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.

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.

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.

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.

Establishment of Emotional Memories Is Mediated by Vagal Nerve Activation: Evidence from Noninvasive taVNS.

Emotional memories are better remembered than neutral ones, but the mechanisms leading to this memory bias are not well understood in humans yet. Based on animal research, it is suggested that the memory-enhancing effect of emotion is based on central noradrenergic release, which is triggered by afferent vagal nerve activation. To test the causal link between vagus nerve activation and emotional memory in humans, we applied continuous noninvasive transcutaneous auricular vagus nerve stimulation (taVNS) during exposure to emotional arousing and neutral scenes and tested subsequent, long-term recognition memory after 1 week. We found that taVNS, compared with sham, increased recollection-based memory performance for emotional, but not neutral, material. These findings were complemented by larger recollection-related brain potentials (parietal ERP Old/New effect) during retrieval of emotional scenes encoded under taVNS, compared with sham. Furthermore, brain potentials recorded during encoding also revealed that taVNS facilitated early attentional discrimination between emotional and neutral scenes. Extending animal research, our behavioral and neural findings confirm a modulatory influence of the vagus nerve in emotional memory formation in humans.SIGNIFICANCE STATEMENT Emotionally relevant information elicits stronger and more enduring memories than nonrelevant information. Animal research has shown that this memory-enhancing effect of emotion is related to the noradrenergic activation in the brain, which is triggered by afferent fibers of the vagus nerve (VN). In the current study, we show that noninvasive transcutaneous auricular VN stimulation enhances recollection-based memory formation specifically for emotionally relevant information as indicated by behavioral and electrophysiological indices. These human findings give novel insights into the mechanisms underlying the establishment of emotional episodic memories by confirming the causal link between the VN and memory formation which may help understand the neural mechanisms underlying disorders associated with altered memory functions and develop treatment options.

Transfer of exposure therapy effects to a threat context not considered during treatment in patients with panic disorder and agoraphobia: Implications for potential mechanisms of change.

Further developments of exposure-based therapy (EBT) require more knowledge about transfer of treatment to non-trained everyday contexts. However, little is known about transfer effects of EBT. Using a standardized EBT protocol in 275 patients with panic disorder and agoraphobia we investigated the transfer of EBT to a highly standardized context during a Behavioral Avoidance Test (BAT; being entrapped in a small and dark test chamber) and not part of the exposure sessions. Patients of a treatment group underwent the BATs before treatment (t1), after a preparatory treatment phase (t2), and after an agoraphobic exposure phase (t3) and were compared with wait-list control patients, who repeated BAT assessments across the same time period. We found stronger reductions in avoidance behavior, reported fear, and autonomic arousal during the BAT from t1 to t3 in the treatment group patients who were anxious during t1 relative to the anxious but untreated patients. Fear reduction was related to treatment outcome indicating the contribution of transfer effects to successful EBT. Interestingly, reduction varied for different fear response systems suggesting different processes to may be involved in transfer effects. Importantly, final BAT assessment still evoked residual fear in the treatment group as compared to BAT non-anxious control patients, suggesting limited transfer effects - one possible reason for the return of symptoms in new situations.

Neural adaptation of cingulate and insular activity during delayed fear extinction: A replicable pattern across assessment sites and repeated measurements.

Adapting threat-related memories towards changing environments is a fundamental ability of organisms. One central process of fear reduction is suggested to be extinction learning, experimentally modeled by extinction training that is repeated exposure to a previously conditioned stimulus (CS) without providing the expected negative consequence (unconditioned stimulus, US). Although extinction training is well investigated, evidence regarding process-related changes in neural activation over time is still missing. Using optimized delayed extinction training in a multicentric trial we tested whether: 1) extinction training elicited decreasing CS-specific neural activation and subjective ratings, 2) extinguished conditioned fear would return after presentation of the US (reinstatement), and 3) results are comparable across different assessment sites and repeated measures. We included 100 healthy subjects (measured twice, 13-week-interval) from six sites. 24 h after fear acquisition training, extinction training, including a reinstatement test, was applied during fMRI. Alongside, participants had to rate subjective US-expectancy, arousal and valence. In the course of the extinction training, we found decreasing neural activation in the insula and cingulate cortex as well as decreasing US-expectancy, arousal and negative valence towards CS+. Re-exposure to the US after extinction training was associated with a temporary increase in neural activation in the anterior cingulate cortex (exploratory analysis) and changes in US-expectancy and arousal ratings. While ICCs-values were low, findings from small groups suggest highly consistent effects across time-points and sites. Therefore, this delayed extinction fMRI-paradigm provides a solid basis for the investigation of differences in neural fear-related mechanisms as a function of anxiety-pathology and exposure-based treatment.

Vagal control of the heart decreases during increasing imminence of interoceptive threat in patients with panic disorder and agoraphobia.

Theoretically, panic disorder and agoraphobia pathology can be conceptualized as a cascade of dynamically changing defensive responses to threat cues from inside the body. Guided by this trans-diagnostic model we tested the interaction between defensive activation and vagal control as a marker of prefrontal inhibition of subcortical defensive activation. We investigated ultra-short-term changes of vagally controlled high frequency heart rate variability (HRV) during a standardized threat challenge (entrapment) in n = 232 patients with panic disorder and agoraphobia, and its interaction with various indices of defensive activation. We found a strong inverse relationship between HRV and heart rate during threat, which was stronger at the beginning of exposure. Patients with a strong increase in heart rate showed a deactivation of prefrontal vagal control while patients showing less heart rate acceleration showed an increase in vagal control. Moreover, vagal control collapsed in case of imminent threat, i.e., when body symptoms increase and seem to get out of control. In these cases of defensive action patients either fled from the situation or experienced a panic attack. Active avoidance, panic attacks, and increased sympathetic arousal are associated with an inability to maintain vagal control over the heart suggesting that teaching such regulation strategies during exposure treatment might be helpful to keep prefrontal control, particularly during the transition zone from post-encounter to circa strike defense.Trial Registration Number: ISRCTN80046034.

Attentive immobility in the face of inevitable distal threat-Startle potentiation and fear bradycardia as an index of emotion and attention.

During fear conditioning, a cue (CS) signals an inevitable distal threat (US) and evokes a conditioned response that can be described as attentive immobility (freezing). The organism remains motionless and monitors the source of danger while startle responses are potentiated, indicating a state of defensive hypervigilance. Although in animals vagally mediated fear bradycardia is also reliably observed under such circumstances, results are mixed in human fear conditioning. Using a single-cue fear conditioning and extinction protocol, we tested cardiac reactivity and startle potentiation indexing low-level defensive strategies in a fear-conditioned (n = 40; paired presentations of CS and US) compared with a non-conditioned control group (n = 40; unpaired presentations of CS and US). Additionally, we assessed shock expectancy ratings on a trial-by-trial basis indexing declarative knowledge of the previous contingencies. Half of each group underwent extinction under sham or active transcutaneous vagus nerve stimulation (tVNS), serving as additional proof of concept. We found stronger cardiac deceleration during CS presentation in the fear learning relative to the control group. This learned fear bradycardia was positively correlated with conditioned startle potentiation but not with declarative knowledge of CS-US contingencies. TVNS abolished differences in heart rate changes between both groups and removed the significant correlation between late cardiac deceleration and startle potentiation in the fear learning group. Results suggest, fear-conditioned cues evoke attentive immobility in humans, characterized by cardiac deceleration and startle potentiation. Such defensive response pattern is elicited by cues predicting inevitable distal threat and resembles conditioned fear responses observed in rodents.

Decreased defensive reactivity to interoceptive threat after successful exposure-based psychotherapy in patients with panic disorder.

Panic disorder (PD) is characterized by a dysfunctional defensive responding to panic-related body symptoms that is assumed to contribute to the persistence of panic symptomatology. The present study aimed at examining whether this dysfunctional defensive reactivity to panic-related body symptoms would no longer be present following successful cognitive behavior therapy (CBT) but would persist when patients show insufficient symptom improvement. Therefore, in the present study, effects of CBT on reported symptoms and defensive response mobilization during interoceptive challenge were investigated using hyperventilation as a respiratory symptom provocation procedure. Changes in defensive mobilization to body symptoms in the course of CBT were investigated in patients with a primary diagnosis of PD with or without agoraphobia by applying a highly standardized hyperventilation task prior to and after a manual-based CBT (n = 38) or a waiting period (wait-list controls: n = 20). Defensive activation was indexed by the potentiation of the amygdala-dependent startle eyeblink response. All patients showed a pronounced defensive response mobilization to body symptoms at baseline. After treatment, no startle reflex potentiation was found in those patients who showed a clinically significant improvement. However, wait-list controls and treatment non-responders continued to show increased defensive responses to actually innocuous body symptoms after the treatment/waiting period. The present results indicate that the elimination of defensive reactivity to actually innocuous body symptoms might be a neurobiological correlate and indicator of successful CBT in patients with PD, which may help to monitor and optimize CBT outcomes.

Latent class growth analyses reveal overrepresentation of dysfunctional fear conditioning trajectories in patients with anxiety-related disorders compared to controls.

Recent meta-analyses indicated differences in fear acquisition and extinction between patients with anxiety-related disorders and comparison subjects. However, these effects are small and may hold for only a subsample of patients. To investigate individual trajectories in fear acquisition and extinction across patients with anxiety-related disorders (N = 104; before treatment) and comparison subjects (N = 93), data from a previous study (Duits et al., 2017) were re-analyzed using data-driven latent class growth analyses. In this explorative study, subjective fear ratings, shock expectancy ratings and startle responses were used as outcome measures. Fear and expectancy ratings, but not startle data, yielded distinct fear conditioning trajectories across participants. Patients were, compared to controls, overrepresented in two distinct dysfunctional fear conditioning trajectories: impaired safety learning and poor fear extinction to danger cues. The profiling of individual patterns allowed to determine that whereas a subset of patients showed trajectories of dysfunctional fear conditioning, a significant proportion of patients (≥50 %) did not. The strength of trajectory analyses as opposed to group analyses is that it allows the identification of individuals with dysfunctional fear conditioning. Results suggested that dysfunctional fear learning may also be associated with poor treatment outcome, but further research in larger samples is needed to address this question.

Reading the Mind in the Eyes of Children Test (RME-C-T): Development and Validation of a Complex Emotion Recognition Test.

Much research has been devoted to the development of emotion recognition tests that can be used to investigate how individuals identify and discriminate emotional expressions of other individuals. One of the most prominent emotion recognition tests is the Reading the Mind in the Eyes Test (RME-T). The original RME-T has been widely used to investigate how individuals recognize complex emotional expressions from the eye region of adult faces. However, the RME-T can only be used to investigate inter-individual differences in complex emotion recognition during the processing of adult faces. To extend its usefulness, we developed a modified version of the RME-T, the Reading the Mind in the Eyes of Children Test (RME-C-T). The RME-C-T can be used to investigate how individuals recognize complex emotional expressions from the eye region of child faces. However, the validity of the RME-C-T has not been evaluated yet. We, thus, administered the RME-C-T together with the RME-T to a sample of healthy adult participants (n = 119). The Interpersonal Reactivity Index (IRI) and the Toronto Alexithymia Scale (TAS) were also administered. Participants' RME-C-T performance correlated with participants' RME-T performance, implying that the RME-C-T measures similar emotion recognition abilities as the RME-T. Participants' RME-C-T performance also correlated with participants' IRI and TAS scores, indicating that these emotion recognition abilities are affected by empathetic and alexithymic traits. Moreover, participants' RME-C-T performance differed between participants with high and low TAS scores, suggesting that the RME-C-T is sensitive enough to detect impairments in these emotion recognition abilities. The RME-C-T, thus, turned out to be a valid measure of inter-individual differences in complex emotion recognition during the processing of child faces.

Facilitating translational science in anxiety disorders by adjusting extinction training in the laboratory to exposure-based therapy procedures.

Extinction learning is suggested to be a central mechanism during exposure-based cognitive behavioral psychotherapy. A positive association between the patients' pretreatment extinction learning performance and treatment outcome would corroborate the hypothesis. Indeed, there is first correlational evidence between reduced extinction learning and therapy efficacy. However, the results of these association studies may be hampered by extinction-training protocols that do not match treatment procedures. Therefore, we developed an extinction-training protocol highly tailored to the procedure of exposure therapy and tested it in two samples of 46 subjects in total. By using instructed fear acquisition training, including a consolidation period overnight, we wanted to ensure that the conditioned fear response was well established prior to extinction training, which is the case in patients with anxiety disorders prior to treatment. Moreover, the extinction learning process was analyzed on multiple response levels, comprising unconditioned stimulus (US) expectancy ratings, autonomic responses, defensive brain stem reflexes, and neural activation using functional magnetic resonance imaging. Using this protocol, we found robust fear conditioning and slow-speed extinction learning. We also observed within-group heterogeneity in extinction learning, albeit a stable fear response at the beginning of the extinction training. Finally, we found discordance between different response systems, suggesting that multiple processes are involved in extinction learning. The paradigm presented here might help to ameliorate the association between extinction learning performance assessed in the laboratory and therapy outcomes and thus facilitate translational science in anxiety disorders.