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

Abstract

As overgeneralization of fear is a pathogenic marker of anxiety disorders, we investigated whether pre-treatment levels of fear generalization in spider-phobic patients are associated with their response to exposure-based treatment, in order to identify pre-treatment correlates of treatment success. Ninety patients with spider phobia completed pre-treatment clinical and magnetoencephalography (MEG) assessments, one session of virtual reality exposure therapy, and a post-treatment clinical assessment. Based on the primary outcome (30% symptom reduction in self-reported symptoms from pre- to post-treatment) they were categorized as responders or non-responders. In a pre-treatment MEG fear generalization paradigm involving fear conditioning with two unconditioned stimuli (UCS), we obtained fear ratings, UCS-expectancy ratings, and event-related fields to conditioned stimuli (CS+, CS-) and 7 different generalization stimuli (GS) on a perceptual continuum from CS+ to CS-. Prior to treatment, non-responders showed behavioral overgeneralization indicated by more linear generalization gradients in fear ratings. Analyses of MEG source estimations revealed that non-responders showed a decline of their (inhibitory) frontal activations to safety-signaling CS- and GS compared to CS+ over time, while responders maintained these activations at early (<300ms) and late processing stages. Results provide initial evidence that pre-treatment differences of behavioral and neural markers of fear generalization are associated with later responses to behavioral exposure. Findings demonstrate the relevance of inhibitory learning functions and their spatio-temporal neural reflections in this interplay. Findings stimulate research on mechanism-based augmentation strategies for behavioral therapies.

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

“…The basic structure of the Baseline, Conditioning and Test MEG phases was based on a prior fMRI study by Onat and Büchel (2015) and adapted for the recording of ERFs ( Roesmann et al, 2022a , Roesmann et al, 2022b , 2022c). CS+ , CS-, and – in the Baseline and Test MEG phases – the seven GSs were presented separately for 800 ms in the center of the screen (visual angle = 5.09 degrees, edge to edge) on a grey background.…”

“…The PM task was adopted from research on perceptual learning mechanisms ( McMahon and Leopold, 2012 ) and was employed in our previous experiments on fear generalization ( Roesmann et al, 2022a , Roesmann et al, 2022b ). Performance in the PM task was measured before (Baseline PM-task) and after (Test PM-task) the Conditioning and Generalization phases (see Fig.…”

“…The rejection of artifact-contaminated trials and the interpolation of artifact-contaminated sensors relies on the calculation of statistical parameters for the absolute measured magnetic field amplitudes over time, their standard deviation over time, as well as on the determination of boundaries for each parameter based on their distribution across trials. If the goodness of test topography interpolations based on the residual sensor configuration within a given trial did not reach an a-priori defined minimum criterion (k = 0.01; Roesmann et al, 2022b , Roesmann et al, 2022c , Roesmann et al, 2020 ; identical for each subject and run) the respective trial was rejected. If more than 30% of the trials in any run of either the Baseline or the Test phase did not meet this criterion (e.g.…”

“…a small ring) via perceptually similar GS (e.g., medium sized rings) to the threat-signaling CS+ (e.g., a large ring, Lissek et al, 2008 ). The level of fear generalization can be characterized by linear and quadratic functions of these generalization parameters ( Lissek et al, 2008 , Onat and Büchel, 2015 , Roesmann et al, 2022b , Schiele et al, 2016 , Stegmann et al, 2019 ), whereby shallower linear gradients may indicate overgeneralization of fear ( Lissek et al, 2014 , Lissek et al, 2010 ).…”

“…Developmental aspects of fear generalization are likely related to the maturation of brain structures that modulate efficient discrimination between danger and safety cues. Animal and human neuroimaging studies have highlighted the role of the prefrontal cortex (PFC), subcortical (amygdala, hippocampus) and cortical visual (temporal, occipito-parietal) areas in fear learning ( LeDoux, 2000 , Miskovic and Keil, 2012 , Shin and Liberzon, 2010 ) and fear generalization ( Dymond et al, 2015 , Lissek, 2012 , McTeague et al, 2015 , Onat and Büchel, 2015 , Roesmann et al, 2020 , Roesmann et al, 2022a , Roesmann et al, 2022b ). Our previous MEG-studies on fear generalization in healthy adults ( Roesmann et al, 2022a , Roesmann et al, 2020 ) and adults with AD ( Roesmann et al, 2022b ) yielded evidence for reduced neural responses to GS that perceptually resembled the CS+ (vs. the CS-; i.e.…”