Extinction resistant changes in the human auditory association cortex following threat learning

Abstract

Research in humans has highlighted the importance of the amygdala for transient modulation of cortical areas for enhanced processing of emotional stimuli. However, non-human animal data has shown that amygdala dependent threat (fear) learning can also lead to long lasting changes in cortical sensitivity, persisting even after extinction of fear responses. The neural mechanisms of long-lasting traces of such conditioning in humans have not yet been explored. We used functional magnetic resonance imaging (fMRI) and assessed skin conductance responses (SCR) during threat acquisition, extinction learning and extinction retrieval. We provide evidence of lasting cortical plasticity in the human brain following threat extinction and show that enhanced blood oxygen level-dependent (BOLD) signal to the learned threat stimulus in the auditory association cortex is resistant to extinction. These findings point to a parallel avenue by which cortical processing of potentially dangerous stimuli can be long lasting, even when immediate threat and the associated amygdala modulation have subsided.

Keywords: Auditory fear conditioning; Fear conditioning; Fear extinction.

Fig. 1

Skin conductance response (SCR) during auditory threat learning. Square root transformed mean SCR to the CS+ (black bar) and CS− (white bar) averaged for all subjects (n = 16) across acquisition, day 1 and day 2 extinction. Data is divided into an early (19 trials of each stimulus) and late phase (19 trials of each stimulus) for each session. Asterisks represent a significant difference (P < 0.01) of CS+ vs. CS−, and during extinction between CS+ in early vs. late extinction.

Fig. 2

Amygdala and vmPFC BOLD signal during threat acquisition and extinction. (A) Left Amygdala activation. (B) Amygdala mean% BOLD signal changes to CS− and CS+ during acquisition, extinction day 1, extinction day 2. (C) vmPFC activation. (D) vmPFC mean% BOLD signal changes to CS− and CS+ during acquisition, extinction day 1 and extinction day 2. Asterisks represent significantly greater BOLD responses to the CS+ than the CS− for each phase, P < 0.01.

Fig. 3

Auditory thalamus (MGB) and Auditory Cortex BOLD signal during threat acquisition and extinction. (A) Auditory thalamus activation (circle). (B) Auditory thalamus mean% BOLD signal changes to CS− and CS+ during acquisition, extinction day 1, extinction day 2. (C) Primary auditory cortex (dashed circle) and auditory association (solid circle) cortex activation revealed by the CS+ and CS− against background noise contrast. (D) Primary auditory cortex mean% BOLD signal changes to CS+ and CS− during acquisition, extinction day 1, extinction day 2. (E) Auditory association cortex mean% BOLD signal changes to CS− and CS+ during acquisition, extinction day 1, extinction day 2. Asterisks represent significantly greater BOLD responses to the CS+ than the CS− for each phase, P < 0.01.

Fig. 4

Difference scores (CS+ minus CS−) for the final stage of extinction on day 2, showing sustained activation to the conditioned tone only in the Auditory Association Cortex, P < 0.01.