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Fear Conditioning and Extinction in Anxious Youth: Identifying Neuro-cognitive Abnormalities and Their Relation to Pediatric Anxiety Treatment Outcomes

Final Report Summary - ERBT (Fear Conditioning and Extinction in Anxious Youth: Identifying Neuro-cognitive Abnormalities and Their Relation to Pediatric Anxiety Treatment Outcomes)

Anxiety disorders are the most common form of pediatric psychopathology, affecting 5 – 20% of children and adolescents. Despite therapeutic advances, treatment-resistance remains high. In addition, progress towards early detection of at-risk populations and more effective treatments has stalled. The main research objective was to target information-processing functions, specifically fear learning and extinction, in an effort to link pediatric anxiety to dysfunction in cognitive mechanisms and in underlying fear circuits.

Two objectives guided the current research:
Objective 1: To examine differences in fear learning anxious and non-anxious children, using a laboratory novel fear conditioning paradigm. This aim extended previous work to a younger age group; Objective 2: To test the therapeutic relevance of dysfunction in fear learning and extinction for treatment. Exposure Therapy is one of the most effective interventions for anxiety disorders. This intervention relies on extinction learning principles and may produce beneficial effects by altering brain function. The proposed study was designed to assess fear conditioning and extinction and brain function in anxious children pre and post exposure therapy.

In the first two years of the grant period, I published a manuscript that described the novel fear conditioning paradigm (the ״bell paradigm״) that was designed for use with children. The paradigm was tested in a study that examined differences in fear conditioning and extinction in anxious and non-anxious youth – directly following the first objective of this grant (Shechner et al., 2015, Depression and Anxiety). Since its publication, at least three additional studies were published using this novel task:

Ginat-Frolich, R., Katz, O, Klein, Z & Shechner, T. (2017). A novel perceptual discrimination training task: Reducing fear overgeneralization in the context of fear learning. Behavioral Research and Therapy, 93, 29-37.
McLaughlin, K.A. Sheridan, A.S. Gold, A.L. Duys, A., Lambert,H.K. Perverill, M., Heleniak, C., Shechner, T., & Pine D. S. (2016). Trauma exposure, brain structure, and fear conditioning in children. Neuropsychopharmacology, 41(8), 1946.
Michalska, K. J., Shechner, T., Britton, J. C., Pine D. S., & Fox, N. A. (2016). A developmental analysis of fear learning and generalization in childhood. Journal of Experimental Child Psychology, 46, 95-105.

In the last two years of the grant period, we have completed the two main studies described in the grant proposal but instead of fMRI we used EEG/ERPs. The first study examined fear conditioning, extinction and extinction recall in 33 typically-developing children (age range: 7.2-14.9 years). Participants first underwent the bell fear conditioning and extinction task (developed during the first period of the grant) consisting of yellow and blue cartoon bells while self-reports and galvanic skin response (GSR) measures were collected. Two weeks later, participants returned to the lab to complete an extinction recall task. In this task, the original yellow and blue bells as well as 3 new bell morphs, ranging in color from blue to yellow, were presented. During this stage, self-reported fear ratings and brain related activity through event related potentials (ERP) were assessed. Results indicated successful fear conditioning and extinction using both self-report and psychophysiological (GSR) measures. Moreover, two weeks later participants reported greater self-reported fear towards the threat cue as compared to the safe cue during extinction recall. In electrophysiology data (ERP), presentation of the threat resulted in a larger late positive potential (LPP) response than did presentation of the safety cue. Further, these differences in brain activation were positively correlated with poorer extinction learning two weeks earlier. This is the first ERP study to demonstrate extinction recall in a youth sample, setting the stage to examine this paradigm with anxious and non-anxious children. The study was submitted for publication and is currently under review.

In a second study, we used the same fear learning paradigm to compare anxious and non-anxious children. Participants were 26 non-anxious (M = 11.29 years, SD = 2.4 years) and 28 clinically anxious youth (M = 11.44 years, SD = 1.99 year). Clinical anxiety was determined using a semi-structured interview administered by a trained clinician. In their first visit to the lab, participants underwent fear conditioning and extinction using the bell paradigm. A week later, participants returned to the lab to complete the extinction recall task described in the first study. Participants were asked to rate their subjective level of fear and to assess the level of risk associated with each bell. In addition, brain activation was measured with ERPs. Anxious participants then received 12 individual sessions of individual anxiety-focused cognitive behavioral therapy (CBT). Following treatment, participants completed the extinction recall task for a second time. Results indicated that anxious and non-anxious youth showed similar learning patterns during fear conditioning and extinction. However, during the extinction recall task, the anxious group reported more fear to the new morphs compared to the non-anxious group. Interestingly, similar patterns where observed in brain activation with group differences in late positive potentials (LPP) amplitudes when new stimuli were presented. Finally, LPP amplitudes in the anxious group following treatment were significantly different from amplitudes before treatment. Namely, post-treatment LPPs during extinction recall were more similar to brain activation patterns observed in the non-anxious group. We are currently writing the paper of this study and hope to submit it to publication by October 2018.

In sum, the experiments conducted with the funding of this Marie Curie CIG grant extended our understanding regarding differences in fear learning among anxious and non-anxious children. The findings highlight the importance of using multi-level analyses to measure such differences, particularly in a pediatric clinical study. In addition, we established a task to measure fear conditioning and extinction across development and adapted it for use with ERP measurements, which could be easily used in both research and clinical settings.

On amore personal level and from a career integration point of view, last year the PI of this project received tenure at the University of Haifa (August 2017).