, investigated genetic and environmental risk factors shared between BI and social, generalized, panic and separation anxiety. Social anxiety shared the greatest proportion of genetic (20%) and environmental (16%) variance with BI with tentative evidence for causality. Etiological factors underlying BI explained little of the risk associated with the other anxiety domains. Findings further clarify etiologic pathways between BI and anxiety disorder domains in children.
Anxiety symptoms gradually emerge during childhood and adolescence. Individual differences in behavioral inhibition (BI), an early-childhood temperament, may shape developmental paths through which these symptoms arise. Cross-sectional research suggests that level of early-childhood BI moderates associations between later anxiety symptoms and threat-related amygdala–prefrontal cortex (PFC) circuitry function. However, no study has characterized these associations longitudinally. Here, we tested whether level of early-childhood BI predicts distinct evolving associations between amygdala–PFC function and anxiety symptoms across development.
Eighty-seven children previously assessed for BI level in early childhood provided data at ages 10 and/or 13 years, consisting of assessments of anxiety and an fMRI-based dot-probe task (including threat, happy, and neutral stimuli). Using linear-mixed-effects models, we investigated longitudinal changes in associations between anxiety symptoms and threat-related amygdala–PFC connectivity, as a function of early-childhood BI.
In children with a history of high early-childhood BI, anxiety symptoms became, with age, more negatively associated with right amygdala–left dorsolateral-PFC connectivity when attention was to be maintained on threat. In contrast, with age, low-BI children showed an increasingly positive anxiety–connectivity association during the same task condition. Behaviorally, at age 10, anxiety symptoms did not relate to fluctuations in attention bias (attention bias variability, ABV) in either group; by age 13, low-BI children showed a negative anxiety–ABV association, whereas high-BI children showed a positive anxiety–ABV association.
Early-childhood BI levels predict distinct neurodevelopmental pathways to pediatric anxiety symptoms. These pathways involve distinct relations among brain function, behavior, and anxiety symptoms, which may inform diagnosis and treatment.
Aberrations in reward and penalty processing are implicated in depression and putatively reflect altered dopamine signalling. This study exploits the advantages of a placebo-controlled design to examine how a novel D2 antagonist with adjunctive antidepressant properties modifies activity in the brain's reward network in depression.
We recruited 43 medication-naïve subjects across the range of depression severity (Beck's Depression Inventory-II score range: 0–43), including healthy volunteers, as well as people meeting full-criteria for major depressive disorder. In a double-blind placebo-controlled cross-over design, all subjects received either placebo or lurasidone (20 mg) across two visits separated by 1 week. Functional magnetic resonance imaging with the Monetary Incentive Delay (MID) task assessed reward functions via neural responses during anticipation and receipt of gains and losses. Arterial spin labelling measured cerebral blood flow (CBF) at rest.
Lurasidone altered fronto-striatal activity during anticipation and outcome phases of the MID task. A significant three-way Medication-by-Depression severity-by-Outcome interaction emerged in the anterior cingulate cortex (ACC) after correction for multiple comparisons. Follow-up analyses revealed significantly higher ACC activation to losses in high- v. low depression participants in the placebo condition, with a normalisation by lurasidone. This effect could not be accounted for by shifts in resting CBF.
Lurasidone acutely normalises reward processing signals in individuals with depressive symptoms. Lurasidone's antidepressant effects may arise from reducing responses to penalty outcomes in individuals with depressive symptoms.
Behavioral inhibition (BI) is a temperament identified in early childhood that is associated with risk for anxiety disorders, yet only about half of behaviorally inhibited children manifest anxiety later in life. We compared brain function and behavior during extinction recall in a sample of nonanxious young adults characterized in childhood with BI (n = 22) or with no BI (n = 28). Three weeks after undergoing fear conditioning and extinction, participants completed a functional magnetic resonance imaging extinction recall task assessing memory and threat differentiation for conditioned stimuli. While self-report and psychophysiological measures of differential conditioning and extinction were similar across groups, BI-related differences in brain function emerged during extinction recall. Childhood BI was associated with greater activation in subgenual anterior cingulate cortex in response to cues signaling safety. This pattern of results may reflect neural correlates that promote resilience against anxiety in a temperamentally at-risk population.
The Twin Study of Negative Valence Emotional Constructs is a multi-site study designed to examine the relationship between a broad selection of potential measures designed to assess putative endophenotypes for negative valence systems (NVS) and early symptoms of internalizing disorders (IDs). In this article, we describe the sample characteristics, data collection protocols, and measures used. Pre-adolescent Caucasian twin pairs were recruited through the Mid-Atlantic Twin Registry; data collection began in February of 2013. Enrolled twins completed various dimensional self-report measures along with cognitive, emotional, and psychophysiological tasks designed to assess NVS function. Parents also completed surveys about their twins and themselves. In addition, a subset of the twins also participated in a neuroimaging protocols. Data collection is in the final stages, and preliminary analyses are underway. The findings will potentially expand our understanding of the mechanisms by which genetic and environmental factors contribute to individual differences in NVS phenotypes and provide new insights into underlying risk factors for IDs.
This paper reviews the literature on gender differences in major depressive disorder (MDD) and bipolar disorder (BPD). Beginning in adolescence, women are at a higher risk than men of becoming depressed. Avenues of investigation that might ultimately help to explain this phenomenon include studies of gender differences in the processing of emotional stimuli, the psychotropic effects of gonadal steroids, and environment/gene interactions in men and women. With the exception of the elevated suicide rate among men, consistent gender differences in the course and symptoms of MDD have not been found. In BPD, women are more likely than men to develop a rapid-cycling course. Gender differences in treatment response, particularly in regard to mood stabilizing medications, warrant further study.
Chronic, severe irritability is common in childhood and is very impairing. Furthermore, childhood irritability predicts suicidality, social impairment, and depressive and anxiety disorders in adulthood. Focusing on both normative and pathologic development, we review the construct of irritability from its origins in aggression and disruptive behavior research to its contemporary relevance for affective psychopathology. We then describe two broad neurocognitive systems that show promise in differentiating irritable from nonirritable youths: aberrant processing of emotional stimuli and impaired context-sensitive regulation. We suggest behavioral, neurocognitive, and physiologic measures that may aid in studying severe irritability and assessing its therapeutics. Finally, we argue for therapeutic trials targeting severe irritability that address emotional aspects of irritability in addition to the associated disruptive behavior.
Children with narrow phenotype bipolar disorder (NP-BD; i.e., history of at least one hypomanic or manic episode with euphoric mood) are deficient when labeling face emotions. It is unknown if this deficit is specific to particular emotions, or if it extends to children with severe mood dysregulation (SMD; i.e., chronic irritability and hyperarousal without episodes of mania). Thirty-nine NP-BD, 31 SMD, and 36 control subjects completed the emotional expression multimorph task, which presents gradations of facial emotions from 100% neutrality to 100% emotional expression (happiness, surprise, fear, sadness, anger, and disgust). Groups were compared in terms of intensity of emotion required before identification occurred and accuracy. Both NP-BD and SMD youth required significantly more morphs than controls to label correctly disgusted, surprised, fearful, and happy faces. Impaired face labeling correlated with deficient social reciprocity skills in NP-BD youth and dysfunctional family relationships in SMD youth. Compared to controls, patients with NP-BD or SMD require significantly more intense facial emotion before they are able to label the emotion correctly. These deficits are associated with psychosocial impairments. Understanding the neural circuitry associated with face-labeling deficits has the potential to clarify the pathophysiology of these disorders.
Much controversy has surrounded the diagnosis of bipolar disorder (BD)
in children and adolescents. However, recent work from an affective
neuroscience perspective has advanced what is known about the boundaries
of emotion regulation in BD compared to typically developing youth. In
this article, we first briefly review the clinical issues that have
contributed to this diagnostic controversy. Second, we discuss our
phenotyping system, which can be used to guide neurobiological research
designed to address these controversial issues. Third, we review what is
known about the fundamentals of emotion regulation in human and nonhuman
primate models. Fourth, we present recent data demonstrating how children
and adolescents with BD differ from those without psychopathology on
measures of emotion regulation. Taken as a whole, this work implicates a
neural circuit encompassing the prefrontal cortex, amygdala, and striatum
in the pathophysiology of pediatric BD.Both
authors are affiliated with the Mood and Anxiety Disorders Program of the
National Institute of Mental Health's Division of Intramural Research
Programs (NIMH DIRP), which funded the work in its entirety. Dr. Dickstein
is currently supported by a career development award (K22-MH
Background. Many changes in social behavior take place during adolescence. Sexuality and romantic interests emerge during this time, and adolescents spend more time with peers and less time with parents and family. While such changes in social behavior have been well documented in the literature, relatively few neurophysiological explanations for these behavioral changes have been presented.
Method. In this article we selectively review studies documenting (a) the neuronal circuits that are dedicated to the processing of social information; (b) the changes in social behavior that take place during adolescence; (c) developmental alterations in the adolescent brain; and (d) links between the emergence of mood and anxiety disorders in adolescence and changes in brain physiology occurring at that time.
Results. The convergence of evidence from this review indicates a relationship between development of brain physiology and developmental changes in social behavior. Specifically, the surge of gonadal steroids at puberty induces changes within the limbic system that alters the emotional attributions applied to social stimuli while the gradual maturation of the prefrontal cortex enables increasingly complex and controlled responses to social information.
Conclusions. Observed alterations in adolescent social behavior reflect developmental changes in the brain social information processing network. We further speculate that dysregulation of the social information processing network in this critical period may contribute to the onset of mood and anxiety disorders during adolescence.
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