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.

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.

Developmental pathways in youth anxiety disorders: potential mechanisms for (mal)adapting to crises and improving treatment - a commentary on Klein et al. (2023).

The ability to cope with threats is crucial in today's troubling times, especially for young people who are still developing coping mechanisms. Psychopathology and the development of anxiety disorders can be viewed as a failure to adapt to changing demands. We draw on a study by Klein et al. (Journal of Child Psychology and Psychiatry, 2023), which showed that anxious youths exhibited stronger conditioned fear responses and, during delayed extinction learning, greater electrocortical differences between threat and safety stimuli. Interestingly, these signatures of learning processes were also associated with treatment outcomes. We argue for developmentally sensitive research: Individual learning and associated cognitive-affective changes are strongly age-dependent and represent the key mechanism for both anxiety development and treatment. They also interact with social and environmental factors. Based on the call for age- and context-sensitive research, future research should focus on establishing reliable risk profiles that consider a variety of factors to enable evidence-based, individualized treatment decisions.

Increased early motivational response to food in adolescent anorexia nervosa revealed by magnetoencephalography.

BACKGROUND: It remains unclear to what extent reduced nutritional intake in anorexia nervosa (AN) is a consequence of a reduced motivational response to food. Although self-reports typically suggest AN patients have a reduced appetitive response, behavioral and neurophysiological measures have revealed evidence for both increased and reduced attentional biases towards food stimuli. The mechanisms influencing food perception in AN, might be clarified using time-sensitive magnetoencephalography (MEG) to differentiate the early (more automatic processing) stages from the late (more controlled) stages. METHODS: MEG was recorded in 22 partially weight-restored adolescent AN patients and 29 age- and gender-matched healthy control (HC) participants during a rapid serial visual presentation paradigm using 100 high-calorie food, 100 low-calorie food, and 100 non-food pictures. Neural sources of event-related fields were estimated using the L2-Minimum-Norm method and analyzed in early (50-300 ms) and late (350-500 ms) time intervals. RESULTS: AN patients rated high-calorie food as less palatable and reported overall less food craving than HC participants. Nevertheless, in response to food pictures AN patients showed relative increased neural activity in the left occipito-temporal and inferior frontal regions in the early time interval. No group differences occurred in the late time interval. CONCLUSIONS: MEG results speak against an overall reduced motivational response to food in AN. Instead, relative increased early food processing in the visual cortex suggests greater motivated attention. A greater appetitive response to food might be an adaptive mechanism in a state of undernourishment. Yet, this relative increased food processing in AN was no longer present later, arguably reflecting rapid downregulation.

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.

Fear generalization of implicit conditioned facial features - Behavioral and magnetoencephalographic correlates.

Acquired fear responses often generalize from conditioned stimuli (CS) towards perceptually similar, but harmless generalization stimuli (GS). Knowledge on similarities between CS and GS may be explicit or implicit. Employing behavioral measures and whole-head magnetoencephalography, we here investigated the neurocognitive mechanisms underpinning implicit fear generalization. Twenty-nine participants underwent a classical conditioning procedure in which 32 different faces were either paired with an aversive scream (16 CS+) or remained unpaired (16 CS-). CS+ and CS- faces systematically differed from each other regarding their ratio of eye distance and mouth width. High versus low values on this "threat-related feature (TF)" implicitly predicted the presence or absence of the aversive scream. In pre- and post-conditioning phases, all CS and 32 novel GS faces were presented. 16 GS+ â€‹faces shared the TF of the 16 CS+ â€‹faces, while 16 â€‹GS- faces shared the TF of the 16 CS- faces. Behavioral tests confirmed that participants were fully unaware of TF-US contingencies. CS+ â€‹compared to CS- faces revealed higher unpleasantness, arousal and US-expectancy ratings. A generalization of these behavioral fear responses to GS+ â€‹compared to GS- faces was observed by trend only. Source-estimations of event-related fields showed stronger neural responses to both CS+ and GS+ â€‹compared to CS- and GS- in anterior temporal (<100 â€‹ms) and temporo-occipital (<150 â€‹ms; 553-587 â€‹ms) ventral brain regions. Reverse effects were found in dorsal frontal areas (<100 â€‹ms; 173-203 â€‹ms; 257-290 â€‹ms). Neural data also revealed selectively enhanced responses to CS+ â€‹but not GS+ â€‹stimuli in occipital regions (110-167 â€‹ms; 330-413 â€‹ms), indicating perceptual discrimination. Our data suggest that the prioritized perceptual analysis of threat-associated conditioned faces in ventral networks rapidly generalizes to novel faces sharing threat-related features. This generalization process occurs in absence of contingency awareness and may thus contribute to implicit attentional biases. The coexisting perceptual discrimination suggests that fear generalization is not a mere consequence of insufficient stimulus discrimination but rather an active, integrative process.

Acute aerobic exercise enhances pleasant compared to unpleasant visual scene processing.

Although acute aerobic exercise benefits different aspects of emotional functioning, it is unclear how exercise influences the processing of emotional stimuli and which brain mechanisms support this relationship. We assessed the influence of acute aerobic exercise on valence biases (preferential processing of negative/positive pictures) by performing source reconstructions of participants' brain activity after they viewed emotional scenes. Twenty-four healthy participants (12 women) were tested in a randomized and counterbalanced design that consisted of three experimental protocols, each lasting 30 min: low-intensity exercise (Low-Int); moderate-intensity exercise (Mod-Int); and a seated rest condition (REST). After each of the protocols, participants viewed negative and positive pictures, during which event-related magnetic fields were recorded. Analyses revealed that exercise strongly impacted the valence processing of emotional scenes within a widely distributed left hemispheric spatio-temporal cluster between 190 and 310 ms after picture onset. Brain activity in this cluster showed that a negativity bias at REST (negative > positive picture processing) diminished after the Low-Int condition (positive = negative) and even reversed to a positivity bias after the Mod-Int condition (positive > negative). Thus, acute aerobic exercise of low and moderate intensities induces a positivity bias which is reflected in early, automatic processes.

The causal role of prefrontal hemispheric asymmetry in valence processing of words - Insights from a combined cTBS-MEG study.

Hemispheric asymmetries play an important role in multiple cerebral functions. Asymmetries in prefrontal cortex (PFC) function have been suggested to regulate emotional processing in that right-hemispheric dominance biases towards negative affect, whereas left PFC dominance favors positive affect. This study used transcranial magnetic stimulation to test the causal role of prefrontal asymmetries in the processing of emotional stimuli. To experimentally induce hemispheric asymmetries, 21 healthy volunteers underwent two separate sessions of inhibitory continuous theta burst stimulation (cTBS) to the left versus right dorsolateral prefrontal cortex. Each stimulation was followed by magnetoencephalographic (MEG) recordings of event-related fields elicited by visually presented emotional words in a silent reading task and a subsequent behavioral emotion categorization task. The asymmetry manipulation influenced valence processing of words in early, mid-latency and late time intervals in right occipitotemporal and parietal brain regions. Left-sided cTBS (inducing right-hemispheric dominance) consistently resulted in enhanced brain responses to negative words, while right-sided cTBS (inducing left-hemispheric dominance) enhanced responses to positive words. On a behavioral level, right-hemispheric dominance resulted in more categorization matches of negative compared to positive words, while left-hemispheric dominance resulted in reverse effects. These results provide direct evidence that bottom-up valence processing is influenced by prefrontal hemispheric asymmetry.

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.

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.

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.

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.

Inhibitory control and its modification in spider phobia - Study protocol for an antisaccade training trial.

OBJECTIVES: Inhibitory control deficits are considered a key pathogenic factor in anxiety disorders. To assess inhibitory control, the antisaccade task is a well-established measure that assesses antisaccade performance via latencies and error rates. The present study follows three aims: (1) to investigate inhibitory control via antisaccade latencies and errors in an antisaccade task, and their associations with multiple measures of fear in patients with spider phobia (SP) versus healthy controls (HC), (2) to investigate the modifiability of antisaccade performance via a fear-specific antisaccade training in patients with SP and HC, and (3) to explore associations between putative training-induced changes in antisaccade performance in SPs and changes in diverse measures of fear. METHODS: Towards aim 1, we assess antisaccade latencies (primary outcome) and error rates (secondary outcome) in an emotional antisaccade task. Further, the baseline assessment includes assessments of psychophysiological, behavioral, and psychometric indices of fear in patients with SP and HCs. To address aim 2, we compare effects of a fear-specific antisaccade training with effects of a prosaccade training as a control condition. The primary and secondary outcomes are reassessed at a post-1-assessment in both SPs and HCs. Aim 3 employs a cross-over design and is piloted in patients with SP, only. Towards this aim, primary and secondary outcomes, as well as psychophysiological, behavioral, and psychometric measures of fear are reassessed at a post-2-assessment after the second training block. CONCLUSION: This study aims to better understand inhibitory control processes and their modifiability in spider phobia. If successful, antisaccade training may assist in the treatment of specific phobia by directly targeting the putative underlying inhibitory control deficits. This study has been preregistered with ISRCTN (ID: ISRCTN12918583) on 28th February 2022.

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.

Self-guided virtual reality therapy for social anxiety disorder: a study protocol for a randomized controlled trial.

BACKGROUND: Social anxiety disorder (SAD) is a highly prevalent mental disorder associated with enormous stress and suffering. Cognitive behavior therapy (CBT) is the first-line treatment for SAD, yet its accessibility is often constrained with long waiting times. Digital therapeutic applications, including psychoeducation and self-guided behavioral experiments in virtual reality (VR), could facilitate access and reduce waiting times. The study aims to investigate if ultra-short-time therapy involving self-guided digital therapeutic applications with VR components can reduce the severity of SAD. METHODS: Forty SAD patients will participate in this randomized controlled trial. Half will get access to a self-guided, digital therapeutic application with exposure-based behavioral experiments in VR, while the other half will receive a control treatment. Both treatments include four therapeutic appointments. Changes in the severity of SAD will be measured after each appointment and on a 6-week follow-up assessment and will be compared between groups, with the change in SAD measured at baseline- and post-assessment as primary outcome. DISCUSSION: Self-guided digital therapeutic applications including ultra-short-time therapy combined with VR could help reduce the waiting time for patients and relieve the health system. The results of this study may inform psychotherapists regarding the potential of self-guided digital therapeutic applications including exposure-based behavioral experiments in VR for SAD and will provide important insight for future research on VR therapy. TRIAL REGISTRATION: Current Controlled Trials ISRCTN18013983 . Registered on 1 February 2022.

Self-guided digital treatment with virtual reality for panic disorder and agoraphobia: a study protocol for a randomized controlled trial.

BACKGROUND: Cognitive behavioral therapy is the first-line treatment for patients with panic disorder (PD) and agoraphobia (AG). Yet, many patients remain untreated due to limited treatment resources. Digital self-guided short-term treatment applications may help to overcome this issue. While some therapeutic applications are already supported by health insurance companies, data on their efficacy is limited. The current study investigates the effect of self-guided digital treatment comprising psychoeducation and virtual reality exposure therapy (VRET). METHODS: Thirty patients diagnosed with PD, AG, or panic disorder with agoraphobia (PDA) will be randomly assigned to either the experimental group (EG) or the control group (CG). Participants of both groups will undergo baseline diagnostics in the first two sessions. The subsequent treatment for the EG consists of a self-guided 6-week phase of application-based psychoeducation, one therapy session preparing for the VRET, and 4 weeks of application-based self-guided VRET. To control for the potential effects of the therapy session with the therapist, the CG will receive relaxation and stress-reduction training instead. All patients will then undergo a closing session which terminates with the post-assessment (~ 10 weeks after baseline assessment) and a follow-up assessment 6 weeks following the closing session. Symptom severity (primary outcome) will be assessed at baseline, interim, post-treatment, and follow-up. Additionally, remission status (secondary outcome) will be obtained at follow-up. Both measures will be compared between the groups. DISCUSSION: The current study aims at providing insights into the efficacy of short-term treatment applications including psychoeducation and self-guided VRET. If successful, this approach might be a feasible and promising way to ease the burden of PD, AG, and PDA on the public health system and contribute to a faster access to treatment. TRIAL REGISTRATION: ISRCTN ISRCTN10661970 . Prospectively registered on 17 January 2022.

Functional neural changes associated with psychotherapy in anxiety disorders - A meta-analysis of longitudinal fMRI studies.

Successful psychotherapy for anxiety disorders is thought to be linked to functional neural changes in prefrontal control areas and fear-related limbic regions. Thus, discovering such therapy-associated neural changes might point to relevant mechanisms of action. Using AES-SDM, we conducted a coordinate-based meta-analysis of 22 whole-brain datasets (n = 419 anxiety patients) from 18 studies identified by our systematic literature search following PRISMA criteria (preregistration available at OSF: https://osf.io/dgc4p). In these studies, fMRI data was collected in response to negative stimuli during cognitive-emotional tasks before and after psychotherapy. Post-psychotherapy, activation decreased in the right insula, the anterior cingulate cortex, and the dorsolateral prefrontal cortex; no region had increased activation. A subgroup analysis for CBT revealed additional decrease in the supplementary motor area. Reduced activation in limbic and frontal regions might indicate therapy-associated normalization regarding the perception of internal and external threat, subsequent allocation of cognitive resources, and changes in cognitive control. Due to the integration of diverse treatments and experimental tasks, these changes presumably reflect global effects of successful psychotherapy.

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.

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.