Specific phobia (SPH) is a prevalent anxiety disorder and may involve advanced biological aging. However, limited brain age research has been conducted in anxiety disorders. This mega-analysis investigated brain aging in SPH participants within the ENIGMA-Anxiety Working Group. 3D brain structural MRI scans from 17 international samples (600 SPH individuals, of whom 504 formally diagnosed and 96 questionnaire-based cases; 1134 controls; age range: 22-75 years) were processed with FreeSurfer. Brain age was estimated from 77 subcortical and cortical regions with a publicly available ENIGMA brain age model. The brain-predicted age difference (brain-PAD) was calculated as brain age minus chronological age. Linear mixed-effects models examined group differences in brain-PAD and moderation by age. No significant group difference in brain-PAD manifested (βdiagnosis [SE] = 0.37 years [0.43], p = 0.39). A negative diagnosis-by-age interaction was identified, which was most pronounced in formally diagnosed SPH (βdiagnosis-by-age = -0.08 [0.03], pFDR = 0.02). This interaction remained significant when excluding participants with anxiety comorbidities, depressive comorbidities, and medication use. Post hoc analyses revealed a group difference for formal SPH diagnosis in younger participants (22-35 years; βdiagnosis = 1.20 [0.60], p < 0.05, mixed-effects d [95% confidence interval] = 0.14 [0.00-0.28]), but not older participants (36-75 years; βdiagnosis = 0.07 [0.65], p = 0.91). Brain aging did not relate to SPH in the full sample. However, a diagnosis-by-age interaction was observed across analyses, and was strongest in formally diagnosed SPH. Post hoc analyses showed subtle advanced brain aging in young adults with formally diagnosed SPH. Taken together, these findings indicate the importance of clinical severity, impairment, and persistence, and may suggest a slightly earlier end to maturational processes or subtle decline of brain structure in SPH.

Anxiety disorders are the most prevalent mental health problems in childhood and adolescence, highlighting the importance to study their underlying mechanisms. One key process in fear reduction, particularly in exposure-based cognitive behavioral therapy, is extinction learning. While extensively studied in adults, its role in youth remains underexplored. The aim of the present study was to examine fear extinction learning and return of fear in a large sample of children and adolescents (N = 274; age range 8-16 years, M = 11.07, SD = 2.22; 55.8 % female) with separation anxiety disorder, social anxiety disorder, and specific phobia (n = 217) in comparison to non-anxious controls (n = 57). All children participated in a 2-day fear conditioning paradigm. Fear acquisition, extinction, and reinstatement were assessed using subjective (valence, arousal, contingency) and psychophysiological (startle) indicators of emotional reactivity. Successful differential fear acquisition could be observed in both groups. Extinction learning was also successful as the fear response to the CS+ decreased. Contradicting previous findings suggesting impairment in extinction in children with anxiety disorders, we could not find differences in fear extinction learning between anxious and non-anxious children and adolescents; both groups learned to inhibit their fear response when the CS+ no longer predicted the occurrence of the aversive outcome. Further research is needed to disentangle the role of fear extinction learning within childhood anxiety disorders and determine whether children with anxiety disorders generally do not show deficits in extinction learning or whether this deficit is limited to disorder specific stimuli.

Recent laboratory research showed that vagus nerve stimulation promotes fear extinction, the inhibitory core mechanism of exposure treatment, presumably via activation of the noradrenergic brain system. However, a translation of this stimulation technique to clinical practice is lacking. We therefore investigated the potential of vagal stimulation to inhibit excessive fear responses and facilitate responding to in-vivo and laboratory exposure in individuals with specific phobia. Spider-phobic participants were subjected to three standardized in-vivo exposures towards a living tarantula, complemented by an exposure in vitro (between exposure in vivo I and II). Transcutaneous auricular vagus nerve stimulation (taVNS) was applied during in-vitro exposure, presenting pictures of the exposed tarantula, other spiders and neutral tools in the laboratory. Fear was assessed by self-reports and behavioral avoidance (in-vivo exposures), and amygdala-mediated autonomic and behavioral fear components (exposure in vitro). Vagal stimulation facilitated the reduction of behavioral avoidance across repeated in-vivo exposures. During laboratory exposure, taVNS inhibited fear tachycardia and corrugator muscle activity specifically in response to pictures of the previously exposed tarantula – an effect that became stronger with increasing stimulation duration. Psychophysiological indices of noradrenergic transmission in the basolateral amygdala were elevated during taVNS and correlated to subsequent attenuation of behavioral avoidance. Our results suggest, that taVNS exerts stimulus-specific and dose-dependent inhibition of multiple automatic response components of excessive fear, highlighting taVNS as a valuable adjunct to exposure-based treatment. A translational mechanism of action is supported, proposing that taVNS exhibits its effects by noradrenergic activation of fear extinction circuitry, particularly targeting the basolateral amygdala.

Expectancy violation has been proposed as a potential core mechanism of action in psychotherapy, particularly in exposure therapy for anxiety disorders. However, various relevant expectations have been discussed, and empirical studies examining their significance are still scarce. This study aimed to investigate one specific form of expectancy violation, based on Rachman's (1994) match-mismatch model, specifically by comparing expected and experienced fear and examining their relationship to safety behaviour during exposure in vivo in 268 patients meeting DSM-IV criteria for panic disorder with agoraphobia. Participants underwent exposure to a highly controlled manual-based cognitive behaviour therapy in a randomised multicenter psychotherapy study. Participants tended to overpredict fear during exposure. Both expected and experienced fear significantly decreased over the course of repeated exposure exercises, while prediction (in)accuracy (difference between expected and experienced fear) remained stable. The decrease in expected fear over time was a strong predictor of treatment outcomes for the Bodily Sensations Questionnaire (BSQ) and Panic and Agoraphobia Scale (PAS) at post. Even more, the reduction in expected fear was a significant predictor of treatment success across all outcome measures in the follow-up assessment. These findings suggest that violating excessive fear expectancies is not a necessary condition for symptom reduction during exposure therapy.

Introduction:Specific phobia (SPH) is a prevalent anxiety disorder and may involve advanced biological aging. However, brain age research in psychiatry has primarily examined mood and psychotic disorders. This mega-analysis investigated brain aging in SPH participants within the ENIGMA-Anxiety Working Group. Methods:3D brain structural MRI scans from 17 international samples (600 SPH individuals, of whom 504 formally diagnosed and 96 questionnaire-based cases; 1,134 controls; age range: 22-75 years) were processed with FreeSurfer. Brain age was estimated from 77 subcortical and cortical regions with a publicly available ENIGMA brain age model. The brain-predicted age difference (brain-PAD) was calculated as brain age minus chronological age. Linear mixed-effect models examined group differences in brain-PAD and moderation by age. Results:No significant group difference in brain-PAD manifested (β diagnosis (SE)=0.37 years (0.43), p=0.39). A negative diagnosis-by-age interaction was identified, which was most pronounced in formally diagnosed SPH (β diagnosis-by-age=-0.08 (0.03), pFDR=0.02). This interaction remained significant when excluding participants with anxiety comorbidities, depressive comorbidities, and medication use. Post-hoc analyses revealed a group difference for formal SPH diagnosis in younger participants (22-35 years; β diagnosis=1.20 (0.60), p<0.05, mixed-effects d (95% confidence interval)=0.14 (0.00-0.28)), but not older participants (36-75 years; β diagnosis=0.07 (0.65), p=0.91). Conclusions:Brain aging did not relate to SPH in the full sample. However, a diagnosis-by-age interaction was observed across analyses, and was strongest in formally diagnosed SPH. Post-hoc analyses showed a subtle advanced brain aging in young adults with formally diagnosed SPH. Taken together, these findings indicate the importance of clinical severity, impairment and persistence, and may suggest a slightly earlier end to maturational processes or subtle decline of brain structure in SPH.

BACKGROUND:Exposure-based CBT is highly effective in treating patients with panic disorder and agoraphobia; however, access to such treatments is often limited. Smartphone-based self-management apps offer a promising low-threshold treatment alternative to face-to-face therapy. Although such health apps have shown to be effective in reducing anxiety symptoms, comparisons to active treatments are still scarce. Therefore, this study compared the effectiveness of a self-help app to an established face-to-face CBT intervention for panic and agoraphobia. METHOD:The present study conducts a post hoc comparison of two independent RCTs examining participants with panic disorder and/or agoraphobia. Interventions in both studies were based on the same CBT manual. Study 1 (n = 138) included face-to-face CBT; Study 2 addressed the effects of a digital self-help intervention (n = 57). Main outcomes comprised symptoms of both panic disorder and agoraphobia, depressive symptoms and agoraphobic avoidance. Data were analysed using linear mixed models in intent-to-treat and completer data sets. RESULTS:Linear mixed models showed that face-to-face treatment was superior to app treatment in reducing panic and agoraphobic symptoms (R2 = 0.32), depressive symptoms (R2 = 0.24) and agoraphobic avoidance (R2 = 0.12 and 0.15). Dropout rates did not differ significantly, and both interventions demonstrated high levels of adherence. DISCUSSION:Although a smartphone-based CBT intervention was effective in reducing symptoms of panic and agoraphobia, its efficacy was significantly below the effects of the same intervention delivered in face-to-face format. Thus, digital interventions might be most suitable within a stepped-care approach or to bridge waiting times for psychotherapy.

Responses to exposure therapy vary across individuals, emphasizing the need for a deeper understanding of its underlying mechanisms. This study examined two key processes during exposure that serve as readouts of different clinical rationales: (1) within-session fear reduction (measured as the decline from peak to end fear within an exposure exercise) and (2) threat expectancy processes (assessed via expectancy violation, expectancy change, and learning rate). Data from 516 patients with anxiety disorders who completed at least 10 exposure exercises in a clinical trial were analyzed. Results showed that expectancy measures and fear reduction were only weakly correlated within exposure exercises. While no significant differences were found in their time courses, both readouts independently predicted treatment success. Specifically, a higher learning rate and greater relative fear reduction were associated with better outcomes. These findings highlight the clinical relevance of monitoring fear reduction and expectancy-related readouts as indicators of two distinct exposure rationales - the fear reduction rationale and the threat expectancy rationale. Although it remains unclear whether they reflect separate mechanisms of change or different aspects of a shared mechanism, addressing both rationales may help optimize and personalize exposure therapy.

Epigenetic mechanisms such as DNA methylation are hypothesized to play a pivotal role in the pathogenesis of anxiety disorders and to predict as well as relate to treatment response. An epigenome-wide association study (EWAS) (Illumina MethylationEPIC BeadChip) was performed at baseline (BL), post-treatment (POST) and 6-month follow-up (FU) in the so far largest longitudinal sample of patients with anxiety disorders (N = 415) treated with exposure-based cognitive behavioral therapy (CBT), and in 315 healthy controls. Independent of comorbidity with depression, anxiety disorders were significantly (p ≤ 6.409E–08) associated with altered DNA methylation at 148 CpGs partly mapping to genes previously implicated in processes related to anxiety, brain disorders, learning or plasticity (e.g., GABBR2, GABRD, GAST, IL12RB2, LINC00293, LOC101928626, MFGE8, NOTCH4, PTPRN2, RIMBP2, SPTBN1) or in a recent cross-anxiety disorders EWAS (TAOK1) after pre-processing and quality control (N = 378 vs. N = 295). Furthermore, BL DNA methylation at seven and three CpGs, respectively, was suggestively (p < 1E–5) associated with treatment response at POST (ABCA7, ADRA2C, LTBR, RPSAP52, SH3RF3, SLC47A2, ZNF251) and FU (ADGRD1, PRSS58, USP47). Finally, suggestive evidence for dynamic epigenome-wide DNA methylation changes along with CBT response emerged at four CpGs from BL to FU (ADIPOR2, EIF3B, OCA2, TMCC1). The identification of epigenetic biomarkers may eventually aid in developing environment-based preventive strategies aimed at increasing resilience by providing deeper molecular insights into the mechanisms underlying anxiety disorders. Defining epigenetic signatures as predictors or key mechanisms in exposure-based interventions could pave the way for more targeted and personalized treatments for anxiety disorders.

Exposure-based CBT is effective in treating anxiety disorders, but individual responses vary substantially, underlining the need to identify and boost mechanisms underlying exposure. In this study, the role of positive emotions occurring after exposure was examined. In an analysis of 8416 exposure records of 648 anxiety patients undergoing exposure therapy, the degree of positive emotions hope and joy occurring after exposure exercises, their predictors, and their role regarding treatment success were investigated. Positive emotions after exposure were medium to high and increased slightly across repeated exposure exercises. They were associated with exposure-related learning indicators (i.e., expectancy violation and change as well as the prediction-error learning rate) and were mainly predicted by adjusted threat expectancy assessed after completing exposure, controlling for baseline depressive symptoms and affect. Higher positive emotions independently predicted better treatment outcome beyond learning indicators, and partially mediated the association between learning indicators and treatment outcome. These findings indicate that positive emotions are partly associated with successful learning during exposure but seem to have a unique contribution to overall treatment success, underlining the need to strengthen positive emotions via different possible means.

BACKGROUND:Externalizing and internalizing disorders are common in youth but are often studied separately, preventing researchers from identifying shared (i.e., transdiagnostic) alterations in brain structure. Using data from the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Consortium, we conducted a mega-analysis to identify shared and distinct cortical and subcortical brain alterations across internalizing (anxiety disorders and depression) and externalizing (attention-deficit/hyperactivity disorder [ADHD] and conduct disorder [CD]) disorders in youth. METHODS:3D T1-weighted magnetic resonance imaging data from youths (age range 4-21 years) with anxiety disorders (n = 1044), depression (n = 504), ADHD (n = 1317), and CD (n = 1172) along with healthy control participants (n = 4743) were analyzed. We assessed group differences in regional cortical thickness, surface area (SA), and subcortical volume using linear models, adjusted for site, age, and sex, as well as total intracranial volume in the SA and subcortical volume models. RESULTS:We observed transdiagnostic associations, with both internalizing and externalizing disorders characterized by lower SA in the insula, entorhinal cortex, and middle temporal gyrus and lower amygdala volume (Cohen's ds = -0.07 to -0.24) as well as total SA and intracranial volume (ds = -0.11 to -0.25). Externalizing-specific reductions in SA were observed in frontoparietal regions (ds = -0.08 to -0.13), but no internalizing-specific associations were identified. Disorder-specific alterations were identified for ADHD, CD, and anxiety disorders but not depression. CONCLUSIONS:Both common and disorder-specific alterations were identified, with regions involved in salience attribution and emotion processing implicated across internalizing and externalizing disorders. These novel findings can guide future research targeting common biological processes across youth psychiatric disorders as well as features unique to individual disorders.

Pavlovian fear conditioning is a fundamental process in both health and disease. We investigate its neural correlates and sources of variability using harmonized functional magnetic resonance imaging data from 2199 individuals across nine countries, including 1888 healthy individuals and 311 with anxiety-related or depressive disorders. Using mega-analysis and normative modeling, we show that fear conditioning consistently engages brain regions within the "central autonomic-interoceptive" or "salience" network. Several task variables strongly modulate activity in these regions, contributing to variability in neural responses. Additionally, brain activation patterns differ between healthy individuals and those with anxiety-related or depressive disorders, with distinct profiles characterizing specific disorders such as post-traumatic stress disorder and obsessive-compulsive disorder. While the neural correlates of fear conditioning are highly generalizable at the population level, variability arises from differences in task design and clinical status, highlighting the importance of methodological diversity in capturing fear learning mechanisms.

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.

Although the mediating role of the stress hormone systems in memory for single— especially emotional— events is well-stablished, less is known about the influence of stress on memory for associated contextual information (source memory). Here, we investigated the impact of acute stress on the neural underpinnings of emotional contextual source memory. Participants underwent a stress or a control manipulation before they encoded objects paired with pleasant, neutral, or unpleasant backgrounds. One week later, item and contextual source memory were tested. Acute stress modulated the neural signature of item and contextual source memory in an opposite fashion: stressed participants showed larger activation in the precuneus and the medial prefrontal cortex (mPFC) during the retrieval of items, while the retrieval of contextual unpleasant information was associated with lower activation in the angular gyrus (AG) and mPFC. Furthermore, as revealed by cross-region representational similarity analyses, stress also reduced the memory reinstatement of the previously encoded visual cortex representations of object/unpleasant background pairings in the AG and mPFC. These results suggest that pre-encoding stress induction increases the activity of memory-related regions for single items but reduces the activity of these regions during the retrieval of contextual unpleasant information. Our findings provide new insights into the dissociative effects of stress on item and contextual source memory which could have clinical relevance for stress-related disorders.

OBJECTIVE:Specific phobia is a common anxiety disorder, but the literature on associated brain structure alterations exhibits substantial gaps. The ENIGMA Anxiety Working Group examined brain structure differences between individuals with specific phobias and healthy control subjects as well as between the animal and blood-injection-injury (BII) subtypes of specific phobia. Additionally, the authors investigated associations of brain structure with symptom severity and age (youths vs. adults).METHODS:Data sets from 31 original studies were combined to create a final sample with 1,452 participants with phobia and 2,991 healthy participants (62.7% female; ages 5-90). Imaging processing and quality control were performed using established ENIGMA protocols. Subcortical volumes as well as cortical surface area and thickness were examined in a preregistered analysis.RESULTS:Compared with the healthy control group, the phobia group showed mostly smaller subcortical volumes, mixed surface differences, and larger cortical thickness across a substantial number of regions. The phobia subgroups also showed differences, including, as hypothesized, larger medial orbitofrontal cortex thickness in BII phobia (N=182) compared with animal phobia (N=739). All findings were driven by adult participants; no significant results were observed in children and adolescents.CONCLUSIONS:Brain alterations associated with specific phobia exceeded those of other anxiety disorders in comparable analyses in extent and effect size and were not limited to reductions in brain structure. Moreover, phenomenological differences between phobia subgroups were reflected in diverging neural underpinnings, including brain areas related to fear processing and higher cognitive processes. The findings implicate brain structure alterations in specific phobia, although subcortical alterations in particular may also relate to broader internalizing psychopathology.

Neuroimaging studies point to neurostructural abnormalities in youth with anxiety disorders. Yet, findings are based on small-scale studies, often with small effect sizes, and have limited generalizability and clinical relevance. These issues have prompted a paradigm shift in the field towards highly powered (i.e., big data) individual-level inferences, which are data-driven, transdiagnostic, and neurobiologically informed. Here, we built and validated neurostructural machine learning (ML) models for individual-level inferences based on the largest-ever multi-site neuroimaging sample of youth with anxiety disorders (age: 10-25 years, N=3,343 individuals from 32 global sites), as compiled by three ENIGMA Anxiety Working Groups: Panic Disorder (PD), Generalized Anxiety Disorder (GAD), and Social Anxiety Disorder (SAD). ML classifiers were trained on MRI-derived regional measures of cortical thickness, surface area, and subcortical volumes to classify patients and healthy controls (HC) for each anxiety disorder separately and across disorders (transdiagnostic classification). Modest, yet robust, classification performance was achieved for PD vs. HC (AUC=0.62), but other disorder-specific and transdiagnostic classifications were not significantly different from chance. However, above chance-level transdiagnostic classifications were obtained in exploratory subgroup analyses of male patients vs. male HC, unmedicated patients vs. HC, and patients with low anxiety severity vs. HC (AUC 0.59-0.63). The above chance-level classifications were based on plausible and specific neuroanatomical features in fronto-striato-limbic and temporo-parietal regions. This study provides a realistic estimate of classification performance in a large, ecologically valid, multi-site sample of youth with anxiety disorders, and may as such serve as a benchmark.

IntroductionIt has long been known that highly arousing emotional single items are better recollected than low arousing neutral items. Despite the robustness of this memory advantage, emotional arousing events may not always promote the retrieval of source details (i.e., source memory) or associated neutral information.MethodsTo shed more light on these effects, we pooled data from seven different studies (N = 333) to investigate the role of emotion on item-context binding in episodic memory, as well as potential interacting factors (e.g., encoding instructions, type of retrieval task, or acute stress). In all studies, participants incidentally encoded common neutral objects (i.e., items), overlaid on different pleasant, neutral, or unpleasant background scenes (i.e., contexts). One week later, the encoded objects were presented intermixed with new ones and memory for item and source contextual details was tested, also considering the contribution of recollection and familiarity-based processes.ResultsLinear mixed models revealed a recollection-based retrieval advantage for unpleasant and pleasant source contextual details compared to neutral ones. Bayes hypothesis-testing analysis further indicated decisive evidence in favor of a relevant role of emotional arousal and recollection in source contextual memory. Regarding item memory, linear mixed models revealed enhanced recollection-based memory for items encoded in pleasant contexts compared to their neutral and unpleasant counterparts. However, Bayes analysis revealed strong to moderate evidence for models without affective category (or its interactions), indicating that the affective category of contexts in which objects were paired during encoding had little influence on item memory performance.DiscussionThe present results are discussed in relation to existing evidence and current neurobiological models of emotional episodic memory by also emphasizing the role of predictive processing as a useful conceptual framework to understand the effects of emotion on memory for source details and associated neutral information.

Das Manual beschreibt eine Expositionsbehandlung, die übergreifend für verschiedene und auch komorbid vorliegende Angststörungen (Panikstörung, Agoraphobie, soziale Angst, multiple spezifische Phobien) geeignet ist. Das Vorgehen wurde in einer groß angelegten Studie mit über 700 Personen erfolgreich evaluiert. Das Manual greift dabei aktuelle Forschungsergebnisse zur Expositionsbehandlung auf und stützt sich insbesondere auf die Erkenntnisse zum inhibitorischen Lernen bei der Exposition. Demnach geht es in der Exposition nicht primär um das passive Aushalten von Angst mit dem Fokus auf den einsetzenden Habituationsprozess, sondern um die Förderung eines aktiven inhibitorischen Lernprozesses. Dieser veränderte Schwerpunkt führt zu einer neuen Fokussierung in der Expositionsbehandlung und zum Einsatz unterschiedlicher therapeutischer Techniken während der Exposition. Da die Maximierung und der Abfall von Ängsten für den Erfolg der Exposition keine entscheidende Rolle spielen, lautet die Botschaft für Therapeut*innen: „Keine Angst vor der Exposition! Gehen Sie den Weg in Ihrem eigenen Tempo!“ Das Vorgehen bei der Vorbereitung und Durchführung der Exposition sowie der Rückfallprophylaxe wird praxisorientiert dargestellt und die einzelnen Behandlungsbausteine können flexibel eingesetzt werden. Darüber hinaus werden Strategien zur Optimierung des Extinktionslernens vorgestellt und ethische Fragen geklärt. Zahlreiche Arbeitsmaterialien unterstützen die Durchführung und können nach erfolgter Registrierung von der Hogrefe Website heruntergeladen werden.

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.

BACKGROUND:Although exposure-based cognitive-behavioral therapy for anxiety disorders has frequently been proven effective, only few studies examined whether it improves everyday behavioral outcomes such as social and physical activity.METHODS:126 participants (85 patients with panic disorder, agoraphobia, social anxiety disorder, or specific phobias, and 41 controls without mental disorders) completed smartphone-based ambulatory ratings (activities, social interactions, mood, physical symptoms) and motion sensor-based indices of physical activity (steps, time spent moving, metabolic activity) at baseline, during, and after exposure-based treatment.RESULTS:Prior to treatment, patients showed reduced mood and physical activity relative to healthy controls. Over the course of therapy, mood ratings, interactions with strangers and indices of physical activity improved, while reported physical symptoms decreased. Overall results did not differ between patients with primary panic disorder/agoraphobia and social anxiety disorder. Higher depression scores at baseline were associated with larger changes in reported symptoms and mood ratings, but smaller changes in physical activity CONCLUSIONS: Exposure-based treatment initiates increased physical activity, more frequent interaction with strangers, and improvements in everyday mood. The current approach provides objective and fine-graded process and outcome measures that may help to further improve treatments and possibly reduce relapse.