Revisiting potential associations between brain morphology, fear acquisition and extinction through new data and a literature review

Mana R Ehlers,Maren Klingelhöfer-Jens,Manuel Kuhn,Tina B Lonsdorf,Janne Nold

doi:10.1038/s41598-020-76683-1

Abstract

Inter-individual differences in defensive responding are widely established but their morphological correlates in humans have not been investigated exhaustively. Previous studies reported associations with cortical thickness of the dorsal anterior cingulate cortex, insula and medial orbitofrontal cortex as well as amygdala volume in fear conditioning studies. However, these associations are partly inconsistent and often derived from small samples. The current study aimed to replicate previously reported associations between physiological and subjective measures of fear acquisition and extinction and brain morphology. Structural magnetic resonance imaging was performed on 107 healthy adults who completed a differential cued fear conditioning paradigm with 24 h delayed extinction while skin conductance response (SCR) and fear ratings were recorded. Cortical thickness and subcortical volume were obtained using the software Freesurfer. Results obtained by traditional null hypothesis significance testing and Bayesians statistics do not support structural brain-behavior relationships: Neither differential SCR nor fear ratings during fear acquisition or extinction training could be predicted by cortical thickness or subcortical volume in regions previously reported. In summary, the current pre-registered study does not corroborate associations between brain morphology and inter-individual differences in defensive responding but differences in experimental design and analyses approaches compared to previous work should be acknowledged.

Highlights

While the basic mechanisms of fear conditioning and extinction and the importance of inter-individual differences in defensive responding are well recognized, research concerning a potential mapping of such interindividual differences onto variability in brain morphology is sparse
All areas that have been reported to show structural associations with inter-individual differences in defensive responding during fear and/or extinction learning have been linked to group averages in functional brain activation as assessed by BOLD fMRI during learning and expression of fear and extinction[18,19]: the amygdala, insula and prefrontal areas
This association was reported for the volume of the right amygdala during early acquisition in sample 1 but during late acquisition in sample 2 despite the identical experimental p rotocol[16] while a smaller earlier study with a largely overlapping sample reported a positive correlation with left amygdala volume in early but not late acquisition[14]

Summary

Introduction

While the basic mechanisms of fear conditioning and extinction and the importance of inter-individual differences in defensive responding are well recognized, research concerning a potential mapping of such interindividual differences onto variability in brain morphology is sparse. A recent study[17] with a large sample of anxiety patients and healthy controls (N = 351) including children and adults, reported the dorsomedial/dorsolateral prefrontal cortex (dm/dlPFC)—a region located substantially more lateral than the area identified by Milad et al.21—to be negatively correlated with a measure of general SCR averaged across both CS types (i.e., CS+ and CS−) and experimental phases (i.e., fear acquisition and extinction training). The interpretation of this aggregate SCR measure, is not straightforward with respect to associative learning processes. Differences in results might be attributable to the fact that the studies used a contextual and a cued fear conditioning paradigm respectively

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