Fearful facial expressions reduce inhibition levels in the dorsolateral prefrontal cortex in subjects with specific phobia.

BACKGROUND: Specific phobias have the highest prevalence among anxiety disorders. Cognitive control involving the dorsolateral prefrontal cortex (DLPFC) is crucial for coping abilities in anxiety disorders. However, there is little research on the DLPFC in specific phobia. METHODS: Using transcranial magnetic stimulation (TMS), we investigated the TMS-evoked potential component N100 in the DLPFC at rest and while watching emotional expressions. The TMS-evoked N100 provides a parameter for gamma-aminobutyric acid (GABA)-B-mediated cortical inhibition. Twenty-two drug-free subjects with specific phobia (21 females and 1 male) were compared with 26 control subjects (23 females and 3 males) regarding N100 in the DLPFC at rest and during an emotional 1-back task with fearful, angry, and neutral facial expressions. RESULTS: At rest, we found reduced N100 amplitudes in the specific phobia compared with the control group. Furthermore, the specific phobia group showed a further reduction in N100 amplitude when memorizing fearful compared with neutral facial expressions. CONCLUSION: There appears to be a decrease in GABA-B-mediated inhibition in the DLPFC in subjects with a specific phobia at rest. This decrease was more pronounced under emotional activation by exposure to fearful facial expressions, pointing towards additional state effects of emotional processing on inhibitory function in the DLPFC.

Neural processing of emotional facial stimuli in specific phobia: An fMRI study.

BACKGROUND: Patients with specific phobia (SP) show altered brain activation when confronted with phobia-specific stimuli. It is unclear whether this pathogenic activation pattern generalizes to other emotional stimuli. This study addresses this question by employing a well-powered sample while implementing an established paradigm using nonspecific aversive facial stimuli. METHODS: N = 111 patients with SP, spider subtype, and N = 111 healthy controls (HCs) performed a supraliminal emotional face-matching paradigm contrasting aversive faces versus shapes in a 3-T magnetic resonance imaging scanner. We performed region of interest (ROI) analyses for the amygdala, the insula, and the anterior cingulate cortex using univariate as well as machine-learning-based multivariate statistics based on this data. Additionally, we investigated functional connectivity by means of psychophysiological interaction (PPI). RESULTS: Although the presentation of emotional faces showed significant activation in all three ROIs across both groups, no group differences emerged in all ROIs. Across both groups and in the HC > SP contrast, PPI analyses showed significant task-related connectivity of brain areas typically linked to higher-order emotion processing with the amygdala. The machine learning approach based on whole-brain activity patterns could significantly differentiate the groups with 73% balanced accuracy. CONCLUSIONS: Patients suffering from SP are characterized by differences in the connectivity of the amygdala and areas typically linked to emotional processing in response to aversive facial stimuli (inferior parietal cortex, fusiform gyrus, middle cingulate, postcentral cortex, and insula). This might implicate a subtle difference in the processing of nonspecific emotional stimuli and warrants more research furthering our understanding of neurofunctional alteration in patients with SP.

The Efficacy of a Virtual Reality Exposure Therapy Treatment for Fear of Flying: A Retrospective Study.

Background: Fear of flying (FoF) is a phobia with 10-40% prevalence in the industrialized world. FoF is accompanied by severe economic, social, vocational, and emotional consequences. In recent years, virtual reality (VR)-based exposure therapy (VRET) for FoF has been introduced. Positive long-term efficacy of FoF-VRET has been reported by several studies, which, however, were limited by relatively small, non-representative samples and a lack of comparative pre/post functional efficacy outcome measures. Our objective was to evaluate the efficacy of a VRET treatment utilizing a large-scale VR system, experienced by a representative sample of self-referred individuals. Methods: We conducted a retrospective survey. Of 274 individuals who received the treatment (over a period of 3 years), 209 met inclusion/criteria, and 98 agreed to participate. We mainly collected information regarding flight activity before and after treatment relying on evidence such as boarding passes and flight tickets. The primary outcome measures were (1) number of flights per month (FpM) and (2) number of flight hours per month (FHpM). For each participant, these outcomes were computed for the post-treatment period (≥6 months after FoF-VRET) and the corresponding pre-treatment period. Results: FpM (mean ± SD) increased from 0.04 ± 0.06 to 0.16 ± 14 flights (p < 0.0001). FHpM rose from 0.19 ± 0.35 to 0.79 ± 0.87 h per month (p < 0.0001). Conclusion: These results are indicative of FoF-VRET treatment efficacy. Future studies should evaluate long-term maintenance of the treatment effect and thus identify the optimal frequency for delivery of periodic booster treatments.

Unraveling the comorbidity of depression and anxiety in a large inpatient sample: Network analysis to examine bridge symptoms.

BACKGROUND: Comorbidities in mental disorders are often understood by assuming a common cause. The network theory of mental disorders offers an alternative to this assumption by understanding comorbidities as mutually reinforced problems. In this study, we used network analysis to examine bridge symptoms between anxiety and depression in a large sample. METHOD: Using data from a sample of patients diagnosed with both depression and an anxiety disorder before and after inpatient treatment (N = 5,614, mean age: 42.24, 63.59% female, average treatment duration: 48.12 days), network models of depression and anxiety symptoms are estimated. Topology, the centrality of nodes, stability, and changes in network structure are analyzed. Symptoms that drive comorbidity are determined by bridge node analysis. As an alternative to network communities based on categorical diagnosis, we performed a community analysis and propose empirically derived symptom subsets. RESULTS: The obtained network models are highly stable. Sad mood and the inability to control worry are the most central. Psychomotor agitation or retardation is the strongest bridge node between anxiety and depression, followed by concentration problems and restlessness. Changes in appetite and suicidality were unique to depression. Community analysis revealed four symptom groups. CONCLUSION: The estimated network structure of depression and anxiety symptoms proves to be highly accurate. Results indicate that some symptoms are considerably more influential than others and that only a small number of predominantly physical symptoms are strong candidates for explaining comorbidity. Future studies should include physiological measures in network models to provide a more accurate understanding.

Limbic and prefrontal neural volume modulate social anxiety in children at temperamental risk.

BACKGROUND: Clinical levels of a social anxiety disorder (SAD) often appear during childhood and rise to a peak during late adolescence. The temperament trait behavioral inhibition (BI), evident early in childhood, has been linked to increased risk for SAD. Functional and structural variations in brain regions associated with the identification of, and response to, fear may support the BI-SAD relation. Whereas relevant functional studies are emerging, the few extant structural studies have focused on adult samples with mixed findings. METHODS: A moderated-mediation model was used to examine the relations between BI, SAD symptoms, and brain-volume individual differences in a sample of children at risk for anxiety (ages 9-12; N = 130, 52 BI). RESULTS: Our findings indicate that at higher levels of BI, children with smaller anterior insula volumes showed stronger correlations between BI and SAD. In addition, larger ventrolateral prefrontal cortex (vlPFC) volumes were associated with fewer SAD symptoms. CONCLUSIONS: These findings support previous reports linking SAD levels with variations in volume and reactivity in both limbic (insula) and prefrontal (vlPFC) regions. These findings set the foundation for further examination of networks of neural structures that influence the transition from BI to SAD across development, helping further clarify mechanisms of risk and resilience.

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.

Specific and social fears in children and adolescents: separating normative fears from problem indicators and phobias

Objective: To distinguish normative fears from problematic fears and phobias. Methods: We investigated 2,512 children and adolescents from a large community school-based study, the High Risk Study for Psychiatric Disorders. Parent reports of 18 fears and psychiatric diagnosis were investigated. We used two analytical approaches: confirmatory factor analysis (CFA)/item response theory (IRT) and nonparametric receiver operating characteristic (ROC) curve. Results: According to IRT and ROC analyses, social fears are more likely to indicate problems and phobias than specific fears. Most specific fears were normative when mild; all specific fears indicate problems when pervasive. In addition, the situational fear of toilets and people who look unusual were highly indicative of specific phobia. Among social fears, those not restricted to performance and fear of writing in front of others indicate problems when mild. All social fears indicate problems and are highly indicative of social phobia when pervasive. Conclusion: These preliminary findings provide guidance for clinicians and researchers to determine the boundaries that separate normative fears from problem indicators in children and adolescents, and indicate a differential severity threshold for specific and social fears.

Clinical and neurobiological effects of aerobic exercise in dental phobia: A randomized controlled trial.

BACKGROUND: Physical activity has shown to be effective in anxiety disorders. For specific phobia, no studies are available that systematically examined the effects of an aerobic exercise intervention on phobic fear within a randomized-controlled design. Therefore, we investigated the acute effect of a standardized aerobic training on clinical symptoms of dental phobia as well as on stress-related neurobiological markers. METHODS: Within a crossover design, 30 patients with dental phobia (mean age: 34.1 years; mean score of the Dental Anxiety Scale: 18.8) underwent two minor dental interventions separated by 7 days. Dental treatment was performed after 30 min of physical activity at either 20% VO2 max (control) or 70% VO2 max (intervention), respectively. To control for habituation, patients were randomly assigned to one of the two conditions prior to the first intervention. Moreover, saliva samples were collected at five times in order to determine changes in salivary cortisol (sC) and alpha-amylase (sAA) due to treatment. RESULTS: In comparison to baseline, aerobic exercise within 70% VO2 max significantly reduced clinical anxiety and sC concentrations before, during, and after the dental treatment. In contrast, the control condition led to decreased sAA levels at different time points of measurement. Habituation occurred at the second study day, independent of the order. CONCLUSIONS: Our study provides evidence for an effect of moderate-intense exercise on clinical symptoms and sC in patients with dental phobia. Therefore, acute aerobic exercise might be a simple and low-cost intervention to reduce disorder-specific phobic fear.

Targeting memory reconsolidation to prevent the return of fear in patients with fear of flying.

BACKGROUND: When a memory is recalled, it may again exist in a labile state and stored information becomes amenable to change, a psychobiological process known as reconsolidation. Exposure therapy for anxiety disorders involves accessing a fear memory and modifying it with less fearful information. A preclinical study reported that providing a reminder of a fear memory 10 min prior to extinction training in humans decreased fear up to 1 year later (Schiller et al., 2010). METHODS: For this pilot clinical study, we used virtual reality exposure therapy (VRE) for fear of flying (FoF) to determine if using a cue to reactivate the memory of the feared stimulus 10 min prior to exposure sessions leads to fewer anxiety-related behaviors and a more durable response compared to a neutral cue. FoF participants (N = 89) received four sessions of anxiety management training followed by four sessions of VRE. Participants were randomly assigned to receive an FoF cue (reactivation group) or a neutral cue (control group) prior to the VRE sessions. Heart rate (HR) and skin conductance levels (SCLs) were collected during posttreatment and 3-month follow-up assessments as objective markers of fear responding. RESULTS: Treatment was effective and all clinical measures improved equally between groups at posttreatment with maintained gains through follow-ups. Significant differences were identified with regard to HR and SCL indices. CONCLUSIONS: These results suggest that memory reactivation prior to exposure therapy did not have an impact on clinical measures but may enhance the effect of exposure therapy at the physiological level.

Brain activation during fear extinction predicts exposure success.

BACKGROUND: Exposure therapy, a gold-standard treatment for anxiety disorders, is assumed to work via extinction learning, but this has never been tested. Anxious individuals demonstrate extinction learning deficits, likely related to less ventromedial prefrontal cortex (vmPFC) and more amygdala activation, but the relationship between these deficits and exposure outcome is unknown. We tested whether anxious individuals who demonstrate better extinction learning report greater anxiety reduction following brief exposure. METHODS: Twenty-four adults with public speaking anxiety completed (1) functional magnetic resonance imaging during a conditioning paradigm, (2) a speech exposure session, and (3) anxiety questionnaires before and two weeks postexposure. Extinction learning was assessed by comparing ratings to a conditioned stimulus (neutral image) that was previously paired with an aversive noise against a stimulus that had never been paired. Robust regression analyses examined whether brain activation during extinction learning predicted anxiety reduction two weeks postexposure. RESULTS: On average, the conditioning paradigm resulted in acquisition and extinction effects on stimulus ratings, and the exposure session resulted in reduced anxiety two weeks post-exposure. Consistent with our hypothesis, individuals with better extinction learning (less negative stimulus ratings), greater activation in vmPFC, and less activation in amygdala, insula, and periaqueductal gray reported greater anxiety reduction two weeks postexposure. CONCLUSION: To our knowledge, this is the first time that the theoretical link between extinction learning and exposure outcome has been demonstrated. Future work should examine whether extinction learning can be used as a prognostic test to determine who is most likely to benefit from exposure therapy.

Effect of as-needed use of intranasal PH94B on social and performance anxiety in individuals with social anxiety disorder.

BACKGROUND: There are no medications approved for as-needed use for feared situations for individuals with social anxiety disorder (SAD). In the present study, intranasal PH94B was provided for use as needed during stressful events. METHODS: Twenty-two subjects were randomized (double-blind) to 2 weeks of treatment with intranasal PH94B or placebo. Following self-administration of medication prior to a feared event, peak levels of anxiety were recorded using the Subjective Units of Distress Scale (SUDS). After 2 weeks, subjects were crossed over to the opposite treatment for 2 weeks. Average peak SUDS during treatment with PH94B and placebo were compared using a paired t-test. RESULTS: Significant differences in favor of PH94B were found on the primary outcome measure: mean peak SUDS change from baseline for all subjects receiving PH94B was 15.6 points versus 8.3 points for placebo (paired t = 3.09, P = .006, effect size of .658). PH94B showed less superiority over placebo when placebo was given second rather than first, likely due to a carryover effect. Looking between groups at just the first 2 weeks of treatment, PH94B also showed trend superiority to placebo on the Liebowitz Social Anxiety Scale (LSAS) (P = .07) and a significant difference on the Patient Global Impression of Change (P = .024) and the LSAS Avoidance subtotal (P = .02). CONCLUSIONS: While further study is needed, these results, combined with earlier findings, suggest that PH94B could represent a useful as-needed treatment for SAD, and continue to validate the nasal chemosensory system as a novel mechanism for medication delivery.

CLASSIFICATION OF ANXIETY DISORDERS COMORBID WITH MAJOR DEPRESSION: COMMON OR DISTINCT INFLUENCES ON RISK?

BACKGROUND: Anxiety and depression display frequent comorbidity. Individuals with comorbid disorders also often have more extreme symptomatology than those with single disorders. This correlation between comorbidity and severity poses an interesting question: Are comorbid forms of anxiety and depression essentially just more severe versions of the pure disorders? METHODS: In a large major depression (MD) case-control sample of individuals from the China, Oxford and VCU Experimental Research on Genetic Epidemiology project, we examined the patterns of lifetime anxiety comorbidity (including generalized anxiety disorder--GAD, panic disorder, and five phobia subtypes) among MD cases (N = 5,864) in this population. Binary and multinomial logistic regression was used to estimate associations between risk factors and outcomes including MD as well as latent class membership, which were compared using continuation ratios. RESULTS: We found a five-class solution to fit best, and each resulting class had a distinct pattern of association with the tested risk factors. The use of continuation ratios suggests that a class characterized by high endorsement of GAD is comparable to a more severely affected "pure MD" group. The other three classes (characterized by agoraphobia, various specific phobias, and by high endorsement of all comorbid anxiety disorders, respectively) appear to differ meaningfully from MD alone. CONCLUSIONS: Risk for MD resulting from environmental and psychosocial factors may also predispose individuals to GAD, and less consistently, other anxiety disorders. Presentations of MD with certain phobias display distinguishably different patterns of risk, however, and are therefore likely qualitatively distinct.

Intranasal oxytocin administration prior to exposure therapy for arachnophobia impedes treatment response.

BACKGROUND: Recent years have seen the emergence of a new paradigm for treatment of anxiety disorders focusing on development of drugs that facilitate psychotherapies via targeted effects on neuroplasticity. One compound that has generated interest in this regard is oxytocin (OT), a mammalian neuropeptide that modulates activity of the neurocircuit mediating fear extinction and memory processes. Recent research in healthy humans has suggested that intranasal OT administered prior to fear extinction training enhances fear extinction performance, supporting its potential to augment exposure-based psychotherapy. Here, we tested the hypothesis that OT treatment would facilitate response to exposure therapy in patients with specific phobia. METHODS: We conducted a small proof-of-concept trial investigating the effect of pretreatment intranasal OT administration on a brief, single-session exposure treatment for arachnophobia (fear of spiders). The study was randomized, double-blind, and placebo controlled (n = 13 placebo, 11 females; n = 10 OT, 8 females) with 1-week and 1-month follow-up assessments. Dependent measures attended to arachnophobia symptoms (self-report), phobic behavior (behavioral avoidance of spider task), and treatment credibility/therapeutic alliance. RESULTS: Administration of OT prior to exposure therapy tended to impede treatment response as measured by self-report of symptoms at both follow-up periods. OT treatment did not significantly affect behavioral measures of fear. Immediately after OT administration but before therapy, the OT group trended toward less confidence in the treatment. The OT group also trended toward lower ratings of therapeutic alliance than placebo. CONCLUSIONS: These results suggest that OT administration effects on extinction may vary depending on conditions and population.

Aerobic exercise training facilitates the effectiveness of cognitive behavioral therapy in panic disorder.

BACKGROUND: Physical activity has been discussed as a therapeutic alternative or add-on for the treatment of anxiety disorders. We studied whether aerobic exercise compared to physical activity with low impact can improve the effect of cognitive behavioral therapy (CBT) in patients with panic disorder (PD) with/without agoraphobia. METHODS: Forty-seven patients received group CBT treatment over 1 month, which was augmented with an 8-week protocol of either aerobic exercise (three times/week, 30 min, 70% VO(2) max; n = 24) or a training program including exercises with very low intensity (n = 23) in a randomized controlled double-blind design. The primary outcome measure was the total score on the Hamilton Anxiety Scale (Ham-A). A 2 × 3 analysis of covariance (ANCOVA) with baseline value as a covariate was conducted for data analysis. RESULTS: Time × group interaction for the Ham-A revealed a significant effect (P = .047, η(2) p = .072), which represented the significant group difference at a 7-month follow-up. For the other clinical outcome measures no statistical significance emerged, although improvement was more sustained in the exercise group. CONCLUSIONS: For patients with PD, regular aerobic exercise adds an additional benefit to CBT. This supports previous results and provides evidence about the intensity of exercise that needs to be performed.

Avoidance moderates the association between mothers' and children's fears: findings from a novel motion-tracking behavioral assessment.

BACKGROUND: Fear and anxiety in children are associated with similar symptoms in parents. Parental modeling of fearful or avoidant behavior is believed to contribute to this association. We employed a novel motion-tracking experimentation platform to test the hypothesis that mothers' behavioral avoidance of spiders moderates the association between fear of spiders in mothers and children. METHOD: Participants were 86 children (aged 7-17) presenting with an anxiety disorder, and their mothers. Children and mothers completed the Spider Phobia Questionnaire. Mothers completed a motion-tracking assessment of behavioral avoidance of spiders. RESULTS: Fear of spiders in mothers was associated with fear of spiders in children (r85  = 0.48, 95%CI 0.30 - 0.63, P < 0.001). Two metrics of behavioral avoidance in mothers were associated with mothers' self-reported fear of spiders (r = -0.49, 95% CI 0.31-0.64, P < 0.001; and r = 0.42, 95%CI 0.23 - 0.58 P < 0.001). Mothers' behavioral avoidance moderated the association between fear of spiders in mothers and in children. When mothers' avoidance was intermediate or high the association was significant, and as mothers' behavioral avoidance increased the strength of the association increased. Fear of spiders in mothers with low behavioral avoidance was not associated with fear of spiders in their children. CONCLUSIONS: The study demonstrates that behavioral avoidance can be measured using the motion-tracking platform and can be useful in understanding the links between symptoms of anxiety in mothers and children. Reducing parents' overt expressions of avoidance may lower the risk of fears being transmitted to children.

Anxiety disorders are independently associated with suicide ideation and attempts: propensity score matching in two epidemiological samples.

BACKGROUND: Research suggests that suicidal behavior in individuals with anxiety disorders is attributable to co-occurring risk factors, such as depression. We argue that these conclusions are founded primarily in statistical adjustments that may obscure independent associations. We explored independent associations between specific anxiety disorders and suicide attempts and ideation by means of propensity score matching, a process that simulates a case-control study by creating matched groups that differ in group status (e.g., diagnosis of a specific anxiety disorder) but that are statistically equivalent on observed covariates. METHODS: We made use of the National Comorbidity Survey Replication (NCS-R) and the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), which include a total of 43,935 adults. Diagnoses included agoraphobia without panic disorder, generalized anxiety disorder, panic disorder with or without agoraphobia, posttraumatic stress disorder, social anxiety disorder, and specific phobia. RESULTS: Each anxiety disorder was (95% confidence intervals) associated with increased odds of lifetime suicide attempts (odds ratios 3.57-6.64 [NCS-R], 3.03-7.00 [NESARC]) and suicidal ideation (odds ratios 2.62-4.87 [NCS-R], 3.34-10.57 [NESARC]). Odds ratios for each disorder remained statistically significant after matching on diagnostic status of dysthymia, major depressive disorder, alcohol abuse/dependence, substance abuse/dependence, bipolar disorder I, bipolar disorder II, all other anxiety disorders, and on sociodemographic variables. CONCLUSIONS: This is the first report to present evidence that each anxiety disorder is associated with suicide ideation and suicide attempts beyond the effects of co-occurring mental disorders. These findings warrant consideration in assessment, intervention, and related policies.