Fear-potentiated startle during extinction is associated with white matter microstructure and functional connectivity

Abstract

Background: Extinction of conditioned fear is an associative learning process that involves communication among the hippocampus, medial prefrontal cortex, and amygdala. Strength of connectivity between the hippocampus and the anterior cingulate cortex (ACC), and between the amygdala and ventromedial prefrontal cortex (vmPFC), may influence fear-potentiated startle (FPS) responses during extinction. Specific white matter tracts, the cingulum and uncinate fasciculus (UF), serve as primary routes of communication for these areas. Our objective was to investigate associations between FPS during extinction and cingulum and UF connectivity.

Method: Diffusion tensor imaging (DTI) and probabilistic tractography analyses were used to examine cingulum and UF structural connectivity in 40 female African-Americans with psychological trauma exposure. FPS responses during fear conditioning and extinction were assessed via electromyography (EMG) of the right orbicularis oculi muscle. Secondarily, functional connectivity analyses were performed with the seed regions of interest (ROIs) used for tractography.

Results: A significant negative association between cingulum microstructure and FPS during early extinction (r = -.42, p = .01) and late extinction (r = -.36, p = .03) was observed after accounting for the effects of age, trauma exposure, and psychopathology (post-traumatic stress disorder symptoms); this pattern was similar for early extinction and functional connectivity between these regions (p < .05(corrected)). No significant correlations were observed between FPS and UF microstructure.

Conclusions: These data indicate that structural integrity of the cingulum is directly associated with extinction learning and appears to influence functional connectivity between these regions. Decrements in cingulum microstructure may interfere with extinction learning, thereby increasing risk for the development of pathological anxiety.

Keywords: Anterior cingulate cortex; Cingulum; Connectivity; Extinction; Fear-potentiated startle; Hippocampus.