Behavioral and neural responses during fear conditioning and extinction in a large transdiagnostic sample

Abstract

Background: Dysregulation of fear learning has been associated with psychiatric disorders that have altered positive and negative valence domain function. While amygdala-insula-prefrontal circuitry is considered important for fear learning, there have been inconsistencies in neural findings in healthy and clinical human samples. This study aimed to delineate the neural substrates and behavioral responses during fear learning in a large, transdiagnostic sample with predominantly depressive and/or anxious dysfunction.

Methods: Two-hundred and eighty-two individuals (52 healthy participants; 230 participants with depression and/or anxiety-related problems) from the Tulsa 1000 study, an ongoing, naturalistic longitudinal study based on a dimensional psychopathological framework, completed a Pavlovian fear learning task during functional magnetic resonance imaging. Linear mixed-effects analyses examined condition-by-time effects on brain activation (CS+, CS- across familiarization, conditioning, and extinction trials). A data-driven latent profile analysis (LPA) examined distinct patterns of behavioral and neural responses to threat across fear conditioning and extinction, while logistic regression analyses evaluated cognitive-affective predictors of latent profiles.

Results: Whole-brain analyses revealed a condition-by-time interaction in the anterior insula, postcentral gyrus, superior temporal gyrus, middle frontal gyrus, and cerebellum but not amygdala. The LPA identified distinct latent profiles across subjective and neural levels of measurement. Anterior insula profiles were characterized by marginal differences in age and state anxiety.

Conclusions: Our findings demonstrate that human fear learning recruits a distributed network of regions involved in interoceptive, cognitive, motivational, and psychomotor processes. Data-driven analyses identified distinct profiles of subjective and neural responses during fear learning that transcended clinical diagnoses, but no robust relationships to demographic or cognitive-affective variable were identified.

Trial registration: ClinicalTrials.gov NCT02450240.

Fig. 1

Fear conditioning / extinction paradigm. (a) During the task, participants viewed two neutral, non-social, abstract images, one of which was paired with a loud scream. The task consisted of three consecutive phases: familiarization, conditioning, and extinction. (b) Following each run, participants rated their levels of anxiety, arousal, and image valence. Images were counterbalanced across participants. Trials were presented in a fixed, pseudo-randomized order. NS = neutral stimulus; CS+_paired = conditioned stimulus that was paired with the scream, paired trial; CS+_unpaired = conditioned stimulus that was paired with the scream, but not in this trial); US = unconditioned stimulus.

Fig. 2

Task ratings and activation network for condition (CS+, CS-) by time (Familiarization [R1], Early Conditioning [R2], Late Conditioning [R3], and Extinction [R4; split in two equal timepoints for fMRI data]) linear mixed effect model. The activation maps are projected on the MNI152 standard-space T1-weighted average structural template. Left is left.

Fig. 3

Results of the latent profile analysis on behavioral and neural responses of interest to the conditioned stimulus (CS+). Lines represent distinct response profiles for models with optimal significant number of components. Behavioral runs include Familiarization (r1), Early Conditioning (r2), Late Conditioning (r3), and Extinction (r4). FMRI timepoints include Familiarization (t1), Early Conditioning (t2), Late Conditioning (t3), and Extinction (early [t4e] and late [t4l]). The activation maps for the whole brain analysis and Brainnetome atlas defined regions of interests are projected on the MNI152 standard-space T1-weighted average structural template. Left is left. aMCC, anterior midcingulate cortex; MFG, medial frontal gyrus; rHIPP, rostral hippocampus; superior temporal gyrus, (STG); vmPFC, ventromedial prefrontal cortex.