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.

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.

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.

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.

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.

Theranostic markers for personalized therapy of spider phobia: Methods of a bicentric external cross-validation machine learning approach.

OBJECTIVES: Embedded in the Collaborative Research Center "Fear, Anxiety, Anxiety Disorders" (CRC-TRR58), this bicentric clinical study aims at identifying biobehavioral markers of treatment (non-)response by applying machine learning methodology with an external cross-validation protocol. We hypothesize that a priori prediction of treatment (non-)response is possible in a second, independent sample based on multimodal markers. METHODS: One-session virtual reality exposure treatment (VRET) with patients with spider phobia was conducted on two sites. Clinical, neuroimaging, and genetic data were assessed at baseline, post-treatment and after 6 months. The primary and secondary outcomes defining treatment response are as follows: 30% reduction regarding the individual score in the Spider Phobia Questionnaire and 50% reduction regarding the individual distance in the behavioral avoidance test. RESULTS: N = 204 patients have been included (n = 100 in Würzburg, n = 104 in Münster). Sample characteristics for both sites are comparable. DISCUSSION: This study will offer cross-validated theranostic markers for predicting the individual success of exposure-based therapy. Findings will support clinical decision-making on personalized therapy, bridge the gap between basic and clinical research, and bring stratified therapy into reach. The study is registered at ClinicalTrials.gov (ID: NCT03208400).