Social anxiety and age are associated with neural response to social evaluation during adolescence.

Adolescence is a sensitive period for the development of adaptive social behaviors and social anxiety, possibly due to aspects of brain development. However, research is needed to examine interactions among age, social anxiety, and social dynamics previously shown to influence neural responding. The current functional magnetic resonance imaging (fMRI) study examines brain function in 8-18 year-olds with varying levels of social anxiety. Interactions are examined among age, social anxiety, and two key task factors: valence and predictability of social interactions. Results demonstrate age, social anxiety severity, and each of the two key task-based factors interact to predict neural response in the caudate, middle and superior temporal gyri. In particular, among adolescents less-than 13 years of age, higher social anxiety predicted greater responding to unpredictable negative evaluations. However, in this same age group, the opposite pattern emerged during receipt of unpredictable positive evaluations, with less neural response in more anxious youth. Adolescents aged 13 and older overall showed less robust effects. We discuss these findings in terms of age- and anxiety-related differences in socioemotional processing.

Early-childhood social reticence predicts SCR-BOLD coupling during fear extinction recall in preadolescent youth.

Social Reticence (SR) is a temperament construct identified in early childhood that is expressed as shy, anxiously avoidant behavior and, particularly when stable, robustly associated with risk for anxiety disorders. Threat circuit function may develop differently for children high on SR than low on SR. We compared brain function and behavior during extinction recall in a sample of 11-to-15-year-old children characterized in early childhood on a continuum of SR. 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. Whereas self-report and psychophysiological measures of differential conditioning, extinction, and extinction recall were largely similar across participants, SR-related differences in brain function emerged during extinction recall. Specifically, childhood SR was associated with a distinct pattern of hemodynamic-autonomic covariation in the brain when recalling extinguished threat and safety cues. SR and attention focus impacted associations between trial-by-trial variation in autonomic responding and in brain activation. These interactions occurred in three main brain areas: the anterior insular cortex (AIC), the anterior subdivision of the medial cingulate cortex (aMCC), and the dorsolateral prefrontal cortex (dlPFC). This pattern of SCR-BOLD coupling may reflect selective difficulty tracking safety in a temperamentally at-risk population.

Frontal alpha asymmetry moderates the relations between behavioral inhibition and social-effect ERN.

Behavioral inhibition (BI) is an early temperamental precursor of anxiety disorders, characterized by withdrawal from novel situations. Some but not all young children with BI go on to display anxiety disorders. Neural correlates, such as frontal alpha asymmetry or event-related negativity (ERN), could moderate the relations between early BI and later anxiety. The goal of this longitudinal study was to test frontal alpha asymmetry as a potential moderator of the relation between BI and later anxiety, and of the relation between BI and the social-effect ERN. 100 children were assessed for BI at ages 2 and 3, and we collected EEG during resting state and the social Flanker task at age 12. Frontal alpha asymmetry did not correlate with BI or anxiety, nor did it moderate the relation between early BI and later anxiety. However, frontal alpha asymmetry did moderate the relation between BI and the social-effect ERN. This suggests that, in adolescents who previously manifested BI, a pattern of resting EEG associated with avoidance predicts hypersensitivity to errors in a social context.

Discriminant validity, diagnostic utility, and parent-child agreement on the Screen for Child Anxiety Related Emotional Disorders (SCARED) in treatment- and non-treatment-seeking youth.

The Screen for Child Anxiety and Related Emotional Disorder (SCARED) may be differentially sensitive to detecting specific or comorbid anxiety diagnoses in treatment-seeking and non-treatment-seeking youth. We assessed the SCARED's discriminant validity, diagnostic utility, and informant agreement using parent- and self-report from healthy and treatment-seeking anxious youth (Study 1, N=585) and from non-treatment-seeking anxious youth (Study 2, N=331) diagnosed with generalized anxiety disorder (GAD), social anxiety disorder (SAD), or comorbid GAD+SAD. Among treatment-seeking youth, the SCARED showed good diagnostic utility and specificity, differentiating healthy, comorbid, and non-comorbid anxious youth. Child-parent agreement was modest: healthy child self-reports were higher than parent-reports whereas anxious child self-reports were similar or lower than parent-reports. Less consistent results emerged for diagnostic utility, specificity, and informant agreement among non-treatment-seeking youth. Given the number of non-treatment seeking anxious youth (N=33), generalizability of these findings may be limited. Together, results suggest informants may provide distinct information about children's anxiety symptoms.

Reduced optimism and a heightened neural response to everyday worries are specific to generalized anxiety disorder, and not seen in social anxiety.

BACKGROUND: Generalized anxiety disorder (GAD) and social anxiety disorder (SAD) are co-morbid and associated with similar neural disruptions during emotion regulation. In contrast, the lack of optimism examined here may be specific to GAD and could prove an important biomarker for that disorder. METHOD: Unmedicated individuals with GAD (n = 18) and age-, intelligence quotient- and gender-matched SAD (n = 18) and healthy (n = 18) comparison individuals were scanned while contemplating likelihoods of high- and low-impact negative (e.g. heart attack; heartburn) or positive (e.g. winning lottery; hug) events occurring to themselves in the future. RESULTS: As expected, healthy subjects showed significant optimistic bias (OB); they considered themselves significantly less likely to experience future negative but significantly more likely to experience future positive events relative to others (p < 0.001). This was also seen in SAD, albeit at trend level for positive events (p < 0.001 and p < 0.10, respectively). However, GAD patients showed no OB for positive events (t 17 = 0.82, n.s.) and showed significantly reduced neural modulation relative to the two other groups of regions including the medial prefrontal cortex (mPFC) and caudate to these events (p < 0.001 for all). The GAD group further differed from the other groups by showing increased neural responses to low-impact events in regions including the rostral mPFC (p < 0.05 for both). CONCLUSIONS: The neural dysfunction identified here may represent a unique feature associated with reduced optimism and increased worry about everyday events in GAD. Consistent with this possibility, patients with SAD did not show such dysfunction. Future studies should consider if this dysfunction represents a biomarker for GAD.

Clinical anxiety promotes excessive response inhibition.

BACKGROUND: Laboratory tasks to delineate anxiety disorder features are used to refine classification and inform our understanding of etiological mechanisms. The present study examines laboratory measures of response inhibition, specifically the inhibition of a pre-potent motor response, in clinical anxiety. Data on associations between anxiety and response inhibition remain inconsistent, perhaps because of dissociable effects of clinical anxiety and experimentally manipulated state anxiety. Few studies directly assess the independent and interacting effects of these two anxiety types (state v. disorder) on response inhibition. The current study accomplished this goal, by manipulating state anxiety in healthy and clinically anxious individuals while they complete a response inhibition task. METHOD: The study employs the threat-of-shock paradigm, one of the best-established manipulations for robustly increasing state anxiety. Participants included 82 adults (41 healthy; 41 patients with an anxiety disorder). A go/nogo task with highly frequent go trials was administered during alternating periods of safety and shock threat. Signal detection theory was used to quantify response bias and signal-detection sensitivity. RESULTS: There were independent effects of anxiety and clinical anxiety on response inhibition. In both groups, heightened anxiety facilitated response inhibition, leading to reduced nogo commission errors. Compared with the healthy group, clinical anxiety was associated with excessive response inhibition and increased go omission errors in both the safe and threat conditions. CONCLUSIONS: Response inhibition and its impact on go omission errors appear to be a promising behavioral marker of clinical anxiety. These results have implications for a dimensional view of clinical anxiety.

Modulation of fear extinction processes using transcranial electrical stimulation.

Research associates processes of fear conditioning and extinction with treatment of anxiety and stress-related disorders. Manipulation of these processes may therefore be beneficial for such treatment. The current study examines the effects of electrical brain stimulation on fear extinction processes in healthy humans in order to assess its potential relevance for treatment enhancement. Forty-five participants underwent a 3-day fear conditioning and extinction paradigm. Electrical stimulation targeting the medial prefrontal cortex was applied during the extinction-learning phase (Day 2). Participants were randomly assigned to three stimulation conditions: direct-current (DC) stimulation, aimed at enhancing extinction-learning; low-frequency alternating-current (AC) stimulation, aimed at interfering with reconsolidation of the activated fear memory; and sham stimulation. The effect of stimulation on these processes was assessed in the subsequent extinction recall phase (Day 3), using skin conductance response and self-reports. Results indicate that AC stimulation potentiated the expression of fear response, whereas DC stimulation led to overgeneralization of fear response to non-reinforced stimuli. The current study demonstrates the capability of electrical stimulation targeting the medial prefrontal cortex to modulate fear extinction processes. However, the stimulation parameters tested here yielded effects opposite to those anticipated and could be clinically detrimental. These results highlight the potential capacity of stimulation to manipulate processes relevant for treatment of anxiety and stress-related disorders, but also emphasize the need for additional research to identify delivery parameters to enable its translation into clinical practice. Clinical trial identifiers: Modulation of Fear Extinction Processes Using Transcranial Electrical Stimulation; https://clinicaltrials.gov/show/NCT02723188; NCT02723188 NCT02723188.

Learning from other people's fear: amygdala-based social reference learning in social anxiety disorder.

BACKGROUND: Social anxiety disorder involves fear of social objects or situations. Social referencing may play an important role in the acquisition of this fear and could be a key determinant in future biomarkers and treatment pathways. However, the neural underpinnings mediating such learning in social anxiety are unknown. Using event-related functional magnetic resonance imaging, we examined social reference learning in social anxiety disorder. Specifically, would patients with the disorder show increased amygdala activity during social reference learning, and further, following social reference learning, show particularly increased response to objects associated with other people's negative reactions? METHOD: A total of 32 unmedicated patients with social anxiety disorder and 22 age-, intelligence quotient- and gender-matched healthy individuals responded to objects that had become associated with others' fearful, angry, happy or neutral reactions. RESULTS: During the social reference learning phase, a significant group × social context interaction revealed that, relative to the comparison group, the social anxiety group showed a significantly greater response in the amygdala, as well as rostral, dorsomedial and lateral frontal and parietal cortices during the social, relative to non-social, referencing trials. In addition, during the object test phase, relative to the comparison group, the social anxiety group showed increased bilateral amygdala activation to objects associated with others' fearful reactions, and a trend towards decreased amygdala activation to objects associated with others' happy and neutral reactions. CONCLUSIONS: These results suggest perturbed observational learning in social anxiety disorder. In addition, they further implicate the amygdala and dorsomedial prefrontal cortex in the disorder, and underscore their importance in future biomarker developments.

Selective prevention of combat-related post-traumatic stress disorder using attention bias modification training: a randomized controlled trial.

BACKGROUND: Efficacy of pre-trauma prevention for post-traumatic stress disorder (PTSD) has not yet been established in a randomized controlled trial. Attention bias modification training (ABMT), a computerized intervention, is thought to mitigate stress-related symptoms by targeting disruptions in threat monitoring. We examined the efficacy of ABMT delivered before combat in mitigating risk for PTSD following combat. METHOD: We conducted a double-blind, four-arm randomized controlled trial of 719 infantry soldiers to compare the efficacy of eight sessions of ABMT (n = 179), four sessions of ABMT (n = 184), four sessions of attention control training (ACT; n = 180), or no-training control (n = 176). Outcome symptoms were measured at baseline, 6-month follow-up, 10 days following combat exposure, and 4 months following combat. Primary outcome was PTSD prevalence 4 months post-combat determined in a clinical interview using the Clinician-Administered PTSD Scale. Secondary outcomes were self-reported PTSD and depression symptoms, collected at all four assessments. RESULTS: PTSD prevalence 4 months post-combat was 7.8% in the no-training control group, 6.7% with eight-session ABMT, 2.6% with four-session ABMT, and 5% with ACT. Four sessions of ABMT reduced risk for PTSD relative to the no-training condition (odds ratio 3.13, 95% confidence interval 1.01-9.22, p < 0.05, number needed to treat = 19.2). No other between-group differences were found. The results were consistent across a variety of analytic techniques and data imputation approaches. CONCLUSIONS: Four sessions of ABMT, delivered prior to combat deployment, mitigated PTSD risk following combat exposure. Given its low cost and high scalability potential, and observed number needed to treat, research into larger-scale applications is warranted. The ClinicalTrials.gov identifier is NCT01723215.

Disentangling the autism-anxiety overlap: fMRI of reward processing in a community-based longitudinal study.

Up to 40% of youth with autism spectrum disorder (ASD) also suffer from anxiety, and this comorbidity is linked with significant functional impairment. However, the mechanisms of this overlap are poorly understood. We investigated the interplay between ASD traits and anxiety during reward processing, known to be affected in ASD, in a community sample of 1472 adolescents (mean age=14.4 years) who performed a modified monetary incentive delay task as part of the Imagen project. Blood-oxygen-level dependent (BOLD) responses to reward anticipation and feedback were compared using a 2x2 analysis of variance test (ASD traits: low/high; anxiety symptoms: low/high), controlling for plausible covariates. In addition, we used a longitudinal design to assess whether neural responses during reward processing predicted anxiety at 2-year follow-up. High ASD traits were associated with reduced BOLD responses in dorsal prefrontal regions during reward anticipation and negative feedback. Participants with high anxiety symptoms showed increased lateral prefrontal responses during anticipation, but decreased responses following feedback. Interaction effects revealed that youth with combined ASD traits and anxiety, relative to other youth, showed high right insula activation when anticipating reward, and low right-sided caudate, putamen, medial and lateral prefrontal activations during negative feedback (all clusters PFWE<0.05). BOLD activation patterns in the right dorsal cingulate and right medial frontal gyrus predicted new-onset anxiety in participants with high but not low ASD traits. Our results reveal both quantitatively enhanced and qualitatively distinct neural correlates underlying the comorbidity between ASD traits and anxiety. Specific neural responses during reward processing may represent a risk factor for developing anxiety in ASD youth.

Aberrant intrinsic functional connectivity within and between corticostriatal and temporal-parietal networks in adults and youth with bipolar disorder.

BACKGROUND: Major questions remain regarding the dysfunctional neural circuitry underlying the pathophysiology of bipolar disorder (BD) in both youths and adults. In both age groups, studies implicate abnormal intrinsic functional connectivity among prefrontal, limbic and striatal areas. METHOD: We collected resting-state functional magnetic resonance imaging (fMRI) data from youths and adults (ages 10-50 years) with BD (n = 39) and healthy volunteers (HV; n = 78). We identified brain regions with aberrant intrinsic functional connectivity in BD by first comparing voxel-wise mean global connectivity and then conducting correlation analyses. We used k-means clustering and multidimensional scaling to organize all detected regions into networks. RESULTS: Across the brain, we detected areas of dysconnectivity in both youths and adults with BD relative to HV. There were no significant age-group × diagnosis interactions. When organized by interregional connectivity, the areas of dysconnectivity in patients with BD comprised two networks: one of temporal and parietal areas involved in late stages of visual processing, and one of corticostriatal areas involved in attention, cognitive control and response generation. CONCLUSIONS: These data suggest that two networks show abnormal intrinsic functional connectivity in BD. Regions in these networks have been implicated previously in BD. We observed similar dysconnectivity in youths and adults with BD. These findings provide guidance for refining models of network-based dysfunction in BD.

Attention network functioning in children with anxiety disorders, attention-deficit/hyperactivity disorder and non-clinical anxiety.

BACKGROUND: Research with adults suggests that anxiety is associated with poor control of executive attention. However, in children, it is unclear (a) whether anxiety disorders and non-clinical anxiety are associated with deficits in executive attention, (b) whether such deficits are specific to anxiety versus other psychiatric disorders, and (c) whether there is heterogeneity among anxiety disorders (in particular, specific phobia versus other anxiety disorders). METHOD: We examined executive attention in 860 children classified into three groups: anxiety disorders (n = 67), attention-deficit/hyperactivity disorder (ADHD; n = 67) and no psychiatric disorder (n = 726). Anxiety disorders were subdivided into: anxiety disorders excluding specific phobia (n = 43) and specific phobia (n = 21). The Attention Network Task was used to assess executive attention, alerting and orienting. RESULTS: Findings indicated heterogeneity among anxiety disorders, as children with anxiety disorders (excluding specific phobia) showed impaired executive attention, compared with disorder-free children, whereas children with specific phobia showed no executive attention deficit. Among disorder-free children, executive attention was less efficient in those with high, relative to low, levels of anxiety. There were no anxiety-related deficits in orienting or alerting. Children with ADHD not only had poorer executive attention than disorder-free children, but also higher orienting scores, less accurate responses and more variable response times. CONCLUSIONS: Impaired executive attention in children (reflected by difficulty inhibiting processing of task-irrelevant information) was not fully explained by general psychopathology, but instead showed specific associations with anxiety disorders (other than specific phobia) and ADHD, as well as with high levels of anxiety symptoms in disorder-free children.

Behavioral and neurodevelopmental precursors to binge-type eating disorders: support for the role of negative valence systems.

BACKGROUND: Pediatric loss-of-control (LOC) eating is a robust behavioral precursor to binge-type eating disorders. Elucidating precursors to LOC eating and binge-type eating disorders may refine developmental risk models of eating disorders and inform interventions. METHOD: We review evidence within constructs of the Negative Valence Systems (NVS) domain, as specified by the Research Domain Criteria framework. Based on published studies, we propose an integrated NVS model of binge-type eating-disorder risk. RESULTS: Data implicate altered corticolimbic functioning, neuroendocrine dysregulation, and self-reported negative affect as possible risk factors. However, neuroimaging and physiological data in children and adolescents are sparse, and most prospective studies are limited to self-report measures. CONCLUSIONS: We discuss a broad NVS framework for conceptualizing early risk for binge-type eating disorders. Future neural and behavioral research on the developmental trajectory of LOC and binge-type eating disorders is required.

An fMRI study of emotional face encoding in youth at risk for bipolar disorder.

Face memory deficits may be a bipolar disorder (BD) endophenotype. BD (n=27) and unaffected youth at risk (n=13) exhibited middle frontal gyrus hypoactivation during successful vs. unsuccessful encoding. Parahippocampal gyrus dysfunction was found in BD and at-risk youth (vs. low-risk, n=37). Middle occipital gyrus hypoactivation was only present in BD.

A neurobehavioral account for individual differences in resilience to chronic military stress.

BACKGROUND: Military training is a chronic stressful period that often induces stress-related psychopathology. Stress vulnerability and resilience depend on personality trait anxiety, attentional threat bias and prefrontal-limbic dysfunction. However, how these neurobehavioral elements interact with regard to the development of symptoms following stress remains unclear. METHOD: Fifty-five healthy combat soldiers undergoing intensive military training completed functional magnetic resonance imaging (fMRI) testing while performing the dot-probe task (DPT) composed of angry (threat) and neutral faces. Participants were then stratified according to their bias tendency to avoidance (n = 25) or vigilance (n = 30) groups, categorized as high or low trait anxiety and assessed for post-stress symptom severity. RESULTS: Avoidance compared to vigilance tendency was associated with fewer post-trauma symptoms and increased hippocampal response to threat among high anxious but not low anxious individuals. Importantly, mediation analysis revealed that only among high anxious individuals did hippocampal activity lead to lower levels of symptoms through avoidance bias tendency. However, in the whole group, avoidance bias was modulated by the interplay between the hippocampus and the dorsal anterior cingulate cortex (dACC). CONCLUSIONS: Our results provide a neurobehavioral model to explain the resilience to post-trauma symptoms following chronic exposure. The model points to the importance of considering threat bias tendency in addition to personality traits when investigating the brain response and symptoms of trauma. Such a multi-parametric approach that accounts for individual behavioral sensitivities may also improve brain-driven treatments of anxiety, possibly by targeting the interplay between the hippocampus and the dACC.

Light-activated self-propelled colloids.

Light-activated self-propelled colloids are synthesized and their active motion is studied using optical microscopy. We propose a versatile route using different photoactive materials, and demonstrate a multiwavelength activation and propulsion. Thanks to the photoelectrochemical properties of two semiconductor materials (α-Fe2O3 and TiO2), a light with an energy higher than the bandgap triggers the reaction of decomposition of hydrogen peroxide and produces a chemical cloud around the particle. It induces a phoretic attraction with neighbouring colloids as well as an osmotic self-propulsion of the particle on the substrate. We use these mechanisms to form colloidal cargos as well as self-propelled particles where the light-activated component is embedded into a dielectric sphere. The particles are self-propelled along a direction otherwise randomized by thermal fluctuations, and exhibit a persistent random walk. For sufficient surface density, the particles spontaneously form 'living crystals' which are mobile, break apart and reform. Steering the particle with an external magnetic field, we show that the formation of the dense phase results from the collisions heads-on of the particles. This effect is intrinsically non-equilibrium and a novel principle of organization for systems without detailed balance. Engineering families of particles self-propelled by different wavelength demonstrate a good understanding of both the physics and the chemistry behind the system and points to a general route for designing new families of self-propelled particles.

A microscopic view of the yielding transition in concentrated emulsions.

We use a custom shear cell coupled to an optical microscope to investigate at the particle level the yielding transition in concentrated emulsions subjected to an oscillatory shear deformation. By performing experiments lasting thousands of cycles on samples at several volume fractions and for a variety of applied strain amplitudes, we obtain a comprehensive, microscopic picture of the yielding transition. We find that irreversible particle motion sharply increases beyond a volume-fraction dependent critical strain, which is found to be in close agreement with the strain beyond which the stress-strain relation probed in rheology experiments significantly departs from linearity. The shear-induced dynamics are very heterogenous: quiescent particles coexist with two distinct populations of mobile and 'supermobile' particles. Dynamic activity exhibits spatial and temporal correlations, with rearrangements events organized in bursts of motion affecting localized regions of the sample. Analogies with other sheared soft materials and with recent work on the transition to irreversibility in sheared complex fluids are briefly discussed.