Effects of intranasal oxytocin on fear extinction learning

Abstract

Once a threat no longer exists, extinction of conditioned fear becomes adaptive in order to reduce allotted resources towards cues that no longer predict the threat. In anxiety and stress disorders, fear extinction learning may be affected. Animal findings suggest that the administration of oxytocin (OT) modulates extinction learning in a timepoint-dependent manner, facilitating extinction when administered prior to fear conditioning, but impairing it when administered prior to extinction learning. The aim of the present study was to examine if these findings translate into human research. Using a randomized, double-blind, placebo-controlled, 2-day fear conditioning and extinction learning design, behavioral (self-reported anxiety), physiological (skin conductance response), neuronal (task-based and resting-state functional magnetic resonance imaging), and hormonal (cortisol) data were collected from 124 naturally cycling (taking no hormonal contraceptives) healthy females. When administered prior to conditioning (Day 1), OT, similar to rodent findings, did not affect fear conditioning, but modulated the intrinsic functional connectivity of the anterior insula immediately after fear conditioning. In contrast to animal findings, OT impaired, not facilitated, extinction learning on the next day and increased anterior insula activity. When administered prior to extinction learning (day 2), OT increased the activity in the bilateral middle temporal gyrus, and similar to animal findings, reduced extinction learning. The current findings suggest that intranasal OT impedes fear extinction learning in humans regardless of the timepoint of administration, providing new insights and directions for future translational research and clinical applications.

Fig. 1. Schematic illustration of experimental procedure.

a Fear conditioning took place on day 1 and extinction learning on day 2 at the same time of the day. Self-reports, salivary, and blood samples were collected at multiple time points. b Participants received either intranasal placebo or oxytocin (OT) on day 1 as well as day 2, resulting in two groups on day 1 and four groups on day 2. c On day 1 (fear conditioning), a circle was presented for 5–8 s and co-terminated with a short (2 ms) electric stimulus in 12 out of 16 trials (CS+ paired) and without an electric stimulus in 4 other trials (CS+ unpaired). A triangle was presented 16 times, and it was never paired with an electric stimulus (CS−). On day 2 (fear extinction), CS− and CS+ unpaired trials were each presented 16 times. No electric stimulus was applied on day 2. CS+ (paired and unpaired) and CS− trials were randomly interleaved. The geometric shapes (circle or triangle) associated with CS− and CS+ were counterbalanced across subjects. CS conditioned stimulus, ITI inter-trial interval.

Fig. 2. Effects of intranasal oxytocin (OT) on fear conditioning.

a State anxiety levels of the placebo and OT groups were not significantly different at baseline or post-MRI. b Skin conductance responses (SCRs) were not significantly different across groups. c Cortisol concentrations in saliva were not significantly different between groups at baseline, pre-MRI, or post-MRI. These results suggest that intranasal OT did not modulate fear acquisition.

Fig. 3. Effects of intranasal oxytocin (OT) on fear memory consolidation following fear conditioning.

a Seed-to-voxel resting-state functional connectivity after fear conditioning revealed that in the OT compared to the placebo group the left anterior insula showed a stronger negative correlation with the left postcentral gyrus (blue bulb) as well as a stronger positive correlation with the right ventromedial prefrontal cortex (vmPFC) and the right superior frontal gyrus (red bulb). b Significant negative correlation between the anterior insula-postcentral gyrus connectivity and baseline cortisol levels on the next day prior to extinction learning. c Significant negative correlation between the anterior insula-postcentral gyrus connectivity and the baseline state anxiety on day 2 prior to extinction learning. The red line represents the fitted line and the gray areas are the confidence intervals at 95%.

Fig. 4. Effects of intranasal oxytocin (OT) on extinction learning.

a Compared to participants who received placebo on both days (PP), other groups who received OT on day 1 (OP), on day 2 (PO), or on both days (OO) showed a greater skin conductance response (SCR). b Salivary cortisol was elevated in the OP group compared to three other groups post-MRI. c Whole-brain analysis revealed that the BOLD activation for the CS+ versus CS− contrast was stronger in the left anterior insula of the OP compared to the PP group. d Whole-brain analysis showed a stronger differential BOLD signal (CS+ > CS−) in the bilateral middle temporal gyrus for the PO versus PP group. These results suggest that intranasal OT (regardless of being administered prior to fear conditioning or extinction learning) increases anxiety responses towards extinguished conditioned stimulus.