Characterizing the neural circuitry associated with configural threat learning.

Contextual threat learning is often associated with two processes: elemental and configural learning. Few studies have examined configural learning where subjects form a representation of the threat-related context as a gestalt whole from the individual features in the environment. The goal of the current study was to compare and contrast neural circuitry recruited by variation in demands placed on configural threat encoding. Subjects (N = 25) completed a configural threat learning task, where we manipulated the amount of configural encoding required to learn the threat association (low demand: changes to a discrete element of the context; and high demand: rearrangement of elements). US expectancy ratings, skin conductance responses (SCR), and functional magnetic resonance imaging (fMRI) were collected. Subjects successfully learned the configural threat association as measured by US expectancy ratings, SCR, and BOLD activity. Hippocampal and amygdala region of interest analyses indicated differential configural threat learning and predicted SCR measures of learning. Furthermore, whole brain analyses identified four circuits that were impacted by the amount of differential configural encoding required, but none correlated with SCR. These results set the stage for a more detailed understanding of how configural threat learning is instantiated in the brain-an important mechanism associated with PTSD and other fear-related disorders.

Neural measures associated with configural threat acquisition.

Contextual threat learning reflects two often competing processes: configural and elemental learning. Configural threat learning is a hippocampal-dependent process of forming a conjunctive representation of a context through binding of several multi-modal elements. In contrast, elemental threat-learning is governed by the amygdala and involves forming associative relationships between individual features within the context. Contextual learning tasks in humans however, rarely probe if a learned fear response is truly due to configural learning vs. simple elemental associations. The aim of the current study was to probe both constructs separately to enable a more refined interpretation of configural vs. elemental threat learning performance and mediating circuits. Subjects (n = 25) performed both a novel feature-identical contextual threat conditioning task and a discrete cue threat acquisition task while undergoing functional magnetic resonance imaging. Results demonstrated increased hippocampus activity for the threat configuration compared to the safe configuration. This pattern was not observed in the amygdala. In contrast, elemental threat learning was associated with increased amygdala, but not hippocampus activity. Whole-brain analyses revealed that both configural and elemental threat acquisition share neural circuitry related to fear expression. These results provide support for the importance of the hippocampus specifically in configural threat acquisition and fear expression.

The Future of Contextual Fear Learning for PTSD Research: A Methodological Review of Neuroimaging Studies.

There has been a great deal of recent interest in human models of contextual fear learning, particularly due to the use of such paradigms for investigating neural mechanisms related to the etiology of posttraumatic stress disorder. However, the construct of "context" in fear conditioning research is broad, and the operational definitions and methods used to investigate contextual fear learning in humans are wide ranging and lack specificity, making it difficult to interpret findings about neural activity. Here we will review neuroimaging studies of contextual fear acquisition in humans. We will discuss the methodology associated with four broad categories of how contextual fear learning is manipulated in imaging studies (colored backgrounds, static picture backgrounds, virtual reality, and configural stimuli) and highlight findings for the primary neural circuitry involved in each paradigm. Additionally, we will offer methodological recommendations for human studies of contextual fear acquisition, including using stimuli that distinguish configural learning from discrete cue associations and clarifying how context is experimentally operationalized.

Effects of military service and deployment on clinical symptomatology: The role of trauma exposure and social support.

The Marine Resiliency Study-II examined changes in symptomatology across a deployment cycle to Afghanistan. U.S. Servicemembers (N = 1041) received clinical testing at two time points either bracketing a deployment (855) or not (186). Factor analyses were used to generate summary and change scores from Time 1 to Time 2. A between-subject design was used to examine changes across the deployment cycle with deployment (low-trauma, high-trauma, and non-deployed) and social support (low vs. high) as the grouping variables. Insomnia increased post-deployment regardless of deployment trauma (std. effect for high-trauma and low-trauma = 0.39 and 0.26, respectively). Only the high-trauma group showed increased PTSD symptoms and non-perspective-taking (std. effect = 0.40 and 0.30, respectively), while low-trauma showed decreased anxiety symptoms after deployment (std. effect = -0.17). These associations also depend on social support, with std. effects ranging from -0.22 to 0.51. When the groups were compared, the high-trauma deployed group showed significantly worse PTSD and non-perspective-taking than all other groups. Similar to studies in other military divisions, increased clinical symptoms were associated with high deployment stress in active duty Servicemembers, and social support shows promise as a moderator of said association.

Fear learning alterations after traumatic brain injury and their role in development of posttraumatic stress symptoms.

BACKGROUND: It is unknown how traumatic brain injury (TBI) increases risk for posttraumatic stress disorder (PTSD). One potential mechanism is via alteration of fear-learning processes that could affect responses to trauma memories and cues. We utilized a prospective, longitudinal design to determine if TBI is associated with altered fear learning and extinction, and if fear processing mediates effects of TBI on PTSD symptom change. METHODS: Eight hundred fifty two active-duty Marines and Navy Corpsmen were assessed before and after deployment. Assessments included TBI history, PTSD symptoms, combat trauma and deployment stress, and a fear-potentiated startle task of fear acquisition and extinction. Startle response and self-reported expectancy and anxiety served as measures of fear conditioning, and PTSD symptoms were measured with the Clinician-Administered PTSD Scale. RESULTS: Individuals endorsing "multiple hit" exposure (both deployment TBI and a prior TBI) showed the strongest fear acquisition and highest fear expression compared to groups without multiple hits. Extinction did not differ across groups. Endorsing a deployment TBI was associated with higher anxiety to the fear cue compared to those without deployment TBI. The association of deployment TBI with increased postdeployment PTSD symptoms was mediated by postdeployment fear expression when recent prior-TBI exposure was included as a moderator. TBI associations with increased response to threat cues and PTSD symptoms remained when controlling for deployment trauma and postdeployment PTSD diagnosis. CONCLUSIONS: Deployment TBI, and multiple-hit TBI in particular, are associated with increases in conditioned fear learning and expression that may contribute to risk for developing PTSD symptoms.

On the Road to Translation for PTSD Treatment: Theoretical and Practical Considerations of the Use of Human Models of Conditioned Fear for Drug Development.

The use of quantitative, laboratory-based measures of threat in humans for proof-of-concept studies and target development for novel drug discovery has grown tremendously in the last 2 decades. In particular, in the field of posttraumatic stress disorder (PTSD), human models of fear conditioning have been critical in shaping our theoretical understanding of fear processes and importantly, validating findings from animal models of the neural substrates and signaling pathways required for these complex processes. Here, we will review the use of laboratory-based measures of fear processes in humans including cued and contextual conditioning, generalization, extinction, reconsolidation, and reinstatement to develop novel drug treatments for PTSD. We will primarily focus on recent advances in using behavioral and physiological measures of fear, discussing their sensitivity as biobehavioral markers of PTSD symptoms, their response to known and novel PTSD treatments, and in the case of d-cycloserine, how well these findings have translated to outcomes in clinical trials. We will highlight some gaps in the literature and needs for future research, discuss benefits and limitations of these outcome measures in designing proof-of-concept trials, and offer practical guidelines on design and interpretation when using these fear models for drug discovery.

HIGH AND LOW THRESHOLD FOR STARTLE REACTIVITY ASSOCIATED WITH PTSD SYMPTOMS BUT NOT PTSD RISK: EVIDENCE FROM A PROSPECTIVE STUDY OF ACTIVE DUTY MARINES.

BACKGROUND: Heightened startle response is a symptom of PTSD, but evidence for exaggerated startle in PTSD is inconsistent. This prospective study aimed to clarify whether altered startle reactivity represents a trait risk-factor for developing PTSD or a marker of current PTSD symptoms. METHODS: Marines and Navy Corpsmen were assessed before (n = 2,571) and after (n = 1,632) deployments to Iraq or Afghanistan with the Clinician-Administered PTSD Scale (CAPS). A predeployment startle-threshold task was completed with startle probes presented over 80-114 dB[A] levels. Latent class mixture modeling identified three growth classes of startle performance: "high," "low," and "moderate" threshold classes. Zero-inflated negative binomial regression was used to assess relationships between predeployment startle threshold and pre- and postdeployment psychiatric symptoms. RESULTS: At predeployment, the low-threshold class had higher PTSD symptom scores. Relative to the moderate-threshold class, low-threshold class membership was associated with decreased likelihood of being symptom-free at predeployment, based on CAPS, with particular associations with numbing and hyperarousal subscales, whereas high-threshold class membership was associated with more severe predeployment PTSD symptoms, in particular avoidance. Associations between low-threshold membership and CAPS symptoms were independent from measures of trauma burden, whereas associations between high-threshold membership and CAPS were not. Predeployment startle threshold did not predict postdeployment symptoms. CONCLUSIONS: This study found that both low startle threshold (heightened reactivity) and high startle threshold (blunted reactivity) were associated with greater current PTSD symptomatology, suggesting that startle reactivity is associated with current PTSD rather than a risk marker for developing PTSD.

The effect of glucose on hippocampal-dependent contextual fear conditioning.

BACKGROUND: The metabolic challenge of trauma disrupts hippocampal functioning, which is necessary for processing the complex co-occurring elements comprising the traumatic context. Poor contextual memory of trauma may subsequently contribute to intrusive memories and overgeneralization of fear. Glucose consumption following trauma may be a means to protect hippocampal functioning and contextual fear learning. This study experimentally examined the effect of glucose on hippocampal-dependent contextual learning versus cued fear learning in humans. METHODS: Forty-two male participants underwent cued conditioning with an unconditional stimulus (US) (shock) paired with a discrete conditional stimulus (geometric shape) and context conditioning (requiring hippocampal processing) with a US unpredictably paired with a background context (picture of room). Participants were then blindly randomized to consume either a 25 g glucose or sweet-tasting placebo drink and returned for a test phase 24 hours later. Measures included acoustic startle response, US expectancy, blood glucose levels, and arousal ratings. RESULTS: The glucose group showed superior retention of hippocampal-dependent contextual learning at test relative to the placebo group, as demonstrated by acoustic startle response and US expectancy ratings. Glucose and placebo groups did not differ on any measure of cued fear learning at test. CONCLUSIONS: This study provides experimental evidence that in mildly stressed humans postconditioning glucose consumption improves retention of hippocampal-dependent contextual learning but not cued learning. Ultimately, glucose consumption following trauma may be a means of improving learning about the traumatic context, thereby preventing subsequent development of symptoms of posttraumatic stress.

CBT competence in novice therapists improves anxiety outcomes.

OBJECTIVE: This study explores the relationships between therapist variables (cognitive behavioral therapy [CBT] competence, and CBT adherence) and clinical outcomes of computer-assisted CBT for anxiety disorders delivered by novice therapists in a primary care setting. METHODS: Participants were recruited for a randomized controlled trial of evidence-based treatment, including computer-assisted CBT, versus treatment as usual. Therapists (anxiety clinical specialists; ACSs) were nonexpert clinicians, many of whom had no prior experience in delivering psychotherapy (and in particular, very little experience with CBT). Trained raters reviewed randomly selected treatment sessions from 176 participants and rated therapists on measures of CBT competence and CBT adherence. Patients were assessed at baseline and at 6-, 12-, and 18-month follow-ups on measures of anxiety, depression, and functioning, and an average Reliable Change Index was calculated as a composite measure of outcome. CBT competence and CBT adherence were entered as predictors of outcome, after controlling for baseline covariates. RESULTS: Higher CBT competence was associated with better clinical outcomes whereas CBT adherence was not. Also, CBT competence was inversely correlated with years of clinical experience and trended (not significantly, though) down as the study progressed. CBT adherence was inversely correlated with therapist tenure in the study. CONCLUSIONS: Therapist competence was related to improved clinical outcomes when CBT for anxiety disorders was delivered by novice clinicians with technology assistance. The results highlight the value of the initial training for novice therapists as well as booster training to limit declines in therapist adherence.

A randomized controlled trial of a self-guided, multimedia, stress management and resilience training program.

BACKGROUND: Stress is a common and costly behavioral health issue. Technology-based behavioral health programs (e.g., computer or web-based programs) are effective for treating anxiety or depression. These programs increase availability of evidence-based interventions to individuals who are not able or willing to receive such in-person treatments. Stress management training has empirical support, but little data exists on its efficacy with stressed but healthy individuals, and there are no prior studies employing a self-guided, multimedia intervention. We conducted a randomized controlled trial of a self-guided, multimedia stress management and resilience training program (SMART-OP) with a stressed but healthy sample. METHODS: Participants (N = 66) were randomized to SMART-OP or an attention control (AC) group that received marketed videos and published material on stress management. Participants were evaluated on self-report measures and Trier Social Stress Test (TSST) performance. Analyses were based on study completers (N = 59). RESULTS: SMART-OP group reported significantly less stress, more perceived control over stress, and rated SMART-OP as significantly more useful than AC. During the TSST, the data suggests the SMART-OP group showed greater within-task α-amylase recovery at post-assessment. CONCLUSIONS: SMART-OP is highly usable and is a more effective and useful stress management training program than an educational comparison.

A dimensional approach to measuring anxiety for DSM-5.

In preparation for DSM-5's planned inclusion of dimensional assessments of psychopathology as a complement to traditional categorical diagnoses, we developed brief self-rated scales for anxiety disorders that are consistent in content and structure. In the present paper, we discuss the creation of the scales and examine their psychometric properties and clinical sensitivity. Phase One assessed psychometric properties of the initial versions of the scales in a large non-clinical sample (n = 702). Phase Two assessed the psychometric properties of revised versions of the scales, including test-retest reliability, in a non-clinical sample (n = 57). Phase Three examined the scales' psychometric properties and relationship with clinician ratings of disorder severity in a clinical sample (n = 48). The scales demonstrated internal consistency (α = 0.85-0.92), convergent validity (r(s) = 0.39-0.69), and test-retest reliability in the non-clinical samples (ICC = 0.51-0.81). In the clinical sample, the scales demonstrated significantly higher total scores than in the non-clinical sample (Cohen's d = 0.72-1.50) and moderate to high correlations with clinician ratings of disorder severity (r = 0.43-0.82) Although further evaluation and refinement of the scales (particularly the specific phobia and agoraphobia scales) is needed, the results provide preliminary support for the use of these scales in DSM-5 and thus take an important step toward the integration of standardized dimensional measurement into the diagnosis of anxiety disorders.

Dimensional indicators of generalized anxiety disorder severity for DSM-V.

For DSM-V, simple dimensional measures of disorder severity will accompany diagnostic criteria. The current studies examine convergent validity and test-retest reliability of two potential dimensional indicators of worry severity for generalized anxiety disorder (GAD): percent of the day worried and number of worry domains. In study 1, archival data from diagnostic interviews from a community sample of individuals diagnosed with one or more anxiety disorders (n = 233) were used to assess correlations between percent of the day worried and number of worry domains with other measures of worry severity (clinical severity rating (CSR), age of onset, number of comorbid disorders, Penn state worry questionnaire (PSWQ)) and DSM-IV criteria (excessiveness, uncontrollability and number of physical symptoms). Both measures were significantly correlated with CSR and number of comorbid disorders, and with all three DSM-IV criteria. In study 2, test-retest reliability of percent of the day worried and number of worry domains were compared to test-retest reliability of DSM-IV diagnostic criteria in a non-clinical sample of undergraduate students (n = 97) at a large west coast university. All measures had low test-retest reliability except percent of the day worried, which had moderate test-retest reliability. Findings suggest that these two indicators capture worry severity, and percent of the day worried may be the most reliable existing indicator. These measures may be useful as dimensional measures for DSM-V.