Elevated accuracy in recognition of subliminal happy facial expressions in patients with panic disorder after psychotherapy.

Background: Individuals with anxiety disorders (ADs) often display hypervigilance to threat information, although this response may be less pronounced following psychotherapy. This study aims to investigate the unconscious recognition performance of facial expressions in patients with panic disorder (PD) post-treatment, shedding light on alterations in their emotional processing biases. Methods: Patients with PD (n=34) after (exposure-based) cognitive behavior therapy and healthy controls (n=43) performed a subliminal affective recognition task. Emotional facial expressions (fearful, happy, or mirrored) were displayed for 33 ms and backwardly masked by a neutral face. Participants completed a forced choice task to discriminate the briefly presented facial stimulus and an uncovered condition where only the neutral mask was shown. We conducted a secondary analysis to compare groups based on their four possible response types under the four stimulus conditions and examined the correlation of the false alarm rate for fear responses to non-fearful (happy, mirrored, and uncovered) stimuli with clinical anxiety symptoms. Results: The patient group showed a unique selection pattern in response to happy expressions, with significantly more correct "happy" responses compared to controls. Additionally, lower severity of anxiety symptoms after psychotherapy was associated with a decreased false fear response rate with non-threat presentations. Conclusion: These data suggest that patients with PD exhibited a "happy-face recognition advantage" after psychotherapy. Less symptoms after treatment were related to a reduced fear bias. Thus, a differential facial emotion detection task could be a suitable tool to monitor response patterns and biases in individuals with ADs in the context of psychotherapy.

Cortical and Subcortical Brain Alterations in Specific Phobia and Its Animal and Blood-Injection-Injury Subtypes: A Mega-Analysis From the ENIGMA Anxiety Working Group.

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.

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.

Exposure traced in daily life: improvements in ecologically assessed social and physical activity following exposure-based psychotherapy for anxiety disorders.

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.

Recent advances in studying brain-behavior interactions using functional imaging: The primary startle response pathway and its affective modulation in humans.

The startle response is a cross-species defensive reflex that is considered a key tool for cross-species translational emotion research. While the neural pathway mediating (affective) startle modulation has been extensively studied in rodents, human work on brain-behavior interactions has lagged in the past due to technical challenges, which have only recently been overcome through non-invasive simultaneous EMG-fMRI assessments. We illustrate key paradigms and methodological tools for startle response assessment in rodents and humans and review evidence for primary and modulatory neural circuits underlying startle responses and their affective modulation in humans. Based on this, we suggest a refined and integrative model for primary and modulatory startle response pathways in humans concluding that there is strong evidence from human work on the neurobiological pathway underlying the primary startle response while evidence for the modulatory pathway is still sparse. In addition, we provide methodological considerations to guide future work and provide an outlook on new and exciting perspectives enabled through technical and theoretical advances outlined in this work.

Structural integrity of the insula and emotional facial recognition performance following stroke.

The role of the human insula in facial emotion recognition is controversially discussed, especially in relation to lesion-location-dependent impairment following stroke. In addition, structural connectivity quantification of important white-matter tracts that link the insula to impairments in facial emotion recognition has not been investigated. In a case-control study, we investigated a group of 29 stroke patients in the chronic stage and 14 healthy age- and gender-matched controls. Lesion location of stroke patients was analysed with voxel-based lesion-symptom mapping. In addition, structural white-matter integrity for tracts between insula regions and their primarily known interconnected brain structures was quantified by tractography-based fractional anisotropy. Our behavioural analyses showed that stroke patients were impaired in the recognition of fearful, angry and happy but not disgusted expressions. Voxel-based lesion mapping revealed that especially lesions centred around the left anterior insula were associated with impaired recognition of emotional facial expressions. The structural integrity of insular white-matter connectivity was decreased for the left hemisphere and impaired recognition accuracy for angry and fearful expressions was associated with specific left-sided insular tracts. Taken together, these findings suggest that a multimodal investigation of structural alterations has the potential to deepen our understanding of emotion recognition impairments after stroke.

Effective-and Tolerable: Acceptance and Side Effects of Intensified Exposure for Anxiety Disorders.

Despite striking empirical support, exposure-based treatments for anxiety disorders are underutilized. This is partially due to clinicians' concerns that patients may reject exposure or experience severe side effects, particularly in intensive forms of exposure. We examined acceptance and side effects of two randomly assigned variants of prediction error-based exposure treatment differing in temporal density (1 vs. 3 sessions/week) in 681 patients with panic disorder, agoraphobia, social anxiety disorder, and multiple specific phobias. Treatment acceptance included treatment satisfaction and credibility, engagement (i.e., homework completion), and tolerability (i.e., side effects, dropout, and perceived treatment burden). Side effects were measured with the Inventory for the Balanced Assessment of Negative Effects of Psychotherapy (INEP). We found treatment satisfaction, credibility, and engagement to be equally high in both variants of exposure-based treatment, despite higher treatment burden (ß = 0.25) and stronger side effects (ß = 0.15) in intensified treatment. 94.1% of patients reported positive effects in the INEP. 42.2% reported side effects, with treatment stigma (16.6%), low mood (14.8%) and the experience to depend on the therapist (10.9%) being the most frequently reported. The mean intensity of side effects was low. We conclude that prediction error-based exposure treatment is well accepted by patients with different anxiety disorders and that patients also tolerate temporally intensified treatment, despite higher perceived treatment burden and stronger side effects. Clinicians should be aware of the most frequent side effects to take appropriate countermeasures. In sum, temporal intensification appears to be an acceptable strategy to achieve faster symptom reduction, given patients' well-informed consent.

Oxytocin has sex-specific effects on trust and underlying neurophysiological processes.

The neuropeptide oxytocin (OT) regulates mammalian social approach behavior across sexes. Yet most OT studies in humans exclusively investigated men. Here, we studied sex differences in OT's effects on human trust behavior in 144 heterosexual participants (73 women, 71 men). Participants received 24 international units of intranasal OT or placebo treatment and played a trust game in the role of the investor while undergoing electroencephalography. Trustees were represented by photos of the other sex gradually varying in their pre-rated intensities of facial features signaling attractiveness and threat. On a behavioral level, we observed that OT increased trust in men and reduced it in women when trustees showed weak signals of attractiveness and threat. Correspondingly, on the neurophysiological level, we noted that OT intensified the P100 in male participants, but dampened it in female ones. Our findings demonstrate OT's sex- and context-specific effects on social approach behavior and an underlying early visual attention-related brain process. This evidence demonstrates the need to consider psychobiological mechanisms of sexual dimorphism in human OT research.

Consensus design of a calibration experiment for human fear conditioning.

Fear conditioning is a widely used laboratory model to investigate learning, memory, and psychopathology across species. The quantification of learning in this paradigm is heterogeneous in humans and psychometric properties of different quantification methods can be difficult to establish. To overcome this obstacle, calibration is a standard metrological procedure in which well-defined values of a latent variable are generated in an established experimental paradigm. These intended values then serve as validity criterion to rank methods. Here, we develop a calibration protocol for human fear conditioning. Based on a literature review, series of workshops, and survey of N = 96 experts, we propose a calibration experiment and settings for 25 design variables to calibrate the measurement of fear conditioning. Design variables were chosen to be as theory-free as possible and allow wide applicability in different experimental contexts. Besides establishing a specific calibration procedure, the general calibration process we outline may serve as a blueprint for calibration efforts in other subfields of behavioral neuroscience that need measurement refinement.

Defensive Mobilization During Anticipation of Symptom Provocation: Association With Panic Pathology.

BACKGROUND: Anxious apprehension about feared body symptoms is thought to play a crucial role in the development, chronicity, and treatment of panic disorder (PD). In this study, we therefore aimed to elucidate the role of defensive reactivity to anticipated unpleasant symptoms in PD that can contribute to a better understanding of pathomechanisms of PD as well as identification of potential targets in PD-focused interventions. By measuring amygdala-dependent potentiation of the startle reflex, we aimed to investigate whether 1) patients with PD exhibit a specifically increased defensive reactivity to anticipated unpleasant body symptoms and 2) whether clinical severity of panic symptomatology varies with magnitude of defensive activation. METHODS: Defensive mobilization to anticipated threat was investigated in 73 patients with a primary diagnosis of PD with agoraphobia (PDA) and 52 healthy control subjects. Threat of symptom provocation was established by a standardized hyperventilation task and contrasted to threat of shock to the forearm of the participant. RESULTS: Patients with PDA and healthy control subjects did not differ in their defensive responses during anticipation of shock. In contrast, patients with severe PDA as compared with healthy control subjects exhibited increased defensive response mobilization and reported more anxiety and panic symptoms during anticipation of feared body symptoms. Moreover, startle potentiation during anticipation of hyperventilation covaried with the severity of panic symptomatology. CONCLUSIONS: The present findings suggest that increased defensive mobilization during anticipation of body symptoms is a neurobiological correlate of severe PDA that should be specifically targeted in PD interventions and might be used to monitor treatment success.

Facilitated extinction but impaired extinction recall by eye movement manipulation in humans - Indications for action mechanisms and the applicability of eye movement desensitization.

Eye movement desensitization and reprocessing (EMDR) therapy utilizes the manipulation of eye movements to reduce affective distress during fear-exposure. Animal research recently suggested a potential neural mechanism underlying these effects, by which increased activity of the superior colliculus (SC), mediating visual attention, increases the inhibition of the basolateral amygdala (BLA), mediating defensive plasticity. We tested such mechanism in forty healthy humans using a multiple-day single-cue fear conditioning and extinction paradigm. The activity of the SC during extinction was experimentally manipulated by eye movements, as half of the participants executed saccadic eye movements (n = 20; major SC involvement), while the other half executed smooth eye pursuits (n = 20; minor SC involvement). Amygdala-mediated fear-potentiated startle responses and fear bradycardia, as well as threat expectancy was analyzed. Saccadic eye movements facilitated the extinction of fear bradycardia and fear-potentiated startle responses. Higher saccadic accuracy and range correlated with reduced fear-potentiated startle. However, during extinction recall, fear-potentiated startle and fear bradycardia resurged and partly reached levels obtained after fear acquisition. Threat expectancy was not affected by different eye movements and was not elevated during extinction recall. Within limitations, results support an inhibitory SC-BLA pathway in humans by which eye movements may reduce low-level defensive responding, but not threat expectancy. Yet, manipulating eye movements during extinction learning seems to impair extinction recall for behavioral and physiological defensive response indices. Thus, increasing SC activity might enhance initial efficacy of exposure treatment, but additional strategies seem necessary for sustained fear attenuation.

Sometimes I feel the fear of uncertainty: How intolerance of uncertainty and trait anxiety impact fear acquisition, extinction and the return of fear.

It is hypothesized that the ability to discriminate between threat and safety is impaired in individuals with high dispositional negativity, resulting in maladaptive behavior. A large body of research investigated differential learning during fear conditioning and extinction protocols depending on individual differences in intolerance of uncertainty (IU) and trait anxiety (TA), two closely-related dimensions of dispositional negativity, with heterogenous results. These might be due to varying degrees of induced threat/safety uncertainty. Here, we compared two groups with high vs. low IU/TA during periods of low (instructed fear acquisition) and high levels of uncertainty (delayed non-instructed extinction training and reinstatement). Dependent variables comprised subjective (US expectancy, valence, arousal), psychophysiological (skin conductance response, SCR, and startle blink), and neural (fMRI BOLD) measures of threat responding. During fear acquisition, we found strong threat/safety discrimination for both groups. During early extinction (high uncertainty), the low IU/TA group showed an increased physiological response to the safety signal, resulting in a lack of CS discrimination. In contrast, the high IU/TA group showed strong initial threat/safety discrimination in physiology, lacking discriminative learning on startle, and reduced neural activation in regions linked to threat/safety processing throughout extinction training indicating sustained but non-adaptive and rigid responding. Similar neural patterns were found after the reinstatement test. Taken together, we provide evidence that high dispositional negativity, as indicated here by IU and TA, is associated with greater responding to threat cues during the beginning of delayed extinction, and, thus, demonstrates altered learning patterns under changing environments.

Stimulation of the ventromedial prefrontal cortex blocks the return of subcortically mediated fear responses.

The ventromedial prefrontal cortex (vmPFC) mediates the inhibition of defensive responses upon encounters of cues, that had lost their attribute as a threat signal via previous extinction learning. Here, we investigated whether such fear extinction recall can be facilitated by anodal transcranial direct current stimulation (tDCS). Extinction recall was tested twenty-four hours after previously acquired fear was extinguished. Either anodal tDCS or sham stimulation targeting the vmPFC was applied during this test. After stimulation ceased, we examined return of fear after subjects had been re-exposed to aversive events. Fear was assessed by reports of threat expectancy and modulations of autonomic (skin conductance, heart rate) and protective reflex (startle potentiation) measures, the latter of which are mediated by subcortical defense circuits. While tDCS did not affect initial extinction recall, it abolished the return of startle potentiation and autonomic components of the fear response. Results suggest hierarchical multi-level vmPFC functions in human fear inhibition and indicate, that its stimulation might immunize against relapses into pathological subcortically mediated defensive activation.

Behavioural and functional evidence revealing the role of RBFOX1 variation in multiple psychiatric disorders and traits.

Common variation in the gene encoding the neuron-specific RNA splicing factor RNA Binding Fox-1 Homolog 1 (RBFOX1) has been identified as a risk factor for several psychiatric conditions, and rare genetic variants have been found causal for autism spectrum disorder (ASD). Here, we explored the genetic landscape of RBFOX1 more deeply, integrating evidence from existing and new human studies as well as studies in Rbfox1 knockout mice. Mining existing data from large-scale studies of human common genetic variants, we confirmed gene-based and genome-wide association of RBFOX1 with risk tolerance, major depressive disorder and schizophrenia. Data on six mental disorders revealed copy number losses and gains to be more frequent in ASD cases than in controls. Consistently, RBFOX1 expression appeared decreased in post-mortem frontal and temporal cortices of individuals with ASD and prefrontal cortex of individuals with schizophrenia. Brain-functional MRI studies demonstrated that carriers of a common RBFOX1 variant, rs6500744, displayed increased neural reactivity to emotional stimuli, reduced prefrontal processing during cognitive control, and enhanced fear expression after fear conditioning, going along with increased avoidance behaviour. Investigating Rbfox1 neuron-specific knockout mice allowed us to further specify the role of this gene in behaviour. The model was characterised by pronounced hyperactivity, stereotyped behaviour, impairments in fear acquisition and extinction, reduced social interest, and lack of aggression; it provides excellent construct and face validity as an animal model of ASD. In conclusion, convergent translational evidence shows that common variants in RBFOX1 are associated with a broad spectrum of psychiatric traits and disorders, while rare genetic variation seems to expose to early-onset neurodevelopmental psychiatric disorders with and without developmental delay like ASD, in particular. Studying the pleiotropic nature of RBFOX1 can profoundly enhance our understanding of mental disorder vulnerability.

Pre-surgery optimization of patients' expectations to improve outcome in heart surgery: Study protocol of the randomized controlled multi-center PSY-HEART-II trial.

The PSY-HEART-I trial indicated that a brief expectation-focused intervention prior to heart surgery improves disability and quality of life 6 months after coronary artery bypass graft surgery (CABG). However, to investigate the clinical utility of such an intervention, a large multi-center trial is needed to generalize the results and their implications for the health care system. The PSY-HEART-II study aims to examine whether a preoperative psychological intervention targeting patients' expectations (EXPECT) can improve outcomes 6 months after CABG (with or without heart valve replacement). EXPECT will be compared to Standard of Care (SOC) and an intervention providing emotional support without targeting expectations (SUPPORT). In a 3-arm multi-center randomized, controlled, prospective trial (RCT), N = 567 patients scheduled for CABG surgery will be randomized to either SOC alone or SOC and EXPECT or SOC and SUPPORT. Patients will be randomized with a fixed unbalanced ratio of 3:3:1 (EXPECT: SUPPORT: SOC) to compare EXPECT to SOC and EXPECT to SUPPORT. Both psychological interventions consist of 2 in-person sessions (à 50 minute), 2 phone consultations (à 20 minute) during the week prior to surgery, and 1 booster phone consultation post-surgery 6 weeks later. Assessment will occur at baseline approx. 3-10 days before surgery, preoperatively the day before surgery, 4-6 days later, and 6 months after surgery. The study's primary end point will be patients' illness-related disability 6 months after surgery. Secondary outcomes will be patients' expectations, subjective illness beliefs, quality of life, length of hospital stay and blood sample parameters (eg, inflammatory parameters such as IL-6, IL-8, CRP). This large multi-center trial has the potential to corroborate and generalize the promising results of the PSY-HEART-I trial for routine care of cardiac surgery patients, and to stimulate revisions of treatment guidelines in heart surgery.

Fostering compliance with physical distancing by interactive feedback in the context of the COVID-19 pandemic: A web-based randomized controlled trial.

Background: To slow down the spread of COVID-19, the observance of basic hygiene measures, and physical distancing is recommended. Initial findings suggest that physical distancing in particular can prevent the spread of COVID-19. Objectives: To investigate how information to prevent the spread of infectious diseases should be presented to increase willingness to comply with preventive measures. Methods: In a preregistered online experiment, 817 subjects were presented with either interactively controllable graphics on the spread of COVID-19 and information that enable them to recognize how much the spread of COVID-19 is reduced by physical distancing (experimental group) or text-based information about quantitative evidence (control group). It was hypothesized that participants receiving interactive information on the prevention of COVID-19 infections show a significantly higher willingness to comply with future containment measures than participants reading the text-based information. Explorative analyses were conducted to examine whether other factors influence compliance. Results: As predicted, we found a small effect (d = 0.22, 95% CI: 0.11; 0.23, p < .001) for the tested intervention. The exploratory analysis suggests a decline in compliance later in the study (r = -0.10, 95% CI: -0.15; -0.07). Another significant predictor of change in compliance was health-related anxiety, but the effect was trivial. Conclusions: When presented interactively, information on how the own behavior can help prevent infectious diseases can lead to slightly stronger changes in attitude towards behavioral prevention measures than just text-based information. Given the scalability of this simple internet-based intervention, it could play a role in fostering compliance during a pandemic within universal prevention strategies. Future work on the predictive validity of self-reported compliance and the real-world effects on the intervention is needed.

Measuring extinction learning across the lifespan - Adaptation of an optimized paradigm to closely match exposure treatment procedures.

Here, we tested the feasibility of a new paradigm developed to investigate the mechanisms of exposure-therapy. The protocol was previously developed for the use with adults and optimized to closely model the mechanisms underlying exposure, i.e. extinction learning. We adapted this paradigm for the use with children, and tested its feasibility in children and adult participants. We used an aversive acoustic unconditioned stimulus (US), picture-based rating scales and a child-oriented instruction/practice procedure. Results indicate robust fear acquisition, extinction and reinstatement on a self-report (US-expectancy) and on a physiological (startle reflex) level. We found evidence for the paradigms sensitivity to age and anxiety-dependent individual differences in fear-learning and extinction. We conclude that the present paradigm is capable of modeling the key mechanisms of exposure-therapy, that is extinction-learning, and can be accomplished with children, adolescents and adults, rendering it promising to bridge the gap between experimental protocols and treatment across the lifespan.

Clinical and neurophysiological patterns of impairments to emotion attention and empathy in multiple sclerosis.

Patients suffering from multiple sclerosis experience various cognitive and affective impairments, resulting in a negative impact on social behavior and personal independence to differing degrees. According to these often clinically subtle but conflicting cognitive-affective impairments, recordings of these socially relevant issues are still of demand to stratifying clinical and social support in a sophisticated way. Therefore, we studied specific cognitive and affective capacities in eleven patients with a predominant relapsing-remitting type of multiple sclerosis by applying paradigms of event-related potentials and a well-selected neuropsychological test protocol. Thus far, distinct cognitive disturbances of executive and attentional domains and the Wechsler Memory Test's four memory indices were found in multiple sclerosis patients. Concerning affective domains, patients showed discrete impairments of affect discrimination and affected naming as proved by specific testing (Tuebinger Affect Battery). Neurophysiologically, event-related potentials recordings in multiple sclerosis patients, were associated with decreased implicit emotion processing to cues of different emotion arousal at the early processing stage depending on attentional capacities and alterations of implicit emotion modulation at late processing stages. These clinical neurophysiological and neuropsychological data were correlated in part to quantitative magnetic resonance imaging brain lesions. Summarizing our data, our data indicate certain neurocognitive and neuroaffective dysfunctions in patients with multiple sclerosis, thus highlighting the validity of sensitive recording of less apparent neurologic disturbances in multiple sclerosis for optimizing the individual care management in patients.

Hold your breath: Voluntary breath-holding time predicts defensive activation to approaching internal threat.

Bodily disturbances, like dyspnea, elicit responses to regain homeostasis and ensure survival. However, this life-saving function can become hyperreactive, which may lead to the emergence of psychopathology. This study investigated whether maximal voluntary breath-holding time (mvBHT), a biobehavioral marker that characterizes sensitivity to respiratory stimulation, predicts defensive mobilization to cues signaling the proximity of a mild electric shock vs. a respiratory threat (shortness of breath elicited by forced breath-holding) and the opportunity to avoid threat delivery in 60 healthy participants. While the startle reflex, a measure of defensive mobilization, generally increased with the proximity of an inevitable threat, shorter breath-holding time was specifically associated with greater startle potentiation when anticipating a respiratory threat but not an electric shock. In contrast, when both threats were avoidable, the startle reflex was comparably inhibited, irrespective of mvBHT. This study suggests that mvBHT specifically predicts hypersensitive responding to an anticipated inevitable respiratory threat.

Efficacy of temporally intensified exposure for anxiety disorders: A multicenter randomized clinical trial.

BACKGROUND: The need to optimize exposure treatments for anxiety disorders may be addressed by temporally intensified exposure sessions. Effects on symptom reduction and public health benefits should be examined across different anxiety disorders with comorbid conditions. METHODS: This multicenter randomized controlled trial compared two variants of prediction error-based exposure therapy (PeEx) in various anxiety disorders (both 12 sessions + 2 booster sessions, 100 min/session): temporally intensified exposure (PeEx-I) with exposure sessions condensed to 2 weeks (n = 358) and standard nonintensified exposure (PeEx-S) with weekly exposure sessions (n = 368). Primary outcomes were anxiety symptoms (pre, post, and 6-months follow-up). Secondary outcomes were global severity (across sessions), quality of life, disability days, and comorbid depression. RESULTS: Both treatments resulted in substantial improvements at post (PeEx-I: dwithin = 1.50, PeEx-S: dwithin = 1.78) and follow-up (PeEx-I: dwithin = 2.34; PeEx-S: dwithin = 2.03). Both groups showed formally equivalent symptom reduction at post and follow-up. However, time until response during treatment was 32% shorter in PeEx-I (median = 68 days) than PeEx-S (108 days; TRPeEx-I = 0.68). Interestingly, drop-out rates were lower during intensified exposure. PeEx-I was also superior in reducing disability days and improving quality of life at follow-up without increasing relapse. CONCLUSIONS: Both treatment variants focusing on the transdiagnostic exposure-based violation of threat beliefs were effective in reducing symptom severity and disability in severe anxiety disorders. Temporally intensified exposure resulted in faster treatment response with substantial public health benefits and lower drop-out during the exposure phase, without higher relapse. Clinicians can expect better or at least comparable outcomes when delivering exposure in a temporally intensified manner.