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A Latent Variable Approach to Differentiating Neural Mechanisms of Irritability and Anxiety in Youth.

ABSTRACT: Importance:Comorbidity is ubiquitous in psychiatry, but it is unclear how to differentiate neural mechanisms of co-occurring symptoms. Pediatric irritability and anxiety symptoms are prevalent and frequently co-occur. Threat orienting is pertinent to both phenotypes and is an ideal context in which to examine their unique and common neural mechanisms. Objectives:To decompose the unique and shared variances of pediatric irritability and anxiety symptoms and to determine neural correlates of these differentiated phenotypes during threat orienting. Design, Setting, and Participants:This investigation was a cross-sectional functional magnetic resonance imaging study. The setting was a research clinic at the National Institute of Mental Health. Participants were youth aged 8 to 18 years spanning multiple diagnostic categories (141 youth with disruptive mood dysregulation disorder, anxiety disorder, and/or attention-deficit/hyperactivity disorder and 56 healthy youth). This combination provided wide variation in levels of irritability and anxiety symptoms. Data were acquired between June 30, 2012, and June 28, 2016. Main Outcomes and Measures:Participants and parents rated youth's irritability on the Affective Reactivity Index and anxiety on the Screen for Child Anxiety Related Emotional Disorders. Bifactor analysis decomposed the unique and shared variances. A functional magnetic resonance imaging dot-probe task assessed attention orienting to angry (ie, threat) vs neutral faces. Whole-brain analyses examined associations between the bifactor-derived phenotypes and both neural activity and amygdala functional connectivity. Results:Among 197 participants included in the final analysis, the mean (SD) age was 13.1 (2.7) years, and 91 (46.2%) were female. The best-fit bifactor model (Comparative Fit Index, 0.959; Root Mean Square Error of Approximation, 0.066) included unique factors of parent-reported irritability, youth-reported irritability, and anxiety, as well as a common factor of negative affectivity. When the task required attention away from threat, higher parent-reported irritability was associated with increased activity in the insula, caudate, dorsolateral and ventrolateral prefrontal cortex, and inferior parietal lobule (t189?4.15 for all, P?

SUBMITTER: Kircanski K

PROVIDER: S-EPMC6137523 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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A Latent Variable Approach to Differentiating Neural Mechanisms of Irritability and Anxiety in Youth.

Kircanski Katharina K White Lauren K LK Tseng Wan-Ling WL Wiggins Jillian Lee JL Frank Heather R HR Sequeira Stefanie S Zhang Susan S Abend Rany R Towbin Kenneth E KE Stringaris Argyris A Pine Daniel S DS Leibenluft Ellen E Brotman Melissa A MA

JAMA psychiatry 20180601 6

<h4>Importance</h4>Comorbidity is ubiquitous in psychiatry, but it is unclear how to differentiate neural mechanisms of co-occurring symptoms. Pediatric irritability and anxiety symptoms are prevalent and frequently co-occur. Threat orienting is pertinent to both phenotypes and is an ideal context in which to examine their unique and common neural mechanisms.<h4>Objectives</h4>To decompose the unique and shared variances of pediatric irritability and anxiety symptoms and to determine neural corr ...[more]

PMID: 29625429

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Project description:ImportancePsychiatric comorbidity complicates clinical care and confounds efforts to elucidate the pathophysiology of commonly occurring symptoms in youths. To our knowledge, few studies have simultaneously assessed the effect of 2 continuously distributed traits on brain-behavior relationships in children with psychopathology.ObjectiveTo determine shared and unique effects of 2 major dimensions of child psychopathology, irritability and anxiety, on neural responses to facial emotions during functional magnetic resonance imaging.Design, setting, and participantsCross-sectional functional magnetic resonance imaging study in a large, well-characterized clinical sample at a research clinic at the National Institute of Mental Health. The referred sample included youths ages 8 to 17 years, 93 youths with anxiety, disruptive mood dysregulation, and/or attention-deficit/hyperactivity disorders and 22 healthy youths.Main outcomes and measuresThe child's irritability and anxiety were rated by both parent and child on the Affective Reactivity Index and Screen for Child Anxiety Related Disorders, respectively. Using functional magnetic resonance imaging, neural response was measured across the brain during gender labeling of varying intensities of angry, happy, or fearful face emotions. In mixed-effects analyses, the shared and unique effects of irritability and anxiety were tested on amygdala functional connectivity and activation to face emotions.ResultsThe mean (SD) age of participants was 13.2 (2.6) years; of the 115 included, 64 were male. Irritability and/or anxiety influenced amygdala connectivity to the prefrontal and temporal cortex. Specifically, irritability and anxiety jointly influenced left amygdala to left medial prefrontal cortex connectivity during face emotion viewing (F4,888 = 9.20; P < .001 for mixed model term). During viewing of intensely angry faces, decreased connectivity was associated with high levels of both anxiety and irritability, whereas increased connectivity was associated with high levels of anxiety but low levels of irritability (Wald χ21 = 21.3; P < .001 for contrast). Irritability was associated with differences in neural response to face emotions in several areas (F2, 888 ≥ 13.45; all P < .001). This primarily occurred in the ventral visual areas, with a positive association to angry and happy faces relative to fearful faces.Conclusions and relevanceThese data extend prior work conducted in youths with irritability or anxiety alone and suggest that research may miss important findings if the pathophysiology of irritability and anxiety are studied in isolation. Decreased amygdala-medial prefrontal cortex connectivity may mediate emotion dysregulation when very anxious and irritable youth process threat-related faces. Activation in the ventral visual circuitry suggests a mechanism through which signals of social approach (ie, happy and angry expressions) may capture attention in irritable youth.

Project description:Background: Severe irritability is a common, impairing problem among youth referred for mental health services, but evidence to guide care is limited. Treatment research can be advanced by adopting a transdiagnostic perspective, leveraging existing evidence-based treatment (EBT) techniques, and situating irritability within the context of emotion dysregulation. Accordingly, this study examined treatment outcomes for youth with different levels of irritability and dysregulation who received cognitive-behavioral therapy (CBT) or behavioral parent training (BPT) in a modular EBT framework. Method: We analyzed data from a community-based implementation trial of a transdiagnostic youth psychotherapy. Two-hundred treatment-referred youths (7-15 years; 47% female; 33% White, 28% Black, 24% Latinx, 14% multiracial, 2% other) and their caregivers completed measures of clinical problems and emotion dysregulation at baseline, with repeated outcomes assessments over 18 months. First, latent profile analysis was applied to baseline irritability and emotion dysregulation data; then, latent growth curve models were used to examine outcome trajectories, controlling for covariates. Results: A two-class solution fit well, differentiating youth with high (n = 54) vs. low (n = 146) levels of dysregulation and irritability at baseline. Nearly all high-dysregulation youth received either BPT (n = 26) or CBT-Depression (n = 23). Across measures, both groups showed statistically and clinically significant improvements over time. High-dysregulation youth had greater baseline severity than low-dysregulation youth, but otherwise their longitudinal trajectories were mostly similar, with few between-group slope differences. There was virtually no evidence of differential effects for BPT vs. CBT on clinical outcomes. Conclusions: Youth with severe irritability and dysregulation, treated with a transdiagnostic, modular, EBT approach, showed significant within-person improvements over time. Their outcome trajectories did not differ according to whether they received BPT or CBT. Findings extend the literature on modular, transdiagnostic, and EBT approaches for irritability and dysregulation, suggesting comparable benefits associated with BPT and CBT when treatment selection is guided by comprehensive assessment. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03153904.

Project description:BackgroundAnxiety and irritability frequently co-occur in youth and are mediated by aberrant threat responses. However, empirical evidence on neural mechanisms underlying this co-occurrence is limited. To address this, we apply data-driven latent phenotyping to data from a prior report of a well-validated threat extinction recall fMRI paradigm.MethodsParticipants included 59 youth (28 anxiety disorder, 31 healthy volunteers; Mage=13.15 yrs) drawn from a transdiagnostic sample of 331 youth, in which bifactor analysis was conducted to derive latent factors representing shared vs. unique variance of dimensionally-assessed anxiety and irritability. Participants underwent threat conditioning and extinction. Approximately three weeks later, during extinction recall fMRI, participants made threat-safety discriminations under two task conditions: current threat appraisal and explicit recall of threat contingencies. Linear mixed-effects analyses examined associations of a "negative affectivity" factor reflecting shared anxiety and irritability variance with whole-brain activation and task-dependent amygdala connectivity.ResultsDuring recall of threat-safety contingencies, higher negative affectivity was associated with greater prefrontal (ventrolateral/ventromedial, dorsolateral, orbitofrontal), motor, temporal, parietal, and occipital activation. During threat appraisal, higher negative affectivity was associated with greater amygdala-inferior parietal lobule connectivity to threat/safety ambiguity.LimitationsSample included only healthy youth and youth with anxiety disorders. Results may not generalize to other diagnoses for which anxiety and irritability are also common, and our negative affectivity factor should be interpreted as anxiety disorders with elevated irritability. Reliability of some subfactors was poor.ConclusionsAberrant amygdala-prefrontal-parietal circuitry during extinction recall of threat-safety stimuli may be a mechanism underlying the co-occurrence of pediatric anxiety and irritability.

Dataset Information

A Latent Variable Approach to Differentiating Neural Mechanisms of Irritability and Anxiety in Youth.

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A Latent Variable Approach to Differentiating Neural Mechanisms of Irritability and Anxiety in Youth.

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