Resting-state functional connectivity in anxiety disorders: a multicenter fMRI study.

Anxiety disorders (AD) are associated with altered connectivity in large-scale intrinsic brain networks. It remains uncertain how much these signatures overlap across different phenotypes due to a lack of well-powered cross-disorder comparisons. We used resting-state functional magnetic resonance imaging (rsfMRI) to investigate differences in functional connectivity (FC) in a cross-disorder sample of AD patients and healthy controls (HC). Before treatment, 439 patients from two German multicenter clinical trials at eight different sites fulfilling a primary diagnosis of panic disorder and/or agoraphobia (PD/AG, N = 154), social anxiety disorder (SAD, N = 95), or specific phobia (SP, N = 190) and 105 HC underwent an 8 min rsfMRI assessment. We performed categorical and dimensional regions of interest (ROI)-to-ROI analyses focusing on connectivity between regions of the defensive system and prefrontal regulation areas. AD patients showed increased connectivity between the insula and the thalamus compared to controls. This was mainly driven by PD/AG patients who showed increased (insula/hippocampus/amygdala-thalamus) and decreased (dorsomedial prefrontal cortex/periaqueductal gray-anterior cingulate cortex) positive connectivity between subcortical and cortical areas. In contrast, SAD patients showed decreased negative connectivity exclusively in cortical areas (insula-orbitofrontal cortex), whereas no differences were found in SP patients. State anxiety associated with the scanner environment did not explain the FC between these regions. Only PD/AG patients showed pronounced connectivity changes along a widespread subcortical-cortical network, including the midbrain. Dimensional analyses yielded no significant results. The results highlighting categorical differences between ADs at a systems neuroscience level are discussed within the context of personalized neuroscience-informed treatments. PROTECT-AD's registration at NIMH Protocol Registration System: 01EE1402A and German Register of Clinical Studies: DRKS00008743. SpiderVR's registration at ClinicalTrials.gov: NCT03208400.

Lack of evidence for predictive utility from resting state fMRI data for individual exposure-based cognitive behavioral therapy outcomes: A machine learning study in two large multi-site samples in anxiety disorders.

Data-based predictions of individual Cognitive Behavioral Therapy (CBT) treatment response are a fundamental step towards precision medicine. Past studies demonstrated only moderate prediction accuracy (i.e. ability to discriminate between responders and non-responders of a given treatment) when using clinical routine data such as demographic and questionnaire data, while neuroimaging data achieved superior prediction accuracy. However, these studies may be considerably biased due to very limited sample sizes and bias-prone methodology. Adequately powered and cross-validated samples are a prerequisite to evaluate predictive performance and to identify the most promising predictors. We therefore analyzed resting state functional magnet resonance imaging (rs-fMRI) data from two large clinical trials to test whether functional neuroimaging data continues to provide good prediction accuracy in much larger samples. Data came from two distinct German multicenter studies on exposure-based CBT for anxiety disorders, the Protect-AD and SpiderVR studies. We separately and independently preprocessed baseline rs-fMRI data from n = 220 patients (Protect-AD) and n = 190 patients (SpiderVR) and extracted a variety of features, including ROI-to-ROI and edge-functional connectivity, sliding-windows, and graph measures. Including these features in sophisticated machine learning pipelines, we found that predictions of individual outcomes never significantly differed from chance level, even when conducting a range of exploratory post-hoc analyses. Moreover, resting state data never provided prediction accuracy beyond the sociodemographic and clinical data. The analyses were independent of each other in terms of selecting methods to process resting state data for prediction input as well as in the used parameters of the machine learning pipelines, corroborating the external validity of the results. These similar findings in two independent studies, analyzed separately, urge caution regarding the interpretation of promising prediction results based on neuroimaging data from small samples and emphasizes that some of the prediction accuracies from previous studies may result from overestimation due to homogeneous data and weak cross-validation schemes. The promise of resting-state neuroimaging data to play an important role in the prediction of CBT treatment outcomes in patients with anxiety disorders remains yet to be delivered.

Increasing physical activity and healthy diet in outpatients with mental disorders: a randomized-controlled evaluation of two psychological interventions.

INTRODUCTION: While physical activity (PA) can play an important role in the treatment of mental disorders (MD), large proportions of patients with MD do not meet PA recommendations. The aim of this trial was to evaluate whether structured psychological intervention (MoVo-LISA) is effective in helping outpatients with MD to increase their level of PA. As active control group (CG) we modified MoVo-LISA to target healthy diet behavior. METHODS: N = 83 outpatients with MD (F1-F4) were randomized to the two conditions. PA (self-report and accelerometry), dietary behavior, social-cognitive determinants of health behavior change, psychiatric symptoms and health-related quality of life were assessed at baseline, 1 and 12 weeks after the intervention. RESULTS: Significant time*group interaction effects for objectively measured PA, dietary behavior and fruit and vegetable consumption indicated differential effects of the interventions on these outcomes. PA increased in the MoVo-LISA group (IG) from baseline to follow-up while it decreased in CG. IG showed a significant higher level of objectively measured PA at follow-up compared to CG. Dietary behavior and fruit and vegetable consumption significantly increased from baseline to follow-up in CG, but not IG. IG showed a significant increase in some, but not all social cognitive determinants of health behavior change. CONCLUSIONS: MoVo-LISA is effective in helping outpatients with MD to increase their level of PA in short- and mid-term. The used intervention strategies are effective for the promotion of healthy diet in patients with MD as well.

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.

Physical activity in outpatients with mental disorders: status, measurement and social cognitive determinants of health behavior change.

INTRODUCTION: Physical activity (PA) can play an important role in improving the mental and physical health in patients with mental disorders but is not well studied in this population. The aim of this study was to assess the status of PA in outpatients with mental disorders, compare the convergence of self-rating and accelerometer measurement and examine the influence of social cognitive variables from the Motivation-Volition (MoVo) model and clinical measures on PA. METHODS: Eighty-four patients were recruited from three psychiatric outpatient clinics and local psychiatrists (Distribution of ICD-10-Diagnoses: F3.x = 59.5%, F4.x = 20.2%, F2.x = 17.9%, F1.x = 2.4%). PA, Self-efficacy, Outcome-expectancies, Intention, Self-concordance, Action- and Coping-planning, Health-related Quality of Life (SF-12) and Psychiatric Symptoms (SCL-27) were assessed through questionnaires. PA was assessed objectively by accelerometers. RESULTS: Most of the participants did not reach PA recommendations. Subjective and objective measurement of PA showed good accordance for total PA on group level but lower accordance on individual level. Motivational and volitional determinants of health behavior change showed a similar pattern of correlations with PA as in populations without mental disorders. CONCLUSION: Outpatients with mental disorders have the ability and are willing to perform PA but a large proportion of our sample did not meet PA recommendations. To assess group levels of PA, subjective and objective measurement seem equally apt, for individual diagnostics, a combination of both should be considered. Social cognitive determinants of health behavior change seem to be as helpful for the design of PA interventions for patients with mental disorders as they are in other populations.

Heart rate variability in patients with agoraphobia with or without panic disorder remains stable during CBT but increases following in-vivo exposure.

Patients with anxiety disorders have a lower heart rate variability (HRV) than healthy controls. Low HRV is associated with cardiovascular disease and dysfunction of the autonomic nervous system (ANS). The aim of the present study was to investigate if HRV in patients with agoraphobia with or without panic disorder can be influenced by cognitive behavioral therapy (CBT). 73 patients with agoraphobia with or without panic disorder were included in the study. Heart rate (HR) and HRV were recorded at rest before and after CBT and during in-vivo exposure. No changes in HR and HRV were observed throughout therapy. During in-vivo exposure HRV increased significantly and HR exhibited a tendency to decrease. Despite clinical improvement of anxiety symptoms, ANS activity at rest did not seem to be influenced by CBT. However, during in-vivo exposure, HRV changed significantly, indicating a higher parasympathetic activity at the end of exposure.

Running for extinction? Aerobic exercise as an augmentation of exposure therapy in panic disorder with agoraphobia.

Exposure-based Cognitive Behavioral Therapy (eb-CBT) represents the most evidence-based psychotherapeutic approach in anxiety disorders. However, its efficacy may be limited by a delay in onset of action and a substantial number of patients does not respond sufficiently to treatment. In this context, aerobic exercise was found to be effective in reducing clinical anxiety as well as to improve (elements of) disorder-specific CBT in some mental disorders. We therefore investigated the effect of aerobic exercise supplementary to an eb-CBT in panic disorder and agoraphobia (PD/AG). 77 patients with PD/AG performed a 30 min treadmill task with moderate or low intensity (70% or 30% of the maximal oxygen uptake [VO2max]) prior to five exposure sessions within a standardized seven-week CBT. At baseline, after completing the treatment period (post) and six month after post (follow-up), several measures of (un)specific psychopathology (Hamilton Anxiety Rating Scale [Ham-A], Mobility Inventory [MI], Panic and Agoraphobia Scale [PAS], Agoraphobic Cognitions Questionnaire [ACQ], Body Sensations Questionnaire [BSQ]) were established to assess for clinical changes. All patients experienced a significant improvement of symptoms from baseline to post (for all measures p < .001) but repeated-measures analyses of variance found a trend towards a significant time × group interaction in the Ham-A in favor for the moderate intense exercise group (f[1, 74] = 4.15, p = .045, α=.025). This trend, however, disappeared at follow-up since the low-intense exercise group further improved significantly in Ham-A after post. Our findings therefore might point to an accelerating effect of moderate-intense exercise within an exposure-based CBT for AG/PD.