Association between resting-state connectivity patterns in the defensive system network and treatment response in spider phobia-a replication approach.

Although highly effective on average, exposure-based treatments do not work equally well for all patients with anxiety disorders. The identification of pre-treatment response-predicting patient characteristics may enable patient stratification. Preliminary research highlights the relevance of inhibitory fronto-limbic networks as such. We aimed to identify pre-treatment neural signatures differing between exposure treatment responders and non-responders in spider phobia and to validate results through rigorous replication. Data of a bi-centric intervention study comprised clinical phenotyping and pre-treatment resting-state functional connectivity (rsFC) data of n = 79 patients with spider phobia (discovery sample) and n = 69 patients (replication sample). RsFC data analyses were accomplished using the Matlab-based CONN-toolbox with harmonized analyses protocols at both sites. Treatment response was defined by a reduction of >30% symptom severity from pre- to post-treatment (Spider Phobia Questionnaire Score, primary outcome). Secondary outcome was defined by a reduction of >50% in a Behavioral Avoidance Test (BAT). Mean within-session fear reduction functioned as a process measure for exposure. Compared to non-responders and pre-treatment, results in the discovery sample seemed to indicate that responders exhibited stronger negative connectivity between frontal and limbic structures and were characterized by heightened connectivity between the amygdala and ventral visual pathway regions. Patients exhibiting high within-session fear reduction showed stronger excitatory connectivity within the prefrontal cortex than patients with low within-session fear reduction. Whereas these results could be replicated by another team using the same data (cross-team replication), cross-site replication of the discovery sample findings in the independent replication sample was unsuccessful. Results seem to support negative fronto-limbic connectivity as promising ingredient to enhance response rates in specific phobia but lack sufficient replication. Further research is needed to obtain a valid basis for clinical decision-making and the development of individually tailored treatment options. Notably, future studies should regularly include replication approaches in their protocols.

Higher-order comparative reward processing is affected by noninvasive stimulation of the ventromedial prefrontal cortex.

A crucial skill, especially in rapidly changing environments, is to be able to learn efficiently from prior rewards or losses and apply this acquired knowledge in upcoming situations. Often, we must weigh the risks of different options and decide whether an option is worth the risk or whether we should choose a safer option. The ventromedial prefrontal cortex (vmPFC) is suggested as a major hub for basic but also higher-order reward processing. Dysfunction in this region has been linked to cognitive risk factors for depression and behavioral addictions, including reduced optimism and feedback learning. Here, we test whether modulations of vmPFC excitability via noninvasive transcranial direct current stimulation (tDCS) can alter reward anticipation and reward processing. In a financial gambling task, participants chose between a higher and a lower monetary risk option and eventually received feedback whether they won or lost. Simultaneously feedback on the unchosen option was presented as well. Behavioral and magnetoencephalographic correlates of reward processing were evaluated in direct succession of either excitatory or inhibitory tDCS of the vmPFC. We were able to show modulated reward approach behavior (expectancy of greater reward magnitudes) as well as altered reevaluation of received feedback by vmPFC tDCS as indicated by modified choice behavior following the feedback. Thereby, tDCS not only influenced early, rather basic reward processing, but it also modulated higher-order comparative feedback evaluation of gains and losses relative to alternative outcomes. The neural results underline this idea, as stimulation-driven modulations of the basic reward-related effect occurred at rather early time intervals and were followed by stimulation effects related to comparative reward processing. Importantly, behavioral ratings were correlated with neural activity in left frontal areas. Our results imply a dual function of the vmPFC consisting of approaching reward (as indicated by more risky choices) and elaborately evaluating outcomes. In addition, our data suggest that vmPFC activity is associated with adaptive decision-making in the future via modulated behavioral adaptation or reinforcement learning.

Tinnitus-on the interplay between emotion and cognition.

Subjective tinnitus (hereafter tinnitus) is often considered and studied as a perceptual phenomenon. Accordingly, various abnormalities in the area of cognitive processing have been reported in patients with tinnitus. At the same time, the disorder is characterized by considerable emotional distress, which is associated with a high comorbidity of affective disorders. Here, we aim to outline the close link between cognition and emotion, and how current research from the field of cognitive neuroscience examines the processing and acquisition of emotional stimuli. The emotional valence of stimuli can be acquired after brief exposure to learning, leading from neutral to appetitive or aversive evaluation. In contrast to neutral stimuli, emotional stimuli attract attention very early (about 100 ms) during processing, leading to deeper processing and corresponding memory effects. The involved subcortical and cortical network encompasses limbic and sensory areas. In particular, prefrontal regions are involved in the acquisition and evaluation of emotional stimuli as also shown in studies of patients with affect disorders. The interplay of cognitive and emotional processes seems to be central to the development, maintenance, and treatment of tinnitus.

Excitatory stimulation of the ventromedial prefrontal cortex reduces cognitive gambling biases via improved feedback learning.

Humans are subject to a variety of cognitive biases, such as the framing-effect or the gambler's fallacy, that lead to decisions unfitting of a purely rational agent. Previous studies have shown that the ventromedial prefrontal cortex (vmPFC) plays a key role in making rational decisions and that stronger vmPFC activity is associated with attenuated cognitive biases. Accordingly, dysfunctions of the vmPFC are associated with impulsive decisions and pathological gambling. By applying a gambling paradigm in a between-subjects design with 33 healthy adults, we demonstrate that vmPFC excitation via transcranial direct current stimulation (tDCS) reduces the framing-effect and the gambler's fallacy compared to sham stimulation. Corresponding magnetoencephalographic data suggest improved inhibition of maladaptive options after excitatory vmPFC-tDCS. Our analyses suggest that the underlying mechanism might be improved reinforcement learning, as effects only emerge over time. These findings encourage further investigations of whether excitatory vmPFC-tDCS has clinical utility in treating pathological gambling or other behavioral addictions.

Mechanisms of action underlying virtual reality exposure treatment in spider phobia: Pivotal role of within-session fear reduction.

Although virtual-reality exposure treatment (VRET) for anxiety disorders is an efficient treatment option for specific phobia, mechanisms of action for immediate and sustained treatment response need to be elucidated. Towards this aim, core therapy process variables were assessed as predictors for short- and long-term VR treatment outcomes. In a bi-centric study, n = 186 patients with spider phobia completed a baseline-assessment, a one-session VRET, a post-therapy assessment, and a 6-month-follow-up assessment (ClinicalTrials.gov, ID: NCT03208400). Short- and long-term outcomes regarding self-reported symptoms in the spider phobia questionnaire (SPQ) and final patient-spider distance in the behavioral avoidance test (BAT) were predicted via logistic regression models with the corresponding baseline score, age, initial fear activation, within-session fear reduction and fear expectancy violation as predictors. To predict long-term remission status at 6-month-follow-up, dimensional short-term changes in the SPQ and BAT were additionally included. Higher within-session fear reductions predicted better treatment outcomes (long-term SPQ; short- and long-term BAT). Lower initial fear activation tended to be associated with better long-term outcomes (SPQ), while fear expectancy violation was not associated with any outcome measure. Short-term change in the SPQ predicted remission status. Findings highlight that in VRET for spider phobia, the experience of fear reduction is central for short- and long-term treatment success and should be focused by therapists.

[Tinnitus-on the interplay between emotion and cognition. German version]. / Tinnitus im Wechselspiel zwischen Emotion und Kognition.

Subjective tinnitus (hereafter tinnitus) is often considered and studied as a perceptual phenomenon. Accordingly, various abnormalities in the area of cognitive processing have been reported in patients with tinnitus. At the same time, the disorder is characterized by considerable emotional distress, which is associated with a high comorbidity of affective disorders. Here, we aim to outline the close link between cognition and emotion, and how current research from the field of cognitive neuroscience examines the processing and acquisition of emotional stimuli. The emotional valence of stimuli can be acquired after brief exposure to learning, leading from neutral to appetitive or aversive evaluation. In contrast to neutral stimuli, emotional stimuli attract attention very early (about 100 ms) during processing, leading to deeper processing and corresponding memory effects. The involved subcortical and cortical network encompasses limbic and sensory areas. In particular, prefrontal regions are involved in the acquisition and evaluation of emotional stimuli as also shown in studies of patients with affect disorders. The interplay of cognitive and emotional processes seems to be central to the development, maintenance, and treatment of tinnitus.

Non-invasive stimulation reveals ventromedial prefrontal cortex function in reward prediction and reward processing.

Introduction: Studies suggest an involvement of the ventromedial prefrontal cortex (vmPFC) in reward prediction and processing, with reward-based learning relying on neural activity in response to unpredicted rewards or non-rewards (reward prediction error, RPE). Here, we investigated the causal role of the vmPFC in reward prediction, processing, and RPE signaling by transiently modulating vmPFC excitability using transcranial Direct Current Stimulation (tDCS). Methods: Participants received excitatory or inhibitory tDCS of the vmPFC before completing a gambling task, in which cues signaled varying reward probabilities and symbols provided feedback on monetary gain or loss. We collected self-reported and evaluative data on reward prediction and processing. In addition, cue-locked and feedback-locked neural activity via magnetoencephalography (MEG) and pupil diameter using eye-tracking were recorded. Results: Regarding reward prediction (cue-locked analysis), vmPFC excitation (versus inhibition) resulted in increased prefrontal activation preceding loss predictions, increased pupil dilations, and tentatively more optimistic reward predictions. Regarding reward processing (feedback-locked analysis), vmPFC excitation (versus inhibition) resulted in increased pleasantness, increased vmPFC activation, especially for unpredicted gains (i.e., gain RPEs), decreased perseveration in choice behavior after negative feedback, and increased pupil dilations. Discussion: Our results support the pivotal role of the vmPFC in reward prediction and processing. Furthermore, they suggest that transient vmPFC excitation via tDCS induces a positive bias into the reward system that leads to enhanced anticipation and appraisal of positive outcomes and improves reward-based learning, as indicated by greater behavioral flexibility after losses and unpredicted outcomes, which can be seen as an improved reaction to the received feedback.

Acute aerobic exercise benefits allocation of neural resources related to selective attention.

A single session of aerobic exercise has been shown to potentially benefit subsequent performance in a wide range of cognitive tasks, but the underlying mechanisms are still not fully understood. In this study, we investigated the effects of exercise on selective attention, a cognitive process that involves prioritized processing of a subset of available inputs over others. Twenty-four healthy participants (12 women) underwent two experimental interventions in a random, crossover, and counterbalanced design: a vigorous-intensity exercise (60-65% HRR) and a seated rest (control) condition. Before and after each protocol, participants performed a modified selective attention task that demanded attending stimuli of different spatial frequencies. Event-related magnetic fields were concurrently recorded using magnetoencephalography. The results showed that exercise, relative to the seated rest condition, reduced neural processing of unattended stimuli and increased processing of attended stimuli. The findings suggest that changes in neural processing related to selective attention may be one of the mechanisms underlying exercise-induced improvements in cognition.

Tinnitus and Multimodal Cortical Interaction. / Tinnitus und multimodale kortikale Interaktion.

The term of subjective tinnitus is used to describe a perceived noise without an external sound source. Therefore, it seems to be obvious that tinnitus can be understood as purely auditory, sensory problem. From a clinical point of view, however, this is a very inadequate description, as there are significant comorbidities associated with chronic tinnitus. Neurophysiological investigations with different imaging techniques give a very similar picture, because not only the auditory system is affected in chronic tinnitus patients, but also a widely ramified subcortical and cortical network. In addition to auditory processing systems, networks consisting of frontal and parietal regions are particularly disturbed. For this reason, some authors conceptualize tinnitus as a network disorder rather than a disorder of a circumscribed system. These findings and this concept suggest that tinnitus must be diagnosed and treated in a multidisciplinary and multimodal manner.

Implicit threat learning involves the dorsolateral prefrontal cortex and the cerebellum.

Background/Objective: Most studies investigating the neural correlates of threat learning were carried out using an explicit Pavlovian conditioning paradigm where declarative knowledge on contingencies between conditioned (CS) and unconditioned stimuli (US) is acquired. The current study aimed at understanding the neural correlates of threat conditioning when contingency awareness is limited or even absent. Method: We conducted an fMRI report of threat learning in an implicit associative learning paradigm called multi-CS conditioning, in which a number of faces were associated with aversive screams (US) such that participants could not report contingencies between the faces and the screams. Results: The univariate results showed support for the recruitment of threat-related regions including the dorsolateral prefrontal cortex (dlPFC) and the cerebellum during acquisition. Further analyses by the multivariate representational similarity technique identified learning-dependent changes in the bilateral dlPFC. Conclusion: Our findings support the involvement of the dlPFC and the cerebellum in threat conditioning that occurs with highly limited or even absent contingency awareness.

The effects of a single aerobic exercise session on mood and neural emotional reactivity in depressed and healthy young adults: A late positive potential study.

Depression has been characterized by lowered mood and unfavorable changes in neural emotional reactivity (altered brain responses to emotional stimuli). Physical exercise is a well-established strategy to improve the mood of healthy and depressed individuals. Increasing evidence suggests that exercise might also improve emotional reactivity in healthy adults by increasing or decreasing brain responses to positive or negative stimuli, respectively. It is unknown, however, if exercise could also benefit emotional reactivity in depressed individuals. We investigated the effects of a single aerobic exercise session on mood and emotional reactivity in 24 depressed and 24 matched healthy young adults. Self-reported mood and neural reactivity to emotional pictures (indexed by the EEG late positive potential, LPP) were assessed before and after two experimental protocols: exercise (36 min of moderate-intensity exercise at 75% of maximal heart rate) and seated rest condition (36 min). In the healthy control group, exercise improved self-reported mood and neural emotional reactivity (increasing LPP to positive pictures). In the depressed group, exercise improved self-reported mood; however, it did not affect neural emotional reactivity. Additional analyses performed on both groups revealed that exercise-induced changes in emotional reactivity are associated with the severity of depressive symptoms: the effectiveness of exercise in improving emotional reactivity decreases with the severity of depressive symptoms. Overall, the study further strengthens the claim of a beneficial role of exercise on mood and emotional reactivity. It also suggests that a single aerobic exercise session might have a limited influence on neural emotional reactivity in depressed individuals.

Bioelectromagnetism in Human Brain Research: New Applications, New Questions.

Bioelectromagnetism has contributed some of the most commonly used techniques to human neuroscience such as magnetoencephalography (MEG), electroencephalography (EEG), transcranial magnetic stimulation (TMS), and transcranial electric stimulation (TES). The considerable differences in their technical design and practical use give rise to the impression that these are quite different techniques altogether. Here, we review, discuss and illustrate the fundamental principle of Helmholtz reciprocity that provides a common ground for all four techniques. We show that, more than 150 years after its discovery by Helmholtz in 1853, reciprocity is important to appreciate the strengths and limitations of these four classical tools in neuroscience. We build this case by explaining the concept of Helmholtz reciprocity, presenting a methodological account of this principle for all four methods and, finally, by illustrating its application in practical clinical studies.

Noninvasive stimulation of the ventromedial prefrontal cortex modulates rationality of human decision-making.

The framing-effect is a bias that affects decision-making depending on whether the available options are presented with positive or negative connotations. Even when the outcome of two choices is equivalent, people have a strong tendency to avoid the negatively framed option. The ventromedial prefrontal cortex (vmPFC) is crucial for rational decision-making, and dysfunctions in this region have been linked to cognitive biases, impulsive behavior and gambling addiction. Using a financial decision-making task in combination with magnetoencephalographic neuroimaging, we show that excitatory compared to inhibitory non-invasive transcranial direct current stimulation (tDCS) of the vmPFC reduces framing-effects while improving the assessment of loss-probabilities, ultimately leading to increased overall gains. Behavioral and neural data consistently suggest that this improvement in rational decision-making is predominately due to an attenuation of biases towards negative affect (loss-aversion and risk-aversion). These findings recommend further research towards clinical applications of vmPFC-tDCS as in addictive disorders.

Developmental aspects of fear generalization - A MEG study on neurocognitive correlates in adolescents versus adults.

BACKGROUND: Fear generalization is pivotal for the survival-promoting avoidance of potential danger, but, if too pronounced, it promotes pathological anxiety. Similar to adult patients with anxiety disorders, healthy children tend to show overgeneralized fear responses. OBJECTIVE: This study aims to investigate neuro-developmental aspects of fear generalization in adolescence - a critical age for the development of anxiety disorders. METHODS: We compared healthy adolescents (14-17 years) with healthy adults (19-34 years) regarding their fear responses towards tilted Gabor gratings (conditioned stimuli, CS; and slightly differently titled generalization stimuli, GS). In the conditioning phase, CS were paired (CS+) or remained unpaired (CS-) with an aversive stimulus (unconditioned stimuli, US). In the test phase, behavioral, peripheral and neural responses to CS and GS were captured by fear- and UCS expectancy ratings, a perceptual discrimination task, pupil dilation and source estimations of event-related magnetic fields. RESULTS: Closely resembling adults, adolescents showed robust generalization gradients of fear ratings, pupil dilation, and estimated neural source activity. However, in the UCS expectancy ratings, adolescents revealed shallower generalization gradients indicating overgeneralization. Moreover, adolescents showed stronger visual cortical activity after as compared to before conditioning to all stimuli. CONCLUSION: Various aspects of fear learning and generalization appear to be mature in healthy adolescents. Yet, cognitive aspects might show a slower course of development.

Neural correlates of fear conditioning are associated with treatment-outcomes to behavioral exposure in spider phobia - Evidence from magnetoencephalography.

BACKGROUND: Models of anxiety disorders and the rationale of exposure therapy (ET) are grounded on classical fear conditioning. Yet, it is unclear whether lower fear ratings of conditioned safety versus threat cues and corresponding neural markers of safety-learning and/or fear inhibition assessed before treatment would predict better outcomes of behavioral exposure. METHODS: Sixty-six patients with spider phobia completed pre-treatment clinical and experimental fear conditioning assessments, one session of virtual reality ET, a post-treatment clinical assessment, and a 6-month follow-up assessment. Tilted Gabor gratings served as conditioned stimuli (CS) that were either paired (CS+) or remained unpaired (CS-) with an aversive phobia-related and phobia-unrelated unconditioned stimulus (UCS). CS+/CS- differences in fear ratings and magnetoencephalographic event-related fields (ERFs) were related to percentual symptom reductions from pre- to post-treatment, as assessed via spider phobia questionnaire (SPQ), behavioral avoidance test (BAT), and remission status at 6-month follow-up. RESULTS: We observed no associations between pre-treatment CS+/CS- differences in fear ratings and any treatment outcome. CS+/CS- differences in source estimations of ERFs revealed that higher CS- activity in bilateral dorsolateral prefrontal cortex (dlPFC) was related with SPQ- and BAT-reductions. Associations between CS+/CS- differences and treatment outcomes were also observed in left ventromedial prefrontal cortex (vmPFC) regions, which additionally revealed associations with the follow-up remission status. CONCLUSIONS: Results provide initial evidence that neural pre-treatment CS+/CS- differences may hold predictive information regarding outcomes of behavioral exposure. Our findings highlight a key role of neural responses to safety cues with potentially inhibitory effects on affect-generating structures during fear conditioning.

Testing the effect of tACS over parietal cortex in modulating endogenous alpha rhythm and temporal integration windows in visual perception.

Neural oscillations in the alpha band (8-12 Hz) have been proposed as a key mechanism for the temporal resolution of visual perception. Higher alpha frequencies have been related to improved segregation of visual events over time, whereas lower alpha frequencies have been related to improved temporal integration. Similarly, also the phase of ongoing alpha has been shown to correlate with temporal integration/segregation. To test a causal relationship between alpha oscillations and perception, we here employed multi-channel transcranial alternating current stimulation (mc-tACS) over the right parietal cortex, whereas participants performed a visual temporal integration/segregation task that used identical stimuli with different instructions. Before and after mc-tACS we recorded the resting-state electroencephalogram (EEG) to extract the individual alpha frequency (IAF) and delivered electrical stimulation at slightly slower and faster frequencies (IAF±2 Hz). We hypothesized that this would not only drive endogenous alpha rhythms, but also affect temporal integration and segregation in an opposite way. However, the mc-tACS protocol used here did not consistently increase or decrease the IAF after the stimulation and did not affect temporal integration/segregation accuracy as expected. Although we found some preliminary evidence for an influence of tACS phase on temporal integration accuracy, the ongoing phase of mc-tACS oscillations did not reliably modulate temporal integration/segregation accuracy in a sinusoidal way as would have been predicted by an effective entrainment of brain oscillations. These findings may guide future studies using different stimulation montages for investigating the role of cortical alpha oscillations for human vision.

Transcranial Direct Current Stimulation of the Ventromedial Prefrontal Cortex Modulates Perceptual and Neural Patterns of Fear Generalization.

BACKGROUND: Overgeneralization of fear is a pathogenic marker of anxiety and stress-related disorders and has been linked with perceptual discrimination deficits, reduced fear inhibition, and prefrontal hyporeactivity to safety-signaling stimuli. We aimed to examine whether behavioral and neural patterns of fear generalization are influenced by the fear-inhibiting ventromedial prefrontal cortex (vmPFC). METHODS: Three groups of healthy participants received excitatory (n = 27), inhibitory (n = 26), or sham (n = 26) transcranial direct current stimulation of the vmPFC after a fear conditioning phase and before a fear generalization phase. We obtained, as dependent variables, fear ratings and unconditioned stimulus-expectancy ratings, perceptual aspects of fear generalization (perceptual discrimination), pupil dilations, and source estimations of event-related fields elicited by conditioned and generalization stimuli. RESULTS: After inhibitory (compared with excitatory and sham) vmPFC stimulation, we observed reduced performance in perceptual discrimination and less negative inhibitory gradients in frontal structures at midlatency and late time intervals. Fear and unconditioned stimulus-expectancy ratings as well as pupil dilation remained unaffected by stimulation. CONCLUSIONS: These findings reveal a causal contribution of vmPFC reactivity to generalization patterns and suggest that vmPFC hyporeactivity consequent on inhibitory vmPFC stimulation may serve as a model for pathological processes of fear generalization (reduced discrimination, impaired fear inhibition via frontal brain structures). This encourages further basic and clinical research on the potential of targeted brain stimulation to modulate fear generalization and overgeneralization.

Behavioral and Magnetoencephalographic Correlates of Fear Generalization Are Associated With Responses to Later Virtual Reality Exposure Therapy in Spider Phobia.

BACKGROUND: Because overgeneralization of fear is a pathogenic marker of anxiety disorders, we investigated whether pretreatment levels of fear generalization in spider-phobic patients are related to their response to exposure-based treatment to identify pretreatment moderators of treatment success. METHODS: A total of 90 patients with spider phobia completed pretreatment clinical and magnetoencephalography assessments, one session of virtual reality exposure therapy, and a posttreatment clinical assessment. Based on the primary outcome (30% symptom reduction in self-reported symptoms), they were categorized as responders or nonresponders. In a pretreatment magnetoencephalography fear generalization paradigm involving fear conditioning with 2 unconditioned stimuli (UCS), we obtained fear ratings, UCS expectancy ratings, and event-related fields to conditioned stimuli (CS: CS-, CS+) and 7 different generalization stimuli on a perceptual continuum from CS- to CS+. RESULTS: Before treatment, nonresponders showed behavioral overgeneralization indicated by more linear generalization gradients in fear ratings. Analyses of magnetoencephalography source estimations revealed that nonresponders showed a decline of their (inhibitory) frontal activations to safety-signaling CS- and generalization stimuli compared with CS+ over time, while responders maintained these activations at early (<300 ms) and late processing stages. CONCLUSIONS: Results provide initial evidence that pretreatment differences of behavioral and neural markers of fear generalization may act as moderators of later responses to behavioral exposure. Stimulating further research on fear generalization as a potential predictive marker, our findings are an important first step in the attempt to identify patients who may not benefit from exposure therapy and to personalize and optimize treatment strategies for this vulnerable patient group.

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

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

Clinical predictors of treatment response towards exposure therapy in virtuo in spider phobia: A machine learning and external cross-validation approach.

While being highly effective on average, exposure-based treatments are not equally effective in all patients. The a priori identification of patients with a poor prognosis may enable the application of more personalized psychotherapeutic interventions. We aimed at identifying sociodemographic and clinical pre-treatment predictors for treatment response in spider phobia (SP). N = 174 patients with SP underwent a highly standardized virtual reality exposure therapy (VRET) at two independent sites. Analyses on group-level were used to test the efficacy. We applied a state-of-the-art machine learning protocol (Random Forests) to evaluate the predictive utility of clinical and sociodemographic predictors for a priori identification of individual treatment response assessed directly after treatment and at 6-month follow-up. The reliability and generalizability of predictive models was tested via external cross-validation. Our study shows that one session of VRET is highly effective on a group-level and is among the first to reveal long-term stability of this treatment effect. Individual short-term symptom reductions could be predicted above chance, but accuracies dropped to non-significance in our between-site prediction and for predictions of long-term outcomes. With performance metrics hardly exceeding chance level and the lack of generalizability in the employed between-site replication approach, our study suggests limited clinical utility of clinical and sociodemographic predictors. Predictive models including multimodal predictors may be more promising.