Person:

Marin, Marie-France

Background: Findings about sex differences in the field of fear conditioning and fear extinction have been mixed. At the psychophysiological level, sex differences emerge only when taking estradiol levels of women into consideration. This suggests that this hormone may also influence sex differences with regards to activations of brain regions involved in fear conditioning and its extinction. Importantly, the neurobiological correlates associated with the use of hormonal oral contraceptives in women have not been fully contrasted against men and against naturally cycling women with different levels of estradiol. In this study, we begin to fill these scientific gaps. Methods: We recruited 37 healthy men and 48 healthy women. Of these women, 16 were using oral contraceptives (OC) and 32 were naturally cycling. For these naturally cycling women, a median split was performed on their serum estradiol levels to create a high estradiol (HE) group (n = 16) and a low estradiol (LE) group (n = 16). All participants underwent a 2-day fear conditioning and extinction paradigm in a 3 T MR scanner. Using the 4 groups (men, HE women, LE women, and OC users) and controlling for age and coil type, one-way ANCOVAs were performed to look at significant activations within the nodes of the fear circuit. Using post-hoc analyses, beta-weights were extracted in brain regions showing significant effects in order to unveil the differences based on hormonal status (men, HE, LE, OC). Results: Significant main effect of hormonal status group was found across the different phases of the experiment and in different sub-regions of the insular and cingulate cortices, amygdala, hippocampus, and hypothalamus. During conditioning, extinction and recall, most of the observed differences suggested higher activations among HE women relative to men. During the unconditioned response, however, a different pattern was observed with men showing significantly higher brain activations. Conclusions: Our data further support the important contribution of estradiol levels in the activation of brain regions underlying fear learning and extinction. The results highlight the need to document gonadal hormonal levels, menstrual cycle phase as well as oral contraceptive use in women in order to avoid overlooking sex differences when investigating the neurobiology of emotional regulation.

Background: Neurobiological models of posttraumatic stress disorder (PTSD) implicate fear processing impairments in the maintenance of the disorder. Specific deficits in extinction recall, the retention of learned extinction, have been demonstrated. While deficient extinction recall, and the associated activation pattern of prefrontal and hippocampal regions, distinguishes individuals with PTSD from controls, research has not yet examined changes following treatment. We examined the behavioral and neural correlates of extinction recall before and after cognitive behavioral treatment of PTSD. Methods: Fifty-eight participants (30 with PTSD, 28 trauma-exposed matched controls) underwent a 2-day behavioral fear conditioning, extinction, and recall paradigm during functional magnetic resonance imaging (fMRI). The same procedures were repeated 10 weeks later, after PTSD patients had completed prolonged exposure treatment. We analyzed fMRI data from 32 subjects (16 PTSD; 16 controls) and skin conductance response (SCR) data from 33 subjects (16 PTSD; 17 controls). Neural activity during extinction recall, SCR, and PTSD symptoms were compared across groups and over time. Results: PTSD patients exhibited pre- to post-treatment reduction in rostral anterior cingulate cortex (rACC) activation during extinction recall, and increase in functional coherence between the rACC and the ventromedial prefrontal cortex (vmPFC) and subgenual anterior cingulate cortex (sgACC). Reduced PTSD symptom severity from pre- to post-treatment was significantly associated with reduced subgenual ACC and parahippocampal activation during this task. SCR during the extinction recall phase did not significantly change with treatment in the PTSD group, but change in SCR was associated with reduction in PTSD symptom severity. Conclusions: Prolonged exposure treatment appears to alter neural activation in PTSD patients during recall of fear extinction, and change in extinction recall (measured by SCR) is associated with symptom reduction. We discuss results in the context of neural systems involved in response to affective stimuli.