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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.
Eye-tracking-based attentional research implicates sustained attention to threat in posttraumatic stress disorder (PTSD). However, most of this research employed small stimuli set-sizes, small samples that did not include both trauma-exposed healthy participants and non-trauma-exposed participants, and generally failed to report the reliability of used tasks and attention indices. Here, using an established eye-tracking paradigm, we explore attention processes to different negatively-valenced cues in PTSD while addressing these limitations.
PTSD patients (n = 37), trauma-exposed healthy controls (TEHC; n = 34), and healthy controls (HC; n = 30) freely viewed three blocks of 30 different matrices of faces, each presented for 6 s. Each block consisted of matrices depicting eight negatively-valenced faces (anger, fear, or sadness) and eight neutral faces. Gaze patterns on negative and neural areas of interest were compared. Internal consistency and test-retest reliability were evaluated for the entire sample and within groups.
The two trauma-exposed groups dwelled longer on negatively-valenced faces over neutral faces, while HC participants showed the opposite pattern. This attentional bias was more prominent in the PTSD than the TEHC group. Similar results emerged for first-fixation dwell time, but with no differences between the two trauma-exposed groups. No group differences emerged for first-fixation latency or location. Internal consistency and 1-week test-retest reliability were adequate, across and within groups.
Sustained attention on negatively-valenced stimuli emerges as a potential target for therapeutic intervention in PTSD designed to divert attention away from negatively-valenced stimuli and toward neutral ones.
Previous randomized controlled trials (RCTs) suggest that attention control therapy (ACT), targeting aberrant fluctuations of attention toward and away from threats in patients with PTSD, may be effective in reducing symptoms. The current RCT examined whether the use of personalized-trauma stimuli enhances ACT efficacy in patients with PTSD. Additional moderators of treatment outcome were tested on an exploratory basis.
Sixty patients with PTSD were randomly assigned to either personalized ACT, non-personalized ACT, or a control condition. Changes in symptoms were examined across pre-treatment, post-treatment, and a 3-month follow-up. Attentional interference was examined pre- and post-treatment. Baseline clinical and cognitive indices as well as the time elapsed since the trauma were tested as potential moderators of treatment outcome.
A significant reduction in clinical symptoms was noted for all three conditions with no between-group differences. Attention bias variability decreased following ACT treatment. Personalized ACT was more effective relative to the control condition when less time had elapsed since the trauma. Baseline clinical and cognitive indices did not moderate treatment outcome.
In this RCT of patients with PTSD, ACT was no more effective in reducing PTSD symptoms than a control condition. The data also suggest a potential benefit of personalized ACT for patients who experienced their trauma more recently.
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.
By the end of their first year, infants can interpret many different types of complex dynamic visual events, such as caused-motion, chasing, and goal-directed action. Infants of this age are also in the early stages of vocabulary development, producing their first words at around 12 months. The present work examined whether there are meaningful individual differences in infants’ ability to represent dynamic causal events in visual scenes, and whether these differences influence vocabulary development. As part of the longitudinal Language 0–5 Project, 78 10-month-old infants were tested on their ability to interpret three dynamic motion events, involving (a) caused-motion, (b) chasing behaviour, and (c) goal-directed movement. Planned analyses found that infants showed evidence of understanding the first two event types, but not the third. Looking behaviour in each task was not meaningfully related to vocabulary development, nor were there any correlations between the tasks. The results of additional exploratory analyses and simulations suggested that the infants’ understanding of each event may not be predictive of their vocabulary development, and that looking times in these tasks may not be reliably capturing any meaningful individual differences in their knowledge. This raises questions about how to convert experimental group designs to individual differences measures, and how to interpret infant looking time behaviour.
This chapter reviews efforts to use neuroscience to inform clinical practice for mental disorders, discussing anxiety disorders as an exemplary foundation for work on other mental illnesses. The chapter unfolds in four stages. The first portion provides an overview, focusing on three levels of inquiry: clinical state; psychological testing; and brain function, as revealed by functional magnetic resonance imaging. Next, the chapter describes research across these three levels for one narrow area of neuroscience, related to the orienting of attention, where progress in clinically relevant domains has been steady. The third section also focuses on the three levels to summarize work on appraisal, a process closely connected to consciousness, where research has yet to profoundly impact clinical thinking. Finally, the chapter concludes by summarizing problems confronting future attempts to establish a clinical neuroscience approach to mental disorders, problems which are difficult to solve due to unique aspects of human thought.
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.
Despite extensive research, symptom structure of posttraumatic stress disorder (PTSD) is highly debated. The network approach to psychopathology offers a novel method for understanding and conceptualizing PTSD. However, extant studies have mainly used small samples and self-report measures among sub-clinical populations, while also overlooking co-morbid depressive symptoms.
PTSD symptom network topology was estimated in a sample of 1489 treatment-seeking veteran patients based on a clinician-rated PTSD measure. Next, clinician-rated depressive symptoms were incorporated into the network to assess their influence on PTSD network structure. The PTSD-symptom network was then contrasted with the network of 306 trauma-exposed (TE) treatment-seeking patients not meeting full criteria for PTSD to assess corresponding network differences. Finally, a directed acyclic graph (DAG) was computed to estimate potential directionality among symptoms, including depressive symptoms and daily functioning.
The PTSD symptom network evidenced robust reliability. Flashbacks and getting emotionally upset by trauma reminders emerged as the most central nodes in the PTSD network, regardless of the inclusion of depressive symptoms. Distinct clustering emerged for PTSD and depressive symptoms within the comorbidity network. DAG analysis suggested a key triggering role for re-experiencing symptoms. Network topology in the PTSD sample was significantly distinct from that of the TE sample.
Flashbacks and psychological reactions to trauma reminders, along with their strong connections to other re-experiencing symptoms, have a pivotal role in the clinical presentation of combat-related PTSD among veterans. Depressive and posttraumatic symptoms constitute two separate diagnostic entities, but with meaningful between-disorder connections, suggesting two mutually-influential systems.
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.
Combat exposure is associated with elevated risk for post-traumatic stress disorder (PTSD). Despite considerable research on PTSD symptom clustering, it remains unknown how symptoms of PTSD re-organize following combat. Network analysis provides a powerful tool to examine such changes.
A network analysis approach was taken to examine how symptom networks change from pre- to post-combat using longitudinal prospective data from a cohort of infantry male soldiers (Mage = 18.8 years). PTSD symptoms measured using the PTSD Checklist (PCL) were assessed after 6 months of combat training but before deployment and again after 6 months of combat (Ns = 910 and 725 at pre-deployment and post-combat, respectively)
Stronger connectivity between PTSD symptoms was observed post-combat relative to pre-deployment (global strength values of the networks were 7.54 pre v. 7.92 post; S = .38, p < 0.05). Both the re-experiencing symptoms cluster (1.92 v. 2.12; S = .20, p < 0.03) and the avoidance symptoms cluster (2.61 v. 2.96; S = .35, p < 0.005) became more strongly inter-correlated post-combat. Centrality estimation analyses revealed that psychological reaction to triggers was central and linked the intrusion and avoidance sub-clusters at post-combat. The strength of associations between the arousal and reactivity symptoms cluster remained stable over time (1.85 v. 1.83; S = .02, p = .92).
Following combat, PTSD symptoms and particularly the re-experiencing and avoidance clusters become more strongly inter-correlated, indicating high centrality of trigger-reactivity symptoms.
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.
Randomized control trials (RCTs) comparing attention control training (ACT) and attention bias modification (ABM) in posttraumatic stress disorder (PTSD) have shown mixed results. The current RCT extends the extant literature by comparing the efficacy of ACT and a novel bias-contingent-ABM (BC-ABM), in which direction of training is contingent upon the direction of pre-treatment attention bias (AB), in a sample of civilian patients with PTSD.
Fifty treatment-seeking civilian patients with PTSD were randomly assigned to either ACT or BC-ABM. Clinician and self-report measures of PTSD and depression, as well as AB and attention bias variability (ABV), were acquired pre- and post-treatment.
ACT yielded greater reductions in PTSD and depressive symptoms on both clinician-rated and self-reported measures compared with BC-ABM. The BC-ABM condition successfully shifted ABs in the intended training direction. In the ACT group, there was no significant change in ABV or AB from pre- to post-treatment.
The current RCT extends previous results in being the first to apply ABM that is contingent upon AB at pre-treatment. This personalized BC-ABM approach is associated with significant reductions in symptoms. However, ACT produces even greater reductions, thereby emerging as a promising treatment for PTSD.
Cognitive–behavioral group therapy (CBGT) is a first-line treatment for social anxiety disorder (SAD). However, since many patients remain symptomatic post-treatment, there is a need for augmenting procedures. This randomized controlled trial (RCT) examined the potential augmentation effect of attention bias modification (ABM) for CBGT.
Fifty patients with SAD from three therapy groups were randomized to receive an 18-week standard CBGT with either ABM designed to shift attention away from threat (CBGT + ABM), or a placebo protocol not designed to modify threat-related attention (CBGT + placebo). Therapy groups took place in a large mental health center. Clinician and self-report measures of social anxiety and depression were acquired pre-treatment, post-treatment, and at 3-month follow-up. Attention bias was assessed at pre- and post-treatment.
Patients randomized to the CBGT + ABM group, relative to those randomized to the CBGT + placebo group, showed greater reductions in clinician-rated SAD symptoms post-treatment, with effects maintained at 3-month follow-up. Group differences were not evident for self-report or attention-bias measures, with similar reductions in both groups. Finally, reduction in attention bias did not mediate the association between group and reduction in Liebowitz Social Anxiety Scale Structured Interview (LSAS) scores.
This is the first RCT to examine the possible augmenting effect of ABM added to group-based cognitive–behavioral therapy for adult SAD. Training patients’ attention away from threat might augment the treatment response to standard CBGT in SAD, a possibility that could be further evaluated in large-scale RCTs.
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.