Evidence for distinct genetic and environmental influences on fear acquisition and extinction.

BACKGROUND: Anxiety disorders are highly prevalent with an early age of onset. Understanding the aetiology of disorder emergence and recovery is important for establishing preventative measures and optimising treatment. Experimental approaches can serve as a useful model for disorder and recovery relevant processes. One such model is fear conditioning. We conducted a remote fear conditioning paradigm in monozygotic and dizygotic twins to determine the degree and extent of overlap between genetic and environmental influences on fear acquisition and extinction. METHODS: In total, 1937 twins aged 22-25 years, including 538 complete pairs from the Twins Early Development Study took part in a fear conditioning experiment delivered remotely via the Fear Learning and Anxiety Response (FLARe) smartphone app. In the fear acquisition phase, participants were exposed to two neutral shape stimuli, one of which was repeatedly paired with a loud aversive noise, while the other was never paired with anything aversive. In the extinction phase, the shapes were repeatedly presented again, this time without the aversive noise. Outcomes were participant ratings of how much they expected the aversive noise to occur when they saw either shape, throughout each phase. RESULTS: Twin analyses indicated a significant contribution of genetic effects to the initial acquisition and consolidation of fear, and the extinction of fear (15, 30 and 15%, respectively) with the remainder of variance due to the non-shared environment. Multivariate analyses revealed that the development of fear and fear extinction show moderate genetic overlap (genetic correlations 0.4-0.5). CONCLUSIONS: Fear acquisition and extinction are heritable, and share some, but not all of the same genetic influences.

Introducing the Fear Learning and Anxiety Response (FLARe) app and web portal for the remote delivery of fear conditioning experiments.

Experimental paradigms measuring key psychological constructs can enhance our understanding of mechanisms underlying human psychological well-being and mental health. Delivering such paradigms remotely affords opportunities to reach larger, more representative samples than is typically possible with in-person research. The efficiency gained from remote delivery makes it easier to test replication of previously established effects in well-powered samples. There are several challenges to the successful development and delivery of remote experimental paradigms, including use of an appropriate delivery platform, identifying feasible outcome measures, and metrics of participant compliance. In this paper, we present FLARe (Fear Learning and Anxiety Response), open-source software in the form of a smartphone app and web portal for the creation and delivery of remote fear conditioning experiments. We describe the benefits and challenges associated with the creation of a remote delivery platform for fear conditioning, before presenting in detail the resultant software suite, and one instance of deploying this using the FLARe Research infrastructure. We provide examples of the application of FLARe to several research questions which illustrate the benefits of the remote approach to experiment delivery. The FLARe smartphone app and web portal are available for use by other researchers and have been designed to be user-friendly and intuitive. We hope that FLARe will be a useful tool for those interested in conducting well-powered fear conditioning studies to inform our understanding of the development and treatment of anxiety disorders.

Reactivity to unpredictable threat as a treatment target for fear-based anxiety disorders.

BACKGROUND: Heightened reactivity to unpredictable threat (U-threat) is a core individual difference factor underlying fear-based psychopathology. Little is known, however, about whether reactivity to U-threat is a stable marker of fear-based psychopathology or if it is malleable to treatment. The aim of the current study was to address this question by examining differences in reactivity to U-threat within patients before and after 12-weeks of selective serotonin reuptake inhibitors (SSRIs) or cognitive-behavioral therapy (CBT). METHODS: Participants included patients with principal fear (n = 22) and distress/misery disorders (n = 29), and a group of healthy controls (n = 21) assessed 12-weeks apart. A well-validated threat-of-shock task was used to probe reactivity to predictable (P-) and U-threat and startle eyeblink magnitude was recorded as an index of defensive responding. RESULTS: Across both assessments, individuals with fear-based disorders displayed greater startle magnitude to U-threat relative to healthy controls and distress/misery patients (who did not differ). From pre- to post-treatment, startle magnitude during U-threat decreased only within the fear patients who received CBT. Moreover, within fear patients, the magnitude of decline in startle to U-threat correlated with the magnitude of decline in fear symptoms. For the healthy controls, startle to U-threat across the two time points was highly reliable and stable. CONCLUSIONS: Together, these results indicate that startle to U-threat characterizes fear disorder patients and is malleable to treatment with CBT but not SSRIs within fear patients. Startle to U-threat may therefore reflect an objective, psychophysiological indicator of fear disorder status and CBT treatment response.

An examination of the bidirectional relationship between functioning and symptom levels in patients with anxiety disorders in the CALM study.

BACKGROUND: Patients with anxiety disorders suffer marked functional impairment in their activities of daily living. Many studies have documented that improvements in anxiety symptom severity predict functioning improvements. However, no studies have investigated how improvements in functioning simultaneously predict symptom reduction. We hypothesized that symptom levels at a given time point will predict functioning at the subsequent time point, and simultaneously that functioning at a given time point will predict symptom levels at a subsequent time point. METHOD: Patients were recruited from primary-care centers for the Coordinated Anxiety Learning and Management (CALM) study and were randomized to receive either computer-assisted cognitive-behavioral therapy and/or medication management (ITV) or usual care (UC). A cross-lagged panel design examined the relationship between functional impairment and anxiety and depression symptom severity at baseline, 6-, 12-, and 18-month follow-up assessments. RESULTS: Prospective prediction of functioning from symptoms and symptoms from functioning were both important in modeling these associations. Anxiety and depression predicted functioning as strongly as functioning predicted anxiety and depression. There were some differences in these associations between UC and ITV. Where differences emerged, the UC group was best modeled with prospective paths predicting functioning from symptoms, whereas symptoms and functioning were both important predictors in the ITV group. CONCLUSIONS: Treatment outcome is best captured by measures of functional impairment as well as symptom severity. Implications for treatment are discussed, as well as future directions of research.

Social support and fear-inhibition: an examination of underlying neural mechanisms.

Recent work has demonstrated that reminders of those we are closest to have a unique combination of effects on fear learning and represent a new category of fear inhibitors, termed prepared fear suppressors. Notably, social-support-figure images have been shown to resist becoming associated with fear, suppress conditional-fear-responding and lead to long-term fear reduction. Due to the novelty of this category, understanding the underlying neural mechanisms that support these unique abilities of social-support-reminders has yet to be investigated. Here, we examined the neural correlates that enable social-support-reminders to resist becoming associated with fear during a retardation-of-acquisition test. We found that social-support-figure-images (vs stranger-images) were less readily associated with fear, replicating prior work, and that this effect was associated with decreased amygdala activity and increased ventromedial prefrontal cortex (VMPFC) activity for social-support-figure-images (vs stranger-images), suggesting that social-support-engagement of the VMPFC and consequent inhibition of the amygdala may contribute to unique their inhibitory effects. Connectivity analyses supported this interpretation, showing greater connectivity between the VMPFC and left amygdala for social-support-figure-images (vs stranger-images).

The cortisol awakening response predicts major depression: predictive stability over a 4-year follow-up and effect of depression history.

BACKGROUND: The cortisol awakening response (CAR) has been shown to predict major depressive episodes (MDEs) over a 1-year period. It is unknown whether this effect: (a) is stable over longer periods of time; (b) is independent of prospective stressful life events; and (c) differentially predicts first onsets or recurrences of MDEs. METHOD: A total of 270 older adolescents (mean age 17.06 years at cortisol measurement) from the larger prospective Northwestern-UCLA Youth Emotion Project completed baseline diagnostic and life stress interviews, questionnaires, and a 3-day cortisol sampling protocol measuring the CAR and diurnal rhythm, as well as up to four annual follow-up interviews of diagnoses and life stress. RESULTS: Non-proportional person-month survival analyses revealed that higher levels of the baseline CAR significantly predict MDEs for 2.5 years following cortisol measurement. However, the strength of prediction of depressive episodes significantly decays over time, with the CAR no longer significantly predicting MDEs after 2.5 years. Elevations in the CAR did not significantly increase vulnerability to prospective major stressful life events. They did, however, predict MDE recurrences more strongly than first onsets. CONCLUSIONS: These results suggest that a high CAR represents a time-limited risk factor for onsets of MDEs, which increases risk for depression independently of future major stressful life events. Possible explanations for the stronger effect of the CAR for predicting MDE recurrences than first onsets are discussed.

Incremental benefits and cost of coordinated anxiety learning and management for anxiety treatment in primary care.

BACKGROUND: Improving the quality of mental health care requires integrating successful research interventions into 'real-world' practice settings. Coordinated Anxiety Learning and Management (CALM) is a treatment-delivery model for anxiety disorders encountered in primary care. CALM offers cognitive behavioral therapy (CBT), medication, or both; non-expert care managers assisting primary care clinicians with adherence promotion and medication optimization; computer-assisted CBT delivery; and outcome monitoring. This study describes incremental benefits, costs and net benefits of CALM versus usual care (UC). METHOD: The CALM randomized, controlled effectiveness trial was conducted in 17 primary care clinics in four US cities from 2006 to 2009. Of 1062 eligible patients, 1004 English- or Spanish-speaking patients aged 18-75 years with panic disorder (PD), generalized anxiety disorder (GAD), social anxiety disorder (SAD) and/or post-traumatic stress disorder (PTSD) with or without major depression were randomized. Anxiety-free days (AFDs), quality-adjusted life years (QALYs) and expenditures for out-patient visits, emergency room (ER) visits, in-patient stays and psychiatric medications were estimated based on blinded telephone assessments at baseline, 6, 12 and 18 months. RESULTS: Over 18 months, CALM participants, on average, experienced 57.1 more AFDs [95% confidence interval (CI) 31-83] and $245 additional medical expenses (95% CI $-733 to $1223). The mean incremental net benefit (INB) of CALM versus UC was positive when an AFD was valued ≥$4. For QALYs based on the Short-Form Health Survey-12 (SF-12) and the EuroQol EQ-5D, the mean INB was positive at ≥$5000. CONCLUSIONS: Compared with UC, CALM provides significant benefits with modest increases in health-care expenditures.

Neuroticism as a common dimension in the internalizing disorders.

BACKGROUND: Several theories have posited a common internalizing factor to help account for the relationship between mood and anxiety disorders. These disorders are often co-morbid and strongly covary. Other theories and data suggest that personality traits may account, at least in part, for co-morbidity between depression and anxiety. The present study examined the relationship between neuroticism and an internalizing dimension common to mood and anxiety disorders. METHOD: A sample of ethnically diverse adolescents (n=621) completed self-report and peer-report measures of neuroticism. Participants also completed the Structured Clinical Interview for DSM-IV (SCID). RESULTS: Structural equation modeling showed that a single internalizing factor was common to lifetime diagnosis of mood and anxiety disorders, and this internalizing factor was strongly correlated with neuroticism. Neuroticism had a stronger correlation with an internalizing factor (r=0.98) than with a substance use factor (r=0.29). Therefore, neuroticism showed both convergent and discriminant validity. CONCLUSIONS: These results provide further evidence that neuroticism is a necessary factor in structural theories of mood and anxiety disorders. In this study, the correlation between internalizing psychopathology and neuroticism approached 1.0, suggesting that neuroticism may be the core of internalizing psychopathology. Future studies are needed to examine this possibility in other populations, and to replicate our findings.

Functioning and disability levels in primary care out-patients with one or more anxiety disorders.

BACKGROUND: Anxiety disorders are the most prevalent mental health disorders and are associated with substantial disability and reduced well-being. It is unknown whether the relative impact of different anxiety disorders is due to the anxiety disorder itself or to the co-occurrence with other anxiety disorders. This study compared the functional impact of combinations of anxiety disorders in primary care out-patients. METHOD: A total of 1004 patients with panic disorder (PD), generalized anxiety disorder (GAD), social anxiety disorder (SAD) or post-traumatic stress disorder (PTSD) provided data on their mental and physical functioning, and disability. Multivariate regressions compared functional levels for patients with different numbers and combinations of disorders. RESULTS: Of the patients, 42% had one anxiety disorder only, 38% two, 16% three and 3% all four. There were few relative differences in functioning among patients with only one anxiety disorder, although those with SAD were most restricted in their work, social and home activities and those with GAD were the least impaired. Functioning levels tended to deteriorate as co-morbidity increased. CONCLUSIONS: Of the four anxiety disorders examined, GAD appears to be the least disabling, although they all have more in common than in distinction when it comes to functional impairment. A focus on unique effects of specific anxiety disorders is inadequate, as it fails to address the more pervasive impairment associated with multiple anxiety disorders, which is the modal presentation in primary care.

Protocol for a randomized controlled trial examining multilevel prediction of response to behavioral activation and exposure-based therapy for generalized anxiety disorder.

BACKGROUND: Only 40-60% of patients with generalized anxiety disorder experience long-lasting improvement with gold standard psychosocial interventions. Identifying neurobehavioral factors that predict treatment success might provide specific targets for more individualized interventions, fostering more optimal outcomes and bringing us closer to the goal of "personalized medicine." Research suggests that reward and threat processing (approach/avoidance behavior) and cognitive control may be important for understanding anxiety and comorbid depressive disorders and may have relevance to treatment outcomes. This study was designed to determine whether approach-avoidance behaviors and associated neural responses moderate treatment response to exposure-based versus behavioral activation therapy for generalized anxiety disorder. METHODS/DESIGN: We are conducting a randomized controlled trial involving two 10-week group-based interventions: exposure-based therapy or behavioral activation therapy. These interventions focus on specific and unique aspects of threat and reward processing, respectively. Prior to and after treatment, participants are interviewed and undergo behavioral, biomarker, and neuroimaging assessments, with a focus on approach and avoidance processing and decision-making. Primary analyses will use mixed models to examine whether hypothesized approach, avoidance, and conflict arbitration behaviors and associated neural responses at baseline moderate symptom change with treatment, as assessed using the Generalized Anxiety Disorder-7 item scale. Exploratory analyses will examine additional potential treatment moderators and use data reduction and machine learning methods. DISCUSSION: This protocol provides a framework for how studies may be designed to move the field toward neuroscience-informed and personalized psychosocial treatments. The results of this trial will have implications for approach-avoidance processing in generalized anxiety disorder, relationships between levels of analysis (i.e., behavioral, neural), and predictors of behavioral therapy outcome. TRIAL REGISTRATION: The study was retrospectively registered within 21 days of first participant enrollment in accordance with FDAAA 801 with ClinicalTrials.gov, NCT02807480. Registered on June 21, 2016, before results.

Validating the use of a smartphone app for remote administration of a fear conditioning paradigm.

Fear conditioning models key processes related to the development, maintenance and treatment of anxiety disorders and is associated with group differences in anxiety. However, laboratory administration of tasks is time and cost intensive, precluding assessment in large samplesnecessary for the analysis of individual differences. This study introduces a newly developed smartphone app that delivers a fear conditioning paradigm remotely using a loud human scream as an aversive stimulus. Three groups of participants (total n = 152) took part in three studies involving a differential fear conditioning experiment to assess the reliability and validity of a smartphone administered fear conditioning paradigm. This comprised of fear acquisition, generalisation, extinction, and renewal phases during which online US-expectancy ratings were collected during every trial with evaluative ratings of negative affect at three time points. We show that smartphone app delivery of a fear conditioning paradigm results in a pattern of fear learning comparable to traditional laboratory delivery and is able to detect individual differences in performance that show comparable associations with anxiety to the prior group differences literature.

Anxiety: at the intersection of genes and experience.

Human anxiety disorders arise from a combination of genetic vulnerability and traumatic experience. Mice with a GABAA receptor mutation may provide a model for these disorders.

Computer therapy for the anxiety and depression disorders is effective, acceptable and practical health care: An updated meta-analysis.

BACKGROUND: A 2010 meta-analysis of internet-delivered CBT (iCBT) RCTs argued 'computer therapy for the anxiety and depressive disorders was effective, acceptable and practical health care' without data on effectiveness or practicality in routine practice. METHODS: Databases, reviews and meta-analyses were searched for randomised controlled trials of cCBT or iCBT versus a control group (care as usual, waitlist, information control, psychological placebo, pill placebo, etc.) in people who met diagnostic criteria for major depression, panic disorder, social anxiety disorder or generalised anxiety disorder. Number randomised, superiority of treatment versus control (Hedges'g) on primary outcome measure, length of follow-up, follow up outcome, patient adherence and satisfaction/harm were extracted; risk of bias was assessed. A search for studies on effectiveness of iCBT in clinical practice was conducted. RESULTS: 64 trials were identified. The mean effect size (efficacy) was g = 0.80 (NNT 2.34), and benefit was evident across all four disorders. Improvement was maintained at follow-with good acceptability. Research probity was good, and bias risk low. In addition, nine studies comparing iCBT with traditional face-to-face CBT and three comparing iCBT with bibliotherapy were identified. All three modes of treatment delivery appeared equally beneficial. The results of effectiveness studies were congruent with the results of the efficacy trials. LIMITATIONS: Studies variably measured changes in quality of life and disability, and the lack of comparisons with medications weakens the field. CONCLUSIONS: The conclusions drawn in the original meta-analysis are now supported: iCBT for the anxiety and depressive disorders is effective, acceptable and practical health care.

Panic disorder in the primary care setting: comorbidity, disability, service utilization, and treatment.

BACKGROUND: Increased medical service utilization in patients with panic disorder has been described in epidemiologic studies, although service use in primary care panic patients relative to other primary care patients is less well characterized. Inadequate recognition of panic has been shown in several primary care studies, although the nature of usual care for panic in this setting has not been well documented. This study aimed to document increased service use in panic patients relative to other primary care patients and to characterize the nature of their usual care for panic and their outcome. METHOD: Using a waiting room screening questionnaire and follow-up telephone interview with the Composite International Diagnostic Interview, we identified a convenience sample of 81 patients with panic disorder (DSM-IV) and a control group of 183 psychiatrically healthy patients in 3 primary care settings on the West Coast and determined psychiatric diagnostic comorbidity, panic characteristics, disability, and medical and mental health service use, including medications. A subsample (N = 41) of panic patients was reinterviewed 4-10 months later to determine the persistence of panic and the adequacy of intervening treatment received using the Harvard/Brown Anxiety Disorders Research Program study criteria for cognitive-behavioral therapy (CBT) and an algorithm developed by the authors for medications. RESULTS: Seventy percent of panic patients had a comorbid psychiatric diagnosis. Patients had more disability in the last month (days missed or cut down activities) (p < .01), more utilization of emergency room and medical provider visits (p < .01), and more mental health visits (p < .05). Despite the latter, only 42% received psychotropic medication, 36% psychotherapy, and 64% any treatment. On follow-up, 85% still met diagnostic criteria for panic, and only 22% had received adequate medication (type and/or dose) and 12% adequate (i.e., CBT) psychotherapy. CONCLUSION: These findings suggest a need for improved treatment interventions for panic disorder in the primary care setting to decrease disability and potentially inappropriate medical service utilization.

Functional MRI changes during panic anticipation and imagery exposure.

While undergoing fMRI, six patients with DSM IV diagnosis of panic disorder and six normal controls performed directed imagery of neutral, moderate and high anxiety situations based on an individually determined behavioral hierarchy. Brain activity was compared during high vs neutral anxiety blocks for each group of subjects using SPM99b. Panic patients showed increased activity in inferior frontal cortex, hippocampus and throughout the cingulate both anterior and posterior, extending into the orbitofrontal cortex and encompassing both hemispheres. These areas may constitute the important circuit in the psychopathology of panic disorder. We propose that this pattern of activity may enhance the encoding and retrieval of strong emotional events, facilitating the recapitulation of traumatic experiences and leading to panic disorder in vulnerable individuals.

Paths to panic disorder/agoraphobia: an exploratory analysis from age 3 to 21 in an unselected birth cohort.

OBJECTIVE: To evaluate childhood temperamental traits and early illness experiences in the etiology of adult panic disorder with agoraphobia. METHOD: Evaluated temperamental and illness experience factors, at ages 3 through 18, as predictors of panic and agoraphobia at ages 18 or 21 in an unselected sample (N = 992). Analyses were conducted with classification trees. RESULTS: Experience with respiratory ill health predicted panic/agoraphobia relative to other anxiety disorders and healthy controls. Also, temperamental emotional reactivity at age 3 predicted panic/agoraphobia in males but did not predict other anxiety disorders, compared with healthy controls. Furthermore, temperament and ill health interacted with gender. CONCLUSIONS: Results are discussed in terms of cognitive theories of fear of physical symptoms and biological models of respiratory disturbance for panic/agoraphobia.

Alteration of memory in the reduction of children's distress during repeated aversive medical procedures.

The present study sought to reduce children's distress during aversive medical procedures using a brief, cost-effective intervention aimed at reframing memory. Fifty children diagnosed with leukemia (25 treatment, 25 attention control, aged 3-18) were observed as they underwent 3 consecutive lumbar punctures (LPs; baseline, postintervention, and follow-up). Self-report, physiological, and observable distress measures were collected before and after each LP. At posttreatment, children in the intervention group showed reductions in anticipatory physiological and self-report ratings relative to the control group. At follow-up, these effects generalized to reductions in procedural distress. These results suggest that (a) a simple memory-based intervention is efficacious at reducing children's distress and (b) benefits from this intervention are maintained over 1 week even without continued intervention.

Issues of measurement and mechanism in meta-analyses: comment on Westen and Morrison (2001).

The authors suggest that D. Westen and K. Morrison's (2001) meta-analysis of treatment is critically limited in the consideration of measurement and mechanisms of therapeutic change. The measures included in the analysis fail to represent a comprehensive coverage of the domains within which change is expected. Moreover, they do not measure the theoretically derived constructs currently conceived as being central to each disorder. Further, the particular meta-analytical approach taken prohibits evaluation of the treatment components responsible for change. The authors reviewed the most recent data on comorbidity as an issue of treatment efficacy and generalizability, proffer an interpretation for the difference in outcome results across the 3 diagnostic groups, and discuss internally valid methodologies for the bridging from research to clinical practice.

Expectations about arousal and nocturnal panic.

Expectations about arousal were examined in relation to nocturnal panic (NP). Eighteen panic disorder patients suffering from NP attacks and 18 control individuals were assigned randomly to conditions in which they were informed that audio feedback signals reflected heightened arousal that was either (a) expected and harmless or (b) unexpected. Participants relaxed and slept for 45 to 60 min, followed by presentation of periodic audio feedback signals. Physiological recording was continuous while subjective measures were collected at completion of the signals phase. NP patients in the unexpected--no reassurance condition were significantly more anxious and symptomatic than their counterparts in the expected reassurance condition, whereas control individuals did not differ across the 2 conditions. Physiological and behavioral data were less consistent than subjective measures. The results are interpreted as supportive of a cognitive-behavioral model of NP.

Nocturnal panic: response to hyperventilation and carbon dioxide challenges.

To examine the role of ventilatory response in nocturnal panic, subjects experiencing nocturnal panic were compared with those who experienced daytime panic attacks only. In particular, measures of chronic hyperventilation (baseline pCO2) and CO2 hypersensitivity (response to ventilatory challenges) were assessed. Subjective and psychophysiological measures were obtained during baseline, forced hyperventilation, and carbon dioxide inhalation phases of a standardized laboratory-based assessment. The groups did not differ with respect to subjective or physiological measures or to the frequency with which panic occurred during the assessment. The results do not lend support to models that emphasize central CO2 hypersensitivity and chronic hyperventilation as primary mechanisms underlying nocturnal panic.