Reliability of task-evoked neural activation during face-emotion paradigms: Effects of scanner and psychological processes.

Assessing and improving test-retest reliability is critical to efforts to address concerns about replicability of task-based functional magnetic resonance imaging. The current study uses two statistical approaches to examine how scanner and task-related factors influence reliability of neural response to face-emotion viewing. Forty healthy adult participants completed two face-emotion paradigms at up to three scanning sessions across two scanners of the same build over approximately 2 months. We examined reliability across the main task contrasts using Bayesian linear mixed-effects models performed voxel-wise across the brain. We also used a novel Bayesian hierarchical model across a predefined whole-brain parcellation scheme and subcortical anatomical regions. Scanner differences accounted for minimal variance in temporal signal-to-noise ratio and task contrast maps. Regions activated during task at the group level showed higher reliability relative to regions not activated significantly at the group level. Greater reliability was found for contrasts involving conditions with clearly distinct visual stimuli and associated cognitive demands (e.g., face vs. nonface discrimination) compared to conditions with more similar demands (e.g., angry vs. happy face discrimination). Voxel-wise reliability estimates tended to be higher than those based on predefined anatomical regions. This work informs attempts to improve reliability in the context of task activation patterns and specific task contrasts. Our study provides a new method to estimate reliability across a large number of regions of interest and can inform researchers' selection of task conditions and analytic contrasts.

A computational network perspective on pediatric anxiety symptoms.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Threat-anticipatory psychophysiological response is enhanced in youth with anxiety disorders and correlates with prefrontal cortex neuroanatomy.

Background: Threat anticipation engages neural circuitry that has evolved to promote defensive behaviours; perturbations in this circuitry could generate excessive threat-anticipation response, a key characteristic of pathological anxiety. Research into such mechanisms in youth faces ethical and practical limitations. Here, we use thermal stimulation to elicit pain-anticipatory psychophysiological response and map its correlates to brain structure among youth with anxiety and healthy youth. Methods: Youth with anxiety (n = 25) and healthy youth (n = 25) completed an instructed threat-anticipation task in which cues predicted nonpainful or painful thermal stimulation; we indexed psychophysiological response during the anticipation and experience of pain using skin conductance response. High-resolution brain-structure imaging data collected in another visit were available for 41 participants. Analyses tested whether the 2 groups differed in their psychophysiological cue-based pain-anticipatory and pain-experience responses. Analyses then mapped psychophysiological response magnitude to brain structure. Results: Youth with anxiety showed enhanced psychophysiological response specifically during anticipation of painful stimulation (b = 0.52, p = 0.003). Across the sample, the magnitude of psychophysiological anticipatory response correlated negatively with the thickness of the dorsolateral prefrontal cortex (pFWE < 0.05); psychophysiological response to the thermal stimulation correlated positively with the thickness of the posterior insula (pFWE < 0.05). Limitations: Limitations included the modest sample size and the cross-sectional design. Conclusion: These findings show that threat-anticipatory psychophysiological response differentiates youth with anxiety from healthy youth, and they link brain structure to psychophysiological response during pain anticipation and experience. A focus on threat anticipation in research on anxiety could delineate relevant neural circuitry.

Combining fMRI during resting state and an attention bias task in children.

Neuroimaging studies typically focus on either resting state or task-based fMRI data. Prior research has shown that similarity in functional connectivity between rest and cognitive tasks, interpreted as reconfiguration efficiency, is related to task performance and IQ. Here, we extend this approach from adults to children, and from cognitive tasks to a threat-based attention task. The goal of the current study was to examine whether similarity in functional connectivity during rest and an attention bias task relates to threat bias, IQ, anxiety symptoms, and social reticence. fMRI was measured during resting state and during the dot-probe task in 41 children (M = 13.44, SD = 0.70). Functional connectivity during rest and dot-probe was positively correlated, suggesting that functional hierarchies in the brain are stable. Similarity in functional connectivity between rest and the dot-probe task only related to threat bias (puncorr < .03). This effect did not survive correction for multiple testing. Overall, children who allocate more attention towards threat also may possess greater reconfiguration efficiency in switching from intrinsic to threat-related attention states. Finally, functional connectivity correlated negatively across the two conditions of the dot-probe task. Opposing patterns of modulation of functional connectivity by threat-congruent and threat-incongruent trials may reflect task-specific network changes during two different attentional processes.

Symptom structure of PTSD and co-morbid depressive symptoms - a network analysis of combat veteran patients.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Levels of early-childhood behavioral inhibition predict distinct neurodevelopmental pathways to pediatric anxiety.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Developmental pathways to social anxiety and irritability: The role of the ERN.

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.

Bias-contingent attention bias modification and attention control training in treatment of PTSD: a randomized control trial.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

A neuromarker of clinical outcome in attention bias modification therapy for social anxiety disorder.

BACKGROUND: Attention bias modification (ABM) therapy aims to modify threat-related attention patterns via computerized tasks. Despite showing medium clinical effect sizes for anxiety disorders, underlying neural-cognitive mechanisms of change remain unclear. We used visual mismatch negativity (vMMN), an event-related potential sensitive to violations of learned statistical contingencies, to assess therapy-related contingency extraction processes in healthy participants and in patients with social anxiety disorder (SAD). We then assessed whether vMMN amplitude predicts ABM treatment outcome. METHODS: A modified version of the dot-probe task was used to elicit vMMN, in which 80% of trials were standard and 20% were deviant. In study 1, 30 healthy adults were randomly assigned to one of two ABM conditions: one in which threat-congruent targets were deviant trials and threat-incongruent targets were standard trials, and another in which the contingency was reversed. Electroencephalography (EEG) was continuously measured and vMMN analyzed. In study 2, 38 patients with SAD underwent six sessions of ABM therapy. We tested whether rule extraction in the ABM task, indicated by vMMN amplitude, predicts treatment outcome. RESULTS: vMMN clearly emerged over prespecified scalp locations indicating contingency extraction during ABM (study 1). vMMN amplitude predicted clinical improvement after ABM therapy, uniquely accounting for 7% and 14.4% of the variance in clinician-rated and self-reported posttreatment SAD symptoms, respectively. CONCLUSIONS: vMMN emerges as a neural marker for contingency learning in ABM, suggesting a significant role for contingency extraction processes in the clinical efficacy of this therapy.

Modulating Emotional Experience Using Electrical Stimulation of the Medial-Prefrontal Cortex: A Preliminary tDCS-fMRI Study.

OBJECTIVES: Implicit regulation of emotions involves medial-prefrontal cortex (mPFC) regions exerting regulatory control over limbic structures. Diminished regulation relates to aberrant mPFC functionality and psychopathology. Establishing means of modulating mPFC functionality could benefit research on emotion and its dysregulation. Here, we tested the capacity of transcranial direct current stimulation (tDCS) targeting mPFC to modulate subjective emotional states by facilitating implicit emotion regulation. MATERIALS AND METHODS: Stimulation was applied concurrently with functional magnetic resonance imaging to validate its neurobehavioral effect. Sixteen participants were each scanned twice, counterbalancing active and sham tDCS application, while undergoing negative mood induction (clips featuring negative vs. neutral contents). Effects of stimulation on emotional experience were assessed using subjective and neural measures. RESULTS: Subjectively, active stimulation led to significant reduction in reported intensity of experienced emotions to negatively valenced (p = 0.005) clips but not to neutral clips (p > 0.99). Active stimulation further mitigated a rise in stress levels from pre- to post-induction (sham: p = 0.004; active: p = 0.15). Neurally, stimulation increased activation in mPFC regions associated with implicit emotion regulation (ventromedial-prefrontal cortex; subgenual anterior-cingulate cortex, sgACC), and in ventral striatum, a core limbic structure (all ps < 0.05). Stimulation also altered functional connectivity (assessed using whole-brain psycho-physiological interaction) between these regions, and with additional limbic regions. Stimulation-induced sgACC activation correlated with reported emotion intensity and depressive symptoms (rs > 0.64, ps < 0.018), suggesting individual differences in stimulation responsivity. CONCLUSIONS: Results of this study indicate the potential capacity of tDCS to facilitate brain activation in mPFC regions underlying implicit regulation of emotion and accordingly modulate subjective emotional experiences.

Anticipatory Effects on Perceived Pain: Associations With Development and Anxiety.

OBJECTIVE: Naturalistic studies suggest that expectation of adverse experiences such as pain exerts particularly strong effects on anxious youth. In healthy adults, expectation influences the experience of pain. The current study uses experimental methods to compare the effects of expectation on pain among adults, healthy youth, and youth with an anxiety disorder. METHODS: Twenty-three healthy adults, 20 healthy youth, and 20 youth with an anxiety disorder underwent procedures in which auditory cues were paired with noxious thermal stimulation. Through instructed conditioning, one cue predicted low-pain stimulation and the other predicted high-pain stimulation. At test, each cue was additionally followed by a single temperature calibrated to elicit medium pain ratings. We compared cue-based expectancy effects on pain across the three groups, based on cue effects on pain elicited on medium heat trials. RESULTS: Across all groups, as expected, participants reported greater pain with increasing heat intensity (ß = 2.29, t(41) = 29.94, p < .001). Across all groups, the critical medium temperature trials were rated as more painful in the high- relative to low-expectancy condition (ß = 1.72, t(41) = 10.48, p < .001). However, no evidence of between-group differences or continuous associations with age or anxiety was observed. CONCLUSIONS: All participants showed strong effects of expectancy on pain. No influences of development or anxiety arose. Complex factors may influence associations among anxiety, development, and pain reports in naturalistic studies. Such factors may be identified using experiments that employ more complex, yet controlled manipulations of expectancy or assess neural correlates of expectancy.

Association between attention bias to threat and anxiety symptoms in children and adolescents.

BACKGROUND: Considerable research links threat-related attention biases to anxiety symptoms in adults, whereas extant findings on threat biases in youth are limited and mixed. Inconsistent findings may arise due to substantial methodological variability and limited sample sizes, emphasizing the need for systematic research on large samples. The aim of this report is to examine the association between threat bias and pediatric anxiety symptoms using standardized measures in a large, international, multi-site youth sample. METHODS: A total of 1,291 children and adolescents from seven research sites worldwide completed standardized attention bias assessment task (dot-probe task) and child anxiety symptoms measure (Screen for Child Anxiety Related Emotional Disorders). Using a dimensional approach to symptomatology, we conducted regression analyses predicting overall, and disorder-specific, anxiety symptoms severity, based on threat bias scores. RESULTS: Threat bias correlated positively with overall anxiety symptoms severity (ß = 0.078, P = .004). Furthermore, threat bias was positively associated specifically with social anxiety (ß = 0.072, P = .008) and school phobia (ß = 0.076, P = .006) symptoms severity, but not with panic, generalized anxiety, or separation anxiety symptoms. These associations were not moderated by age or gender. CONCLUSIONS: These findings indicate associations between threat bias and pediatric anxiety symptoms, and suggest that vigilance to external threats manifests more prominently in symptoms of social anxiety and school phobia, regardless of age and gender. These findings point to the role of attention bias to threat in anxiety, with implications for translational clinical research. The significance of applying standardized methods in multi-site collaborations for overcoming challenges inherent to clinical research is discussed.

Attention allocation to facial expressions of emotion among persons with Williams and Down syndromes.

Individuals with Williams syndrome and those with Down syndrome are both characterized by heightened social interest, although the manifestation is not always similar. Using a dot-probe task, we examined one possible source of difference: allocation of attention to facial expressions of emotion. Thirteen individuals with Williams syndrome (mean age = 19.2 years, range = 10-28.6), 20 with Down syndrome (mean age = 18.8 years, range = 12.1-26.3), and 19 typically developing children participated. The groups were matched for mental age (mean = 5.8 years). None of the groups displayed a bias to angry faces. The participants with Williams syndrome showed a selective bias toward happy faces, whereas the participants with Down syndrome behaved similarly to the typically developing participants with no such bias. Homogeneity in the direction of bias was markedly highest in the Williams syndrome group whose bias appeared to result from enhanced attention capture. They appeared to rapidly and selectively allocate attention toward positive facial expressions. The complexity of social approach behavior and the need to explore other aspects of cognition that may be implicated in this behavior in both syndromes is discussed.

Postdeployment threat-related attention bias interacts with combat exposure to account for PTSD and anxiety symptoms in soldiers.

BACKGROUND: Recent studies suggest that assessment of threat-related attention bias may be useful in identifying soldiers at risk for clinical symptoms. The present study assessed the degree to which soldiers experienced combat events and showed attentional threat avoidance affected their reported levels of post-traumatic stress disorder (PTSD) and anxiety symptoms. METHODS: Four months after a combat deployment to Iraq, 63 US soldiers completed a survey assessing combat exposures and clinical symptoms as well as a dot-probe task assessing threat-related attention bias. RESULTS: Significant three-way interactions regressing threat reaction times (RTs), neutral RTs, and combat exposure on PTSD and anxiety symptoms were observed. Specifically, soldiers with high levels of combat exposure, who were more likely to demonstrate attentional bias away from threat, were also more symptomatic. CONCLUSION: These results demonstrate the potential of threat-related attention bias as a behavioral marker of PTSD and anxiety symptoms in a high-risk military occupational context.

Attention bias variability and symptoms of posttraumatic stress disorder.

Cognitive theories implicate information-processing biases in the etiology of anxiety disorders. Results of attention-bias studies in posttraumatic stress disorder (PTSD) have been inconsistent, suggesting biases towards and away from threat. Within-subject variability of attention biases in posttraumatic patients may be a useful marker for attentional control impairment and the development of posttrauma symptoms. This study reports 2 experiments investigating threat-related attention biases, mood and anxiety symptoms, and attention-bias variability following trauma. Experiment 1 included 3 groups in a cross-sectional design: (a) PTSD, (b) trauma-exposed without PTSD, and (c) healthy controls with no trauma or Axis I diagnoses. Greater attention-bias variability was found in the PTSD group compared to the other 2 groups (η(p)2=.23); attention-bias variability was significantly and positively correlated (r = .37) with PTSD symptoms. Experiment 2 evaluated combat-exposed and nonexposed soldiers before and during deployment. Attention-bias variability did not differentiate groups before deployment, but did differentiate groups during deployment (ηp2=.16); increased variability was observed in groups with acute posttraumatic stress symptoms and acute depression symptoms only. Attention-bias variability could be a useful marker for attentional impairment related to threat cues associated with mood and anxiety symptoms after trauma exposure.

How adverse childhood experiences get under the skin: A systematic review, integration and methodological discussion on threat and reward learning mechanisms.

Adverse childhood experiences (ACEs) are a major risk factor for the development of multiple psychopathological conditions, but the mechanisms underlying this link are poorly understood. Associative learning encompasses key mechanisms through which individuals learn to link important environmental inputs to emotional and behavioral responses. ACEs may impact the normative maturation of associative learning processes, resulting in their enduring maladaptive expression manifesting in psychopathology. In this review, we lay out a systematic and methodological overview and integration of the available evidence of the proposed association between ACEs and threat and reward learning processes. We summarize results from a systematic literature search (following PRISMA guidelines) which yielded a total of 81 articles (threat: n=38, reward: n=43). Across the threat and reward learning fields, behaviorally, we observed a converging pattern of aberrant learning in individuals with a history of ACEs, independent of other sample characteristics, specific ACE types, and outcome measures. Specifically, blunted threat learning was reflected in reduced discrimination between threat and safety cues, primarily driven by diminished responding to conditioned threat cues. Furthermore, attenuated reward learning manifested in reduced accuracy and learning rate in tasks involving acquisition of reward contingencies. Importantly, this pattern emerged despite substantial heterogeneity in ACE assessment and operationalization across both fields. We conclude that blunted threat and reward learning may represent a mechanistic route by which ACEs may become physiologically and neurobiologically embedded and ultimately confer greater risk for psychopathology. In closing, we discuss potentially fruitful future directions for the research field, including methodological and ACE assessment considerations.

Eye-tracking measurement of attention bias to social threat among youth: A replication and extension study.

Attentional bias to social threat cues has been linked to heightened anxiety and irritability in youth. Yet, inconsistent methodology has limited replication and led to mixed findings. The current study aims to 1) replicate and extend two previous pediatric studies demonstrating a relationship between negative affectivity and attentional bias to social threat and 2) examine the test-retest reliability of an eye-tracking paradigm among a subsample of youth. Attention allocation to negative versus non-negative emotional faces was measured using a free-viewing eye-tracking task among youth (N=185 total, 60% female, M age=13.10 years, SD age=2.77) with three face-pair conditions: happy-angry, neutral-disgust, sad-happy. Replicating procedures of two previous studies, linear mixed-effects models compared attention bias between children with anxiety disorders and healthy controls. Bifactor analysis was used to parse shared versus unique facets of general negative affectivity (i.e., anxiety, irritability), which were then examined in relation to attention bias. Test-retest reliability of the bias-index was estimated among a subsample of youth (N=36). No significant differences in attention allocation or bias emerged between anxiety and healthy control groups. While general negative affectivity across the sample was not associated with attention bias, there was a positive relationship for anxiety and irritability on duration of attention allocation toward negative faces. Test-retest reliability for attention bias was moderate (r=0.50, p<.01). While anxiety-related findings from the two previous studies were not replicated, the relationship between attention bias and facets of negative affect suggests a potential target for treatment. Evidence for test-retest reliability encourages future use of the eye-tracking task for researchers.

Normalization of Fronto-Parietal Activation by Cognitive-Behavioral Therapy in Unmedicated Pediatric Patients With Anxiety Disorders.

OBJECTIVE: Anxiety disorders are prevalent among youths and are often highly impairing. Cognitive-behavioral therapy (CBT) is an effective first-line treatment. The authors investigated the brain mechanisms associated with symptom change following CBT. METHODS: Unmedicated youths diagnosed with an anxiety disorder underwent 12 weeks of CBT as part of two randomized clinical trials testing the efficacy of adjunctive computerized cognitive training. Across both trials, participants completed a threat-processing task during functional MRI before and after treatment. Age-matched healthy comparison youths completed two scans over the same time span. The mean age of the samples was 13.20 years (SD=2.68); 41% were male (youths with anxiety disorders, N=69; healthy comparison youths, N=62). An additional sample including youths at temperamental risk for anxiety (N=87; mean age, 10.51 years [SD=0.43]; 41% male) was utilized to test the stability of anxiety-related neural differences in the absence of treatment. Whole-brain regional activation changes (thresholded at p<0.001) were examined using task-based blood-oxygen-level-dependent response. RESULTS: Before treatment, patients with an anxiety disorder exhibited altered activation in fronto-parietal attention networks and limbic regions relative to healthy comparison children across all task conditions. Fronto-parietal hyperactivation normalized over the course of treatment, whereas limbic responses remained elevated after treatment. In the at-risk sample, overlapping clusters emerged between regions showing stable associations with anxiety over time and regions showing treatment-related changes. CONCLUSIONS: Activation in fronto-parietal networks may normalize after CBT in unmedicated pediatric anxiety patients. Limbic regions may be less amenable to acute CBT effects. Findings from the at-risk sample suggest that treatment-related changes may not be attributed solely to the passage of time.