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Psychiatric symptoms are commonly comorbid in childhood. The ability to disentangle unique and shared correlates of comorbid symptoms facilitates personalized medicine. Cognitive control is implicated broadly in psychopathology, including in pediatric disorders characterized by anxiety and irritability. To disentangle cognitive control correlates of anxiety versus irritability, the current study leveraged both cross-sectional and longitudinal data from early childhood into adolescence.For this study, 89 participants were recruited from a large longitudinal research study on early-life temperament to investigate associations of developmental trajectories of anxiety and irritability symptoms (from ages 2 to 15) as well as associations of anxiety and irritability symptoms measured cross-sectionally at age 15 with neural substrates of conflict and error processing assessed at age 15 using the flanker task.Results of whole-brain multivariate linear models revealed that anxiety at age 15 was uniquely associated with decreased neural response to conflict across multiple regions implicated in attentional control and conflict adaptation. Conversely, irritability at age 15 was uniquely associated with increased neural response to conflict in regions implicated in response inhibition. Developmental trajectories of anxiety and irritability interacted in relation to neural responses to both error and conflict.Our findings suggest that neural correlates of conflict processing may relate uniquely to anxiety and irritability. Continued cross-symptom research on the neural correlates of cognitive control could stimulate advances in individualized treatment for anxiety and irritability during child and adolescent development.

Background In a recent eye-tracking study we found a differential dwell time pattern for negatively-valenced and neutral faces among patients with posttraumatic stress disorder (PTSD), trauma-exposed healthy control (TEHCs), and healthy control (HC) participants. Here, we explored whether these group differences relate to resting-state functional connectivity (rsFC) patterns of brain areas previously linked to both attention processes and PTSD. These encompass the amygdala, dorsal anterior cingulate cortex (dACC), dorsolateral prefrontal cortex (dlPFC), ventrolateral prefrontal cortex (vlPFC), and nucleus accumbens (NAcc). Methods Ten minutes magnetic resonance imaging rsFC scans were recorded in 17 PTSD patients, 21 TEHCs, and 16 HCs. Participants then completed a free-viewing eye-tracking task assessing attention allocation outside the scanner. Dwell time on negatively-valenced stimuli (DT%) were assessed relative to functional connectivity in the aforementioned seed regions of interest (amygdala, dACC, dlPFC, vlPFC, and NAcc) to whole-brain voxel-wise rsFC. Results As previously reported, group differences occurred in attention allocation to negative-valence stimuli, with longer dwell time on negatively valence stimuli in the PTSD and TEHC groups than the HC group. Higher DT% correlated with weaker NAcc-orbitofrontal cortex (OFC) connectivity in patients with PTSD. Conversely, a positive association emerged in the HC group between DT% and NAcc-OFC connectivity. Conclusions While exploratory in nature, present findings may suggest that reward-related brain areas are involved in disengaging attention from negative-valenced stimuli, and possibly in regulating ensuing negative emotions.

Does our mood change as time passes? This question is central to behavioural and affective science, yet it remains largely unexamined. To investigate, we intermixed subjective momentary mood ratings into repetitive psychology paradigms. We demonstrate that task and rest periods lowered participants' mood, an effect we call "Mood Drift Over Time." This finding was replicated in 19 cohorts totaling 28,482 adult and adolescent participants. The drift was relatively large (-13.8% after 7.3 minutes of rest, Cohen's d=0.574) and was consistent across cohorts. Behaviour was also impacted: participants were less likely to gamble in a task that followed a rest period. Importantly, the drift slope was inversely related to reward sensitivity. We show that accounting for time using a linear term significantly improves the fit of a computational model of mood. Our work provides conceptual and methodological reasons for researchers to account for time's effects when studying mood and behaviour.

Excessive fear responses to uncertain threat are a key feature of anxiety disorders (ADs), though most mechanistic work considers adults. As ADs onset in childhood and confer risk for later psychopathology, we sought to identify conditions of uncertain threat that distinguish 8-17-year-old youth with AD (n = 19) from those without AD (n = 33), and assess test-retest reliability of such responses in a companion sample of healthy adults across three sites (n = 19). In an adapted uncertainty of threat paradigm, visual cues parametrically signaled threat of aversive stimuli (fear faces) in 25 % increments (0 %, 25 %, 50 %, 100 %), while participants underwent functional magnetic resonance imaging (fMRI). We compared neural response elicited by cues signaling different degrees of probability regarding the subsequent delivery of fear faces. Overall, youth displayed greater engagement of bilateral inferior parietal cortex, fusiform gyrus, and lingual gyrus during uncertain threat anticipation in general. Relative to healthy youth, AD youth exhibited greater activation in ventrolateral prefrontal cortex (vlPFC)/BA47 during uncertain threat anticipation in general. Further, AD differed from healthy youth in scaling of ventral striatum/sgACC activation with threat probability and attenuated flexibility of responding during parametric uncertain threat. Complementing these results, significant, albeit modest, cross-site test-retest reliability in these regions was observed in an independent sample of healthy adults. While preliminary due to a small sample size, these findings suggest that during uncertainty of threat, AD youth engage vlPFC regions known to be involved in fear regulation, response inhibition, and cognitive control. Findings highlight the potential of isolating neural correlates of threat anticipation to guide treatment development and translational work in youth.

Although youth anxiety treatment research has focused largely on severe and impairing anxiety levels, even milder anxiety levels, including levels that do not meet full criteria for a diagnosis, can be impairing and cause for concern. There is a need to develop and test viable treatments for these concerning anxiety levels to improve functioning and reduce distress. We present findings from a randomized controlled efficacy trial of attention bias modification treatment (ABMT) and attention control training (ACT) for youths with concerning anxiety levels. Fifty-three clinic-referred youths (29 boys, M age = 9.3 years, SD age = 2.6) were randomized to either ABMT or ACT. ABMT and ACT consisted of attention-training trials in a dot-probe task presenting angry and neutral faces; probes appeared in the location of neutral faces in 100% of ABMT trials and 50% of ACT trials. Independent evaluators provided youth anxiety severity ratings; youths and parents provided youth anxiety severity and global impairment ratings; and youths completed measures of attention bias to threat and attention control at pretreatment, posttreatment, and 2-month follow-up. In both arms, anxiety severity and global impairment were significantly reduced at posttreatment and follow-up. At follow-up, anxiety severity and global impairment were significantly lower in ACT compared with ABMT. Attention control, but not attention bias to threat, was significantly improved at follow-up in both arms. Changes in attention control and attention focusing were significantly associated with changes in anxiety severity. Findings support the viability of attention training as a low-intensity treatment for youths with concerning anxiety levels, including levels that do not meet full criteria for a diagnosis. Superior anxiety reduction effects in ACT highlight the critical need for mechanistic research on attention training in this population.

Quantitative sensory testing (QST) allows researchers to evaluate associations between noxious stimuli and acute pain in clinical populations and healthy participants. Despite its widespread use, our understanding of QST's reliability is limited, as reliability studies have used small samples and restricted time windows. We examined the reliability of pain ratings in response to noxious thermal stimulation in 171 healthy volunteers (n = 99 female, n = 72 male) who completed QST on multiple visits ranging from 1 day to 952 days between visits. On each visit, participants underwent an adaptive pain calibration in which they experienced 24 heat trials and rated pain intensity after stimulus offset on a 0 to 10 Visual Analog Scale. We used linear regression to determine pain threshold, pain tolerance, and the correlation between temperature and pain for each session and examined the reliability of these measures. Threshold and tolerance were moderately reliable (Intra-class correlation = .66 and .67, respectively; Plt; .001), whereas temperature-pain correlations had low reliability (Intra-class correlation = .23). In addition, pain tolerance was significantly more reliable in female participants than male participants, and we observed similar trends for other pain sensitive measures. Our findings indicate that threshold and tolerance are largely consistent across visits, whereas sensitivity to changes in temperature vary over time and may be influenced by contextual factors. PERSPECTIVE: This article assesses the reliability of an adaptive thermal pain calibration procedure. We find that pain threshold and tolerance are moderately reliable whereas the correlation between pain rating and stimulus temperature has low reliability. Female participants were more reliable than male participants on all pain sensitivity measures.

BackgroundMany individuals with posttraumatic stress disorder (PTSD) have limited access to first-line treatments, warranting the development of remotely-delivered treatments. Attention bias modification (ABM), targeting perturbed threat-related attentional patterns, shows promise when delivered in-person. However, previous studies found ABM to be ineffective when delivered remotely. Randomized clinical trials usually applied two variations of ABM: ABM away from threat or attention control training (ACT) balancing attention between threat-related and neutral stimuli. We tested remotely-delivered ACT/ABM with tighter supervision and video-based interactions that resemble in-clinic protocols. We expected to replicate the results of in-clinic trials, in which ACT outperformed ABM for PTSD.MethodsIn this double-blinded, parallel-group randomized controlled trial, 60 patients diagnosed with PTSD were randomized (ABMn= 30; ACTn= 30). Patients performed eight bi-weekly remotely-delivered supervised ABM/ACT sessions. Symptoms were assessed pre- and post-treatment with Clinician-Administered PTSD Scale 5 (CAPS-5) severity score and PTSD diagnosis as the primary outcomes. Current depressive episode, current anxiety-related comorbidity, and time elapsed since the trauma were examined as potential moderators of treatment outcome.ResultsSignificant decrease in CAPS-5 severity scores and PTSD diagnosis was observed following both ACT and ABM with no between-group difference. Patients without depression or whose trauma occurred more recently had greater symptom reduction in the ACT than the ABM group.ConclusionsContrary to our expectation, symptoms decreased similarly following ACT and ABM. Moderator analyses suggest advantage for ACT in non-depressed patients and patients whose trauma occurred more recently. Further refinements in remotely-delivered ABM/ACT may be needed.

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.

Typical FMRI analyses assume a canonical hemodynamic response function (HRF) with a focus on the overshoot peak height, while other morphological aspects are largely ignored. Thus, in most reported analyses, the overall effect is reduced from a curve to a single scalar. Here, we adopt a data-driven approach to HRF estimation at the whole-brain voxel level, without assuming a response profile at the individual level. Then, we estimate the response in its entirety with a roughness penalty at the population level to improve predictive accuracy, inferential efficiency, and cross-study reproducibility. Using a fast event-related FMRI dataset, we demonstrate the extent of under-fitting and information loss that occurs when adopting the canonical approach. We also address the following questions:How much does the HRF shape vary across regions, conditions, and groups?Does an agnostic approach improve sensitivity to detect an effect compared to an assumed HRF?Can examining HRF shape help validate the presence of an effect complementing statistical evidence?Could the HRF shape provide evidence for whole-brain BOLD response during a simple task?

Despite considerable progress in pharmacotherapy over the past seven decades, many mental disorders remain insufficiently treated. This situation is in part due to the limited knowledge of the pathophysiology of these disorders and the lack of biological markers to stratify and individualize patient selection, but also to a still restricted number of mechanisms of action being targeted in monotherapy or combination/augmentation treatment, as well as to a variety of challenges threatening the successful development and testing of new drugs. In this paper, we first provide an overview of the most promising drugs with innovative mechanisms of action that are undergoing phase 2 or 3 testing for schizophrenia, bipolar disorder, major depressive disorder, anxiety and trauma‐related disorders, substance use disorders, and dementia. Promising repurposing of established medications for new psychiatric indications, as well as variations in the modulation of dopamine, noradrenaline and serotonin receptor functioning, are also considered. We then critically discuss the clinical trial parameters that need to be considered in depth when developing and testing new pharmacological agents for the treatment of mental disorders. Hurdles and perils threatening success of new drug development and testing include inadequacy and imprecision of inclusion/exclusion criteria and ratings, sub‐optimally suited clinical trial participants, multiple factors contributing to a large/increasing placebo effect, and problems with statistical analyses. This information should be considered in order to de‐risk trial programmes of novel agents or known agents for novel psychiatric indications, increasing their chances of success.

Contains fulltext : 288062.pdf (Publisher’s version ) (Closed access) There is limited convergence in neuroimaging investigations into volumes of subcortical brain regions in social anxiety disorder (SAD). The inconsistent findings may arise from variations in methodological approaches across studies, including sample selection based on age and clinical characteristics. The ENIGMA-Anxiety Working Group initiated a global mega-analysis to determine whether differences in subcortical volumes can be detected in adults and adolescents with SAD relative to healthy controls. Volumetric data from 37 international samples with 1115 SAD patients and 2775 controls were obtained from ENIGMA-standardized protocols for image segmentation and quality assurance. Linear mixed-effects analyses were adjusted for comparisons across seven subcortical regions in each hemisphere using family-wise error (FWE)-correction. Mixed-effects d effect sizes were calculated. In the full sample, SAD patients showed smaller bilateral putamen volume than controls (left: d = -0.077, pFWE = 0.037; right: d = -0.104, pFWE = 0.001), and a significant interaction between SAD and age was found for the left putamen (r = -0.034, pFWE = 0.045). Smaller bilateral putamen volumes (left: d = -0.141, pFWE

Background: Social reticence in early childhood is characterized by shy and anxiously avoidant behavior, and it confers risk for pediatric anxiety disorders later in development. Aberrant threat processing may play a critical role in this association between early reticent behavior and later psychopathology. The goal of this longitudinal study is to characterize developmental trajectories of neural mechanisms underlying threat processing and relate these trajectories to associations between early-childhood social reticence and adolescent anxiety. Methods: In this 16-year longitudinal study, social reticence was assessed from 2 to 7 years of age; anxiety symptoms and neural mechanisms during the dot-probe task were assessed at 10, 13, and 16 years of age. The sample included 144 participants: 71 children provided data at age 10 (43 girls, meanage = 10.62), 85 at age 13 (46 girls, meanage = 13.25), and 74 at age 16 (36 girls, meanage = 16.27). Results: A significant interaction manifested among social reticence, anxiety symptoms, and time, on functional connectivity between the left amygdala and the left dorsolateral prefrontal cortex, voxelwise p < .001, clusterwise familywise error p < .05. Children with high social reticence showed a negative association between amygdala–dorsolateral prefrontal cortex connectivity and anxiety symptoms with age, compared to children with low social reticence, suggesting distinct neurodevelopmental pathways to anxiety. Conclusions: These findings were present across all conditions, suggesting task-general effects in potential threat processing. Additionally, the timing of these neurodevelopmental pathways differed for children with high versus low social reticence, which could affect the timing of effective preventive interventions.

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.

Anxiety disorders are characterized by maladaptive defensive responses to distal or uncertain threats. Elucidating neural mechanisms of anxiety is essential to understand the development and maintenance of anxiety disorders. In fMRI, patients with pathological anxiety (ANX, n = 23) and healthy controls (HC, n = 28) completed a contextual threat learning paradigm in which they picked flowers in a virtual environment comprising a danger zone in which flowers were paired with shock and a safe zone (no shock). ANX compared with HC showed 1) decreased ventromedial prefrontal cortex and anterior hippocampus activation during the task, particularly in the safe zone, 2) increased insula and dorsomedial prefrontal cortex activation during the task, particularly in the danger zone, and 3) increased amygdala and midbrain/periaqueductal gray activation in the danger zone prior to potential shock delivery. Findings suggest that ANX engage brain areas differently to modulate context-appropriate emotional responses when learning to discriminate cues within an environment., Suarez-Jimenez and colleagues use a shock and safe zone experiment with fMRI imaging to examine how pathological anxiety disorders are manifested in the brain. Their findings suggest that safe and dangerous zones within the experiment alter activation in different brain regions.

Approximately two thirds of veterans with posttraumatic stress disorder (PTSD) remain with the disorder following treatment. Pinpointing the per-symptom effectiveness of treatments in real-world clinical settings can highlight relevant domains for treatment augmentation and development. Baseline and posttreatment assessments of PTSD and depression were performed in 709 veterans with PTSD. PTSD remission was 39.4%. Treatment was least effective for intrusion symptoms and had no effect on flashbacks or on poor recall of traumatic features. Of veterans who remitted, 72.8% still met diagnostic criteria for at least one cluster. Poor clinical effectiveness was noted for depression; only 4.1% of the patients remitted following treatment. Treatments for veterans with PTSD show limited overall effectiveness in real-world settings. Enhancing treatment response may require enhancing provider fidelity and patient compliance with extant treatments or the development of new treatments that specifically target the symptoms of PTSD that do not respond well to extant treatments.

This review describes approaches to research on anxiety that attempt to link neural correlates to treatment response and novel therapies. The review emphasizes pediatric anxiety disorders since most anxiety disorders begin before adulthood.Recent literature illustrates how current treatments for anxiety manifest diverse relations with a range of neural markers. While some studies demonstrate post-treatment normalization of markers in anxious individuals, others find persistence of group differences. For other markers, which show no pretreatment association with anxiety, the markers nevertheless distinguish treatment-responders from non-responders. Heightened error related negativity represents the risk marker discussed in the most depth; however, limitations in measures related to error responding necessitate multimodal and big-data approaches. Single risk markers show limits as correlates of treatment response. Large-scale, multimodal data analyzed with predictive models may illuminate additional risk markers related to anxiety disorder treatment outcomes. Such work may identify novel targets and eventually guide improvements in treatment response/outcomes.

Background Pediatric anxiety disorders are linked to dysfunction in multiple functional brain networks, as well as to alterations in the allocation of spatial attention. We used network-level analyses to characterize resting-state functional connectivity (rs-fc) alterations associated with 1) symptoms of anxiety and 2) alterations in stimulus-driven attention associated with pediatric anxiety disorders. We hypothesized that anxiety was related to altered connectivity of the frontoparietal, default mode, cingulo-opercular, and ventral attention networks and that anxiety-related connectivity alterations that include the ventral attention network would simultaneously be related to deviations in stimulus-driven attention. Methods A sample of children (n = 61; mean = 10.6 years of age), approximately half of whom met criteria for a current anxiety disorder, completed a clinical assay, an attention task, and rs-fc magnetic resonance imaging scans. Network-level analyses examined whole-brain rs-fc patterns associated with clinician-rated anxiety and with involuntary capture of attention. Post hoc analyses controlled for comorbid symptoms. Results Elevated clinician-rated anxiety was associated with altered connectivity within the cingulo-opercular network, as well as between the cingulo-opercular network and the ventral attention, default mode, and visual networks. Connectivity between the ventral attention and cingulo-opercular networks was associated with variation in both anxiety and stimulus-driven attention. Conclusions Pediatric anxiety is related to aberrant connectivity patterns among several networks, most of which include the cingulo-opercular network. These results help clarify the within- and between-network interactions associated with pediatric anxiety and its association with altered attention, suggesting that specific network connections could be targeted to improve specific altered processes associated with anxiety.

Objective: The Affective Reactivity Index (ARI) is widely used to assess young people’s irritability symptoms, but youth and caregivers often diverge in their assessments. Such informant discrepancy might stem from poor reliability. However, evidence from genetic, imaging and treatment studies suggests that irritability may not be a unitary construct. Hence informants might be sensitive to different aspects of irritability. We use an out-of-sample replication approach and a longitudinal design to test these hypotheses. Method: Across two independent samples (N1=765, 8-21 years; N2=1910, 6-21 years), we investigate the reliability and measurement invariance of the ARI, examine sociodemographic and clinical predictors of discrepant reporting, and probe the utility of a bifactor model for cross-informant integration. Results: Despite good internal consistency and 6-week-retest-reliability of parent and youth forms, we confirm substantial informant discrepancy in ARI ratings, which is stable over six weeks (n1=177). Measurement invariance across informants was weak, indicating that parents and youth may interpret ARI items differently. Informant-discrepancy increased with irritability severity, but which informant reported higher child-irritability depended on the child’s diagnostic status. In both datasets, a bifactor model parsing informant-specific from shared irritability-related variance fit the data well. Conclusion: Parent and youth ARI reports and their discrepancy are reliable. However, parent and youth ratings may reflect different interpretations of the scale items; hence they should not be averaged. Our findings suggest that irritability is not a unitary construct. Future work should investigate and model different aspects of irritability, which might be more accessible to specific informants.

While it is normal to be scared of things, some children are so scared that it disrupts their lives. This is called an anxiety disorder. To help children with anxiety disorders, we need to know how anxiety disorders start. From other research we knew that toddlers who avoid new situations are more likely to become anxious later in life. They are more likely, which does not mean they all become more anxious, just some of them. We wanted to know if brain activity could predict which children would become anxious. We studied avoidance in toddlers and invited them back as preteens. We studied their brains while they were resting and while they were making mistakes in front of somebody else. We found that brain responses to mistakes predicted which avoidant toddlers became very anxious as preteens. This helps us understand who might develop anxiety, so that we can help!

Aberrant decision-making characterizes various pediatric psychopathologies; however, deliberative choice strategies have not been investigated. A transdiagnostic sample of 95 youths completed a child-friendly sequential sampling paradigm. Participants searched for the best offer by sampling a finite list of offers. Participants’ willingness to explore was measured as the number of offers sampled, and ideal task performance was modeled using a Markov decision-process model. As in previous findings in adults, youths explored more offers when lists were long compared with short, yet participants generally sampled fewer offers relative to model-estimated ideal performance. Searching deeper into the list was associated with choosing better price options. Analyses examining the main and interactive effects of transdiagnostic anxiety and irritability symptoms indicated a negative correlation between anxiety and task performance ( p = .01, η p2 = .08). Findings suggest the need for more research on exploratory decision impairments in youths with anxiety symptoms.