Social avoidance behavior modulates motivational responses to social reward-threat conflict signals: A preliminary fMRI study.

Social avoidance behavior (SAB) produces impairment in multiple domains and contributes to the development and maintenance of several psychiatric disorders. Social behaviors such as SAB are influenced by approach-avoidance (AA) motivational responses to affective facial expressions. Notably, affective facial expressions communicate varying degrees of social reward signals (happiness), social threat signals (anger), or social reward-threat conflict signals (co-occurring happiness and anger). SAB is associated with dysregulated modulation of automatic approach-avoidance (AA) motivational responses exclusively to social reward-threat conflict signals. However, no neuroimaging research has characterized SAB-related modulation of automatic and subjective AA motivational responses to social reward-threat conflict signals. We recruited 30 adults reporting clinical, moderate, or minimal SAB based on questionnaire cutoff scores. SAB groups were matched on age range and gender. During fMRI scanning, participants completed implicit and subjective approach-avoidance tasks (AATs), which involved more incidental or more explicit evaluation of facial expressions that parametrically varied in social reward signals (e.g., 50%Happy), social threat signals (e.g., 50%Angry), or social reward-threat conflict signals (e.g., 50%Happy + 50%Angry). In the implicit AAT, SAB was associated with slower automatic avoidance actions and weaker amygdala-pgACC connectivity exclusively as a function of social reward-threat conflict signals. In the subjective AAT, SAB was associated with smaller increases in approach ratings, smaller decreases in avoidance ratings, and weaker dlPFC-pgACC connectivity exclusively in response to social reward-threat conflict signals. Thus, SAB is associated with dysregulated modulation of automatic and subjective AA motivational sensitivity to social reward-threat conflict signals, which may be facilitated by overlapping neural systems.

Anterior Insula Activation During Cardiac Interoception Relates to Depressive Symptom Severity in HIV-Positive and HIV-Negative Postmenopausal Women.

OBJECTIVE: This study aimed to determine whether subclinical symptoms of depression in postmenopausal women are associated with blood oxygen level-dependent (BOLD) activity within the anterior insula during cardiac interoceptive awareness and whether this association differs for persons living with the human immunodeficiency virus (PWH). METHOD: Twenty-three postmenopausal (mean [standard deviation] age = 56.5 [4.8] years) and 27 HIV-negative women (mean [standard deviation] age = 56.4 [8.0]) underwent functional magnetic resonance imaging while performing a heartbeat detection task. BOLD activation within the bilateral anterior insula based on the contrast of a heartbeat detection condition with and without a distracting tone was entered along with age, HIV status, and psychological stress into two multivariate regression models with self-reported depressive symptom severity as the outcome. RESULTS: Depressive symptoms did not vary by HIV status, nor was there a main effect or interaction for PWH on insula BOLD activation. Depressive symptoms were positively associated with psychological stress for the left ( ß = 0.310, t (49) = 2.352, p = .023) and right brain models ( ß = 0.296, t (49) = 2.265, p = .028) as well as the magnitude of BOLD activation in the left insula ( ß = 0.290, t (49) = 2.218, p = .032) and right insula ( ß = 0.318, t (49) = 2.453, p = .018), respectively. Exploratory analyses revealed that greater magnitude of BOLD activation attributed to exteroceptive noise (tone) was also correlated with self-reported distrust and preoccupation with interoceptive sensations. CONCLUSIONS: Results support an active interference model for interoceptive awareness wherein greater BOLD signal in the anterior insula in the presence of distracting exteroceptive stimuli may reflect greater prediction error, a feature of depression.

Social avoidance behaviour modulates automatic avoidance actions to social reward-threat conflict.

Social avoidance behaviour (SAB) significantly interferes with social engagement and characterises various psychopathologies. Dual-process models propose that social behaviour is directed in part by automatic action tendencies to approach or avoid social stimuli. For example, happy facial expressions often elicit automatic approach actions, whereas angry facial expressions often elicit automatic avoidance actions. When motivation to approach and avoid co-occurs, automatic action tendencies may be uniquely modulated to direct social behaviour. Although research has examined how psychopathology modulates automatic action tendencies, no research has examined how SAB modulates automatic action tendencies. To address this issue, one hundred and three adults (65 females, 20.72 ± 5.06 years) completed a modified approach-avoidance task (AAT) with ambiguous facial stimuli that parametrically varied in social reward (e.g. 50%Happy), social threat (e.g. 50%Angry), or social reward-threat conflict (e.g. 50%Happy/50%Angry). SAB was not associated with automatic actions to any single parametric variation of social reward and/or social threat. Instead, SAB was associated with a quadratic (i.e. U-shaped) pattern in which automatic avoidance actions to social reward-threat conflict were faster relative to unambiguous social reward and social threat. Moreover, this association was independent of internalizing and social anxiety symptoms. These results provide insight into mechanisms underlying SAB, which offers clinical implications.

Differences in neural response to extinction recall in young adults with or without history of behavioral inhibition.

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.

Fear conditioning and extinction in pediatric obsessive-compulsive disorder.

BACKGROUND: Fear acquisition and extinction are central constructs in the cognitive-behavioral model of obsessive-compulsive disorder (OCD), which underlies exposure-based cognitive-behavioral therapy. Youths with OCD may have impairments in fear acquisition and extinction that carry treatment implications. METHODS: Eighty youths (39 OCD, 41 healthy controls [HC]) completed clinical interviews, rating scales, and a differential conditioning task that included habituation, acquisition, and extinction phases. Skin conductance response (SCR) served as the primary dependent measure. RESULTS: During habituation, participants with OCD exhibited a stronger orienting SCR to initial stimuli relative to HC participants. During acquisition, differential fear conditioning was observed for both groups as evidenced by larger SCRs to the visual conditioned stimulus paired with an aversive unconditioned stimulus (CS+) compared with a CS-; OCD participants exhibited a larger SCR to the CS+ relative to HC participants. The absolute magnitude of the unconditioned fear response was significantly larger in participants with OCD, compared with HC participants. During extinction, OCD participants continued to exhibit a differential SCR to the CS+ and CS-, whereas HC participants exhibited diminished SCR to both stimuli. CONCLUSIONS: Participants with OCD exhibit a different pattern of fear extinction relative to HC participants, suggestive of greater fear acquisition and impaired inhibitory learning.

Behavioral and neural stability of attention bias to threat in healthy adolescents.

Considerable translational research on anxiety examines attention bias to threat and the efficacy of attention training in reducing symptoms. Imaging research on the stability of brain functions engaged by attention bias tasks could inform such research. Perturbed fronto-amygdala function consistently arises in attention bias research on adolescent anxiety. The current report examines the stability of the activation and functional connectivity of these regions on the dot-probe task. Functional magnetic resonance imaging (fMRI) activation and connectivity data were acquired with the dot-probe task in 39 healthy youth (f=18, Mean Age=13.71years, SD=2.31) at two time points, separated by approximately nine weeks. Intraclass-correlations demonstrate good reliability in both neural activation for the ventrolateral PFC and task-specific connectivity for fronto-amygdala circuitry. Behavioral measures showed generally poor test-retest reliability. These findings suggest potential avenues for future brain imaging work by highlighting brain circuitry manifesting stable functioning on the dot-probe attention bias task.

Amygdala-Cortical Connectivity: Associations with Anxiety, Development, and Threat.

BACKGROUND: Amygdala-prefrontal cortex (PFC) functional connectivity may be influenced by anxiety and development. A prior study on anxiety found age-specific dysfunction in the ventromedial PFC (vmPFC), but not amygdala, associated with threat-safety discrimination during extinction recall (Britton et al.). However, translational research suggests that amygdala-PFC circuitry mediates responses following learned extinction. Anxiety-related perturbations may emerge in functional connectivity within this circuit during extinction recall tasks. The current report uses data from the prior study to examine how anxiety and development relate to task-dependent amygdala-PFC connectivity. METHODS: Eighty-two subjects (14 anxious youths, 15 anxious adults, 25 healthy youths, 28 healthy adults) completed an extinction recall task, which directed attention to different aspects of stimuli. Generalized psychophysiological interaction analysis tested whether task-dependent functional connectivity with anatomically defined amygdala seed regions differed across anxiety and age groups. RESULTS: Whole-brain analyses showed significant interactions of anxiety, age, and attention task (i.e., threat appraisal, explicit threat memory, physical discrimination) on left amygdala functional connectivity with the vmPFC and ventral anterior cingulate cortex (Talairach XYZ coordinates: -16, 31, -6 and 1, 36, -4). During threat appraisal and explicit threat memory (vs. physical discrimination), anxious youth showed more negative amygdala-PFC coupling, whereas anxious adults showed more positive coupling. CONCLUSIONS: In the context of extinction recall, anxious youths and adults manifested opposite directions of amygdala-vmPFC coupling, specifically when appraising and explicitly remembering previously learned threat. Future research on anxiety should consider associations of both development and attention to threat with functional connectivity perturbations.

A developmental analysis of threat/safety learning and extinction recall during middle childhood.

The current study examined developmental changes in fear learning and generalization in 54 healthy 5-10-year old children using a novel fear conditioning paradigm. In this task, the conditioned stimuli (CS+/CS-) were two blue and yellow colored cartoon bells, and the unconditioned stimulus was an unpleasant loud alarm sound presented with a red cartoon bell. Physiological and subjective data were acquired. Three weeks after conditioning, 48 of these participants viewed the CS-, CS+, and morphed images resembling the CS+. Participants made threat-safety discriminations while appraising threat and remembering the CS+. Although no age-related differences in fear learning emerged, patterns of generalization were qualified by child age. Older children demonstrated better discrimination between the CS+ and CS morphs than younger age groups and also reported more fear to stimuli resembling the CS+ than younger children. Clinical implications and future directions are discussed.

Fear conditioning and extinction in anxious and nonanxious youth and adults: examining a novel developmentally appropriate fear-conditioning task.

BACKGROUND: Fear conditioning and extinction have been implicated in the pathogenesis of anxiety disorders. However, due to ethical and methodological limitations, few studies have examined these learning processes across development, particularly among anxious individuals. The present study examined differences in fear conditioning and extinction in anxious and nonanxious youth and adults using a novel task designed to be more tolerable for children than existing paradigms. METHODS: Twenty-two anxious adults, 15 anxious youth, 30 healthy adults, and 17 healthy youth completed two discriminative fear-conditioning tasks. A well-validated task paired a woman's fearful face with a scream as the unconditioned stimulus. The novel task paired a bell with an aversive alarm as the unconditioned stimulus. Self-reported fear, skin conductance response, and fear-potentiated startle eye blink were measured. RESULTS: Both tasks were well tolerated and elicited fear responses with moderate stability. Anxious youth and adults reported overall greater fear than healthy participants during the tasks, although no group differences occurred in discriminative fear conditioning or extinction, as assessed by self-report or physiology. CONCLUSION: The novel bell-conditioning task is potent in eliciting fear responses but tolerable for pediatric and anxious populations. Our findings are consistent with prior studies that have shown comparable fear learning processes in anxious and nonanxious youth, but dissimilar from studies exhibiting between-group differences in extinction. Given the limited research on fear conditioning in youth, methodological issues and suggestions for future work are discussed.

Cortico-limbic responses to masked affective faces across ptsd, panic disorder, and specific phobia.

BACKGROUND: Exaggerated amygdala and reduced ventromedial prefrontal cortex (vmPFC) responsiveness during emotional processing have been reported in studies examining individual anxiety disorders. Studies are needed, however, which directly compare activation of amygdalo-cortical circuitry across multiple anxiety disorders within the same study. Here we compared cortico-limbic neurocircuitry across three different anxiety disorders using a well-validated emotional probe task. METHODS: Sixty-five adult volunteers, including 22 healthy controls (HC) and participants meeting DSM-IV criteria for either posttraumatic stress disorder (14 PTSD), panic disorder (14 PD), or specific animal phobia (15 SP), underwent functional magnetic resonance imaging (fMRI) at 3 T while passively viewing backward-masked images of faces expressing fear, happy, and neutral emotions. RESULTS: A group comprising all three anxiety disorders showed greater activation within the left amygdala and reduced activation within the vmPFC compared to the HC group during the masked fear versus neutral condition. Pairwise group comparisons showed that amygdala activation only reached significance for the PTSD versus HCs, whereas decreased vmPFC was only evident for SP and PD groups versus the HC group. Furthermore, activation did not differ among the anxiety groups when contrasted directly with one another. A similar pattern was observed for masked happy versus neutral faces. CONCLUSIONS: Exclusive of specific diagnostic category, anxiety disorders were generally associated with increased activation of the amygdala and reduced activation within vmPFC. Categorical distinctions were generally weak or not observed and suggest that functional differences may reflect the magnitude of responses within a common neurocircuitry across disorders rather than activation of distinct systems.

Distinct neural signatures of threat learning in adolescents and adults.

Most teenage fears subside with age, a change that may reflect brain maturation in the service of refined fear learning. Whereas adults clearly demarcate safe situations from real dangers, attenuating fear to the former but not the latter, adolescents' immaturity in prefrontal cortex function may limit their ability to form clear-cut threat categories, allowing pervasive fears to manifest. Here we developed a discrimination learning paradigm that assesses the ability to categorize threat from safety cues to test these hypotheses on age differences in neurodevelopment. In experiment 1, we first demonstrated the capacity of this paradigm to generate threat/safety discrimination learning in both adolescents and adults. Next, in experiment 2, we used this paradigm to compare the behavioral and neural correlates of threat/safety discrimination learning in adolescents and adults using functional MRI. This second experiment yielded three sets of findings. First, when labeling threats online, adolescents reported less discrimination between threat and safety cues than adults. Second, adolescents were more likely than adults to engage early-maturing subcortical structures during threat/safety discrimination learning. Third, adults' but not adolescents' engagement of late-maturing prefrontal cortex regions correlated positively with fear ratings during threat/safety discrimination learning. These data are consistent with the role of dorsolateral regions during category learning, particularly when differences between stimuli are subtle [Miller EK, Cohen JD (2001) Annu Rev Neurosci 24:167-202]. These findings suggest that maturational differences in subcortical and prefrontal regions between adolescent and adult brains may relate to age-related differences in threat/safety discrimination.

Linear mixed-effects modeling approach to FMRI group analysis.

Conventional group analysis is usually performed with Student-type t-test, regression, or standard AN(C)OVA in which the variance-covariance matrix is presumed to have a simple structure. Some correction approaches are adopted when assumptions about the covariance structure is violated. However, as experiments are designed with different degrees of sophistication, these traditional methods can become cumbersome, or even be unable to handle the situation at hand. For example, most current FMRI software packages have difficulty analyzing the following scenarios at group level: (1) taking within-subject variability into account when there are effect estimates from multiple runs or sessions; (2) continuous explanatory variables (covariates) modeling in the presence of a within-subject (repeated measures) factor, multiple subject-grouping (between-subjects) factors, or the mixture of both; (3) subject-specific adjustments in covariate modeling; (4) group analysis with estimation of hemodynamic response (HDR) function by multiple basis functions; (5) various cases of missing data in longitudinal studies; and (6) group studies involving family members or twins. Here we present a linear mixed-effects modeling (LME) methodology that extends the conventional group analysis approach to analyze many complicated cases, including the six prototypes delineated above, whose analyses would be otherwise either difficult or unfeasible under traditional frameworks such as AN(C)OVA and general linear model (GLM). In addition, the strength of the LME framework lies in its flexibility to model and estimate the variance-covariance structures for both random effects and residuals. The intraclass correlation (ICC) values can be easily obtained with an LME model with crossed random effects, even at the presence of confounding fixed effects. The simulations of one prototypical scenario indicate that the LME modeling keeps a balance between the control for false positives and the sensitivity for activation detection. The importance of hypothesis formulation is also illustrated in the simulations. Comparisons with alternative group analysis approaches and the limitations of LME are discussed in details.

Attention bias of anxious youth during extended exposure of emotional face pairs: an eye-tracking study.

BACKGROUND: Previous studies demonstrate that anxiety is characterized by biased attention toward threats, typically measured by differences in motor reaction time to threat and neutral cues. Using eye-tracking methodology, the current study measured attention biases in anxious and nonanxious youth, using unrestricted free viewing of angry, happy, and neutral faces. METHODS: Eighteen anxious and 15 nonanxious youth (8-17 years old) passively viewed angry-neutral and happy-neutral face pairs for 10 s while their eye movements were recorded. RESULTS: Anxious youth displayed a greater attention bias toward angry faces than nonanxious youth, and this bias occurred in the earliest phases of stimulus presentation. Specifically, anxious youth were more likely to direct their first fixation to angry faces, and they made faster fixations to angry than neutral faces. CONCLUSIONS: Consistent with findings from earlier, reaction-time studies, the current study shows that anxious youth, like anxious adults, exhibit biased orienting to threat-related stimuli. This study adds to the existing literature by documenting that threat biases in eye-tracking patterns are manifest at initial attention orienting.

Isolating neural components of threat bias in pediatric anxiety.

BACKGROUND: Attention biases toward threat are often detected in individuals with anxiety disorders. Threat biases can be measured experimentally through dot-probe paradigms, in which individuals detect a probe following a stimulus pair including a threat. On these tasks, individuals with anxiety tend to detect probes that occur in a location previously occupied by a threat (i.e., congruent) faster than when opposite threats (i.e., incongruent). In pediatric anxiety disorders, dot-probe paradigms detect abnormal attention biases toward threat and abnormal ventrolateral prefrontal cortex (vlPFC) function. However, it remains unclear if this aberrant vlPFC activation occurs while subjects process threats (e.g., angry faces) or, alternatively, while they process and respond to probes. This magnetoencephalography (MEG) study was designed to answer this question. METHODS: Adolescents with either generalized anxiety disorder (GAD, n = 17) or no psychiatric diagnosis (n = 25) performed a dot-probe task involving angry and neutral faces while MEG data were collected. Synthetic Aperture Magnetometry (SAM) beamformer technique was used to determine whether there were group differences in power ratios while subjects processed threats (i.e., angry vs. neutral faces) or when subjects responded to incongruent versus. congruent probes. RESULTS: Group differences in vlPFC activation during the response period emerged with a 1-30 Hz frequency band. No group differences in vlPFC activation were detected in response to angry-face cues. CONCLUSIONS: In the dot-probe task, anxiety-related perturbations in vlPFC activation reflect abnormal attention control when responding to behaviorally relevant probes, but not to angry faces. Given that motor responses to these probes are used to calculate threat bias, this study provides insight into the pathophysiology reflected in this commonly used marker of anxiety. In addition, this finding may inform the development of novel anxiety-disorder treatments targeting the vlPFC to enhance attention control to task-relevant demands.

Attention biases, anxiety, and development: toward or away from threats or rewards?

Research on attention provides a promising framework for studying anxiety pathophysiology and treatment. The study of attention biases appears particularly pertinent to developmental research, as attention affects learning and has down-stream effects on behavior. This review summarizes recent findings about attention orienting in anxiety, drawing on findings in recent developmental psychopathology and affective neuroscience research. These findings generate specific insights about both development and therapeutics. The review goes beyond a traditional focus on biased processing of threats and considers biased processing of rewards. Building on this work, we then turn to the treatment of pediatric anxiety, where manipulation of attention to threat and/or reward may serve a therapeutic role as a component of Attention Bias Modification Therapy.

The development of fear learning and generalization in 8-13 year-olds.

The current study examined developmental changes in fear learning and generalization in 40 healthy 8-13 year-olds using an aversive conditioning paradigm adapted from Lau et al. [Lau et al. [2008] Journal of the American Academy of Child and Adolescent Psychiatry 47:94-102]. In this task, the conditioned stimuli (CS+/CS-) are two neutral female faces, and the unconditioned stimulus is a fearful, screaming face. The second phase of the study also included a generalization stimulus (GS): a 50% blend of the CS± faces. The eye-blink startle reflex was utilized to measure defensive responding. Patterns of fear learning and generalization were qualified by child age. Older children demonstrated greater fear learning (i.e., larger startle during CS+ than CS-) than younger children. In addition, older children exhibited the typical pattern of generalization observed in adults, whereas younger children did not. Finally, fear learning also related to contingency awareness; only children who correctly identified the CS+ demonstrated fear-potentiated startle to the CS+. Clinical implications and future directions are discussed.

Development and validation of the Attention Bias Questionnaire (ABQ).

OBJECTIVES: Various psychopathologies are associated with threat-related attention biases, which are typically measured using mechanized behavioral tasks. While useful and objective, behavioral measures do not capture the subjective experience of biased attention in daily-living. To complement extant behavioral measures, we developed and validated a self-report measure of threat-related attention bias - the Attention Bias Questionnaire (ABQ). METHODS: The ABQ consists of nine items reflecting the subjective experience of attention bias towards threats. To enable personalized relevance in threat-content, the general term "threat" was used, and respondents were instructed to refer to specific things that threaten them personally. In a set of five studies, the ABQ was developed and validated. Internal consistency, discriminant validity, test-retest reliability, and convergent validity were tested. RESULTS: The ABQ emerged as a coherent and stable measure with two sub-scales: Engagement with Threat and Difficulty to Disengage from Threat. ABQ scores were positively correlated with trait anxiety, social anxiety, PTSD, and depression, as well as behaviorally measured attention bias. CONCLUSION: Assessing the subjective experience of threat-related attention bias can enrich existing knowledge about the cognitive mechanisms underlying psychopathology and complement extant behavioral bias measures in research and clinical evaluation.

The Reliability and Validity of Response-Based Measures of Attention Bias.

Background: Attention bias to threat is a fundamental transdiagnostic component and potential vulnerability factor for internalizing psychopathologies. However, the measurement of attentional bias, such as traditional scores from the dot-probe paradigm, evidence poor reliability and do not measure intra-individual variation in attentional bias. Methods: The present study examined, in three independent samples, the psychometric properties of a novel attentional bias (AB) scoring method of the dot-probe task based on responses to individual trials. For six AB scores derived using the response-based approach, we assessed the internal consistency, test-retest reliability, familial associations, and external validity (using Social Anxiety Disorder, a disorder strongly associated with attentional bias to threatening faces). Results: Compared to traditional AB scores, response-based scores had generally better internal consistency (range of Cronbach's alphas: 0.68-0.92 vs. 0.41-0.71), higher test-retest reliabilities (range of Pearson's correlations: 0.26-0.77 vs. -0.05-0.35), and were more strongly related in family members (range of ICCs: 0.11-0.27 vs. 0-0.05). Furthermore, three response-based scores added incremental validity beyond traditional scores and gender in the external validators of current and lifetime Social Anxiety Disorder. Conclusions: Findings indicate that response-based AB scores from the dot-probe task have better psychometric properties than traditional scores.

Computational modeling of threat learning reveals links with anxiety and neuroanatomy in humans.

Influential theories implicate variations in the mechanisms supporting threat learning in the severity of anxiety symptoms. We use computational models of associative learning in conjunction with structural imaging to explicate links among the mechanisms underlying threat learning, their neuroanatomical substrates, and anxiety severity in humans. We recorded skin-conductance data during a threat-learning task from individuals with and without anxiety disorders (N=251; 8-50 years; 116 females). Reinforcement-learning model variants quantified processes hypothesized to relate to anxiety: threat conditioning, threat generalization, safety learning, and threat extinction. We identified the best-fitting models for these processes and tested associations among latent learning parameters, whole-brain anatomy, and anxiety severity. Results indicate that greater anxiety severity related specifically to slower safety learning and slower extinction of response to safe stimuli. Nucleus accumbens gray-matter volume moderated learning-anxiety associations. Using a modeling approach, we identify computational mechanisms linking threat learning and anxiety severity and their neuroanatomical substrates.

Development of anxiety: the role of threat appraisal and fear learning.

Anxious individuals exhibit threat biases at multiple levels of information processing. From a developmental perspective, abnormal safety learning in childhood may establish threat-related appraisal biases early, which may contribute to chronic disorders in adulthood. This review illustrates how the interface among attention, threat appraisal, and fear learning can generate novel insights for outcome prediction. This review summarizes data on amygdala function, as it relates to learning and attention, highlights the importance of examining threat appraisal, and introduces a novel imaging paradigm to investigate the neural correlates of threat appraisal and threat-sensitivity during extinction recall. This novel paradigm can be used to investigate key questions relevant to prognosis and treatment. Depression and Anxiety, 2011.© 2010 Wiley-Liss, Inc.