Modulation of fear extinction by stress, stress hormones and estradiol: a review

Fear acquisition and extinction are valid models for the etiology and treatment of anxiety, trauma- and stressor-related disorders. These disorders are assumed to involve aversive learning under acute and/or chronic stress. Importantly, fear conditioning and stress share common neuronal circuits. The stress response involves multiple changes interacting in a time-dependent manner: (a) the fast first-wave stress response [with central actions of noradrenaline, dopamine, serotonin, corticotropin-releasing hormone (CRH), plus increased sympathetic tone and peripheral catecholamine release] and (b) the second-wave stress response [with peripheral release of glucocorticoids (GCs) after activation of the hypothalamus-pituitary-adrenocortical (HPA) axis]. Control of fear during extinction is also sensitive to these stress-response mediators. In the present review, we will thus examine current animal and human data, addressing the role of stress and single stress-response mediators for successful acquisition, consolidation and recall of fear extinction. We report studies using pharmacological manipulations targeting a number of stress-related neurotransmitters and neuromodulators [monoamines, opioids, endocannabinoids (eCBs), neuropeptide Y, oxytocin, GCs] and behavioral stress induction. As anxiety, trauma- and stressor-related disorders are more common in women, recent research focuses on female sex hormones and identifies a potential role for estradiol in fear extinction. We will thus summarize animal and human data on the role of estradiol and explore possible interactions with stress or stress-response mediators in extinction. This also aims at identifying time-windows of enhanced (or reduced) sensitivity for fear extinction, and thus also for successful exposure therapy

Facial Emotion Recognition and Emotional Memory From the Ovarian-Hormone Perspective: A Systematic Review

Background: We review original papers on ovarian-hormone status in two areas of emotional processing: facial emotion recognition and emotional memory. Ovarian-hormone status is operationalized by the levels of the steroid sex hormones 17β-estradiol (E2) and progesterone (P4), fluctuating over the natural menstrual cycle and suppressed under oral contraceptive (OCs) use. We extend previous reviews addressing single areas of emotional processing. Moreover, we systematically examine the role of stimulus features such as emotion type or stimulus valence and aim at elucidating factors that reconcile the inconsistent results. Methods: We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and included papers published until September 2020 indexed in PubMed and Web of Science databases. Search terms were MeSH terms (emotional OR emotion) AND (X) AND (estrogen OR progesterone OR menstrual cycle OR oral contraceptives) with (X) representing our separately searched areas, resulting in (processing OR recognition OR empathy), and (memory OR recall). To be included, articles had to (1) be written and published in English, (2) examine healthy, non-pregnant adult women in their reproductive age, and (3) measure or at least estimate levels of E2 and P4. In PubMed, the search was (4) limited to humans and (5) to the search term present in the title or abstract. Results: Features of the provided stimulus material (emotion type and/or valence) constitute a relevant influence that interacts with E2- and P4-related ovarian-hormone status. For instance, recognition of basic emotions appears to be more related to P4- than E2-levels. Quite consistent, OC intake (vs. natural menstrual cycling) was accompanied by impaired recognition accuracy of basic and also complex emotions, although not in a recent large-sample study assessing complex emotions. Memory recall of negative content was mainly enhanced by P4, especially after having been stressed. Discussion and Conclusion: We document the methodological diversity in the field, presumably contributing to the heterogeneity of results. More studies explicitly contrasting the early follicular phase, mid-cycle phase, mid-luteal, and OC intake while standardizing tasks are needed. Research would take advantage of using within-subject designs and accounting for the recognition of complex emotions

Effects of phase synchronization and frequency specificity in the encoding of conditioned fear–a web-based fear conditioning study

Oscillatory synchronization in the theta-frequency band was found to play a causal role in binding information of different modalities in declarative memory. Moreover, there is first evidence from a laboratory study that theta-synchronized (vs. asynchronized) multimodal input in a classical fear conditioning paradigm resulted in better discrimination of a threat-associated stimulus when compared to perceptually similar stimuli never associated with the aversive unconditioned stimulus (US). Effects manifested in affective ratings and ratings of contingency knowledge. However, theta-specificity was not addressed so far. Thus, in the present pre-registered web-based fear conditioning study, we compared synchronized (vs. asynchronized) input in a theta-frequency band vs. the same synchronization manipulation in a delta frequency. Based on our previous laboratory design, five visual gratings of different orientations (25°, 35°, 45°, 55°, 65°) served as conditioned stimuli (CS) with only one (CS+) paired with the auditory aversive US. Both CS and US were luminance or amplitude modulated, respectively, in a theta (4 Hz) or delta (1.7 Hz) frequency. In both frequencies, CS-US pairings were presented either in-phase (0° phase lag) or out-of-phase (90°, 180°, 270°), resulting in four independent groups (each group N = 40). Phase synchronization augmented the discrimination of CSs in CS-US contingency knowledge but did not affect valence and arousal ratings. Interestingly, this effect occurred independent of frequency. In sum, the current study proves the ability to successfully conduct complex generalization fear conditioning in an online setting. Based on this prerequisite, our data supports a causal role of phase synchronization in the declarative CS-US associations for low frequencies rather than in the specific theta-frequency band

Effects of phase synchronization and frequency specificity in the encoding of fear - an online study

First human studies suggest a causal role of theta-phase synchronization for declarative episodic learning and memory. In a recent laboratory study, we provided evidence for corresponding effects in fear conditioning in humans. In a fear generalization procedure, we presented visual Gabor gratings of different orientations as the conditioned stimuli (CSs) and aversive noise as unconditioned stimulus (US). During acquisition, only one grating was paired with the US (= CS+), while the 4 perceptually similar gratings were not paired (CS-). Luminance of all CS and amplitude of the US were modulated at 4 Hz. In two independent groups, CS+ and US were either presented theta-phase synchronized (0° phase lag) or asynchronized (90°, 180°, 270° phase lag). We found an augmented discrimination of the paired CS+ vs. CS- gratings in the synchronized condition covering affective ratings of valence and arousal as well as CS-US contingency knowledge (US-expectancy ratings). In the current study we move from a laboratory setting to an online context. By applying the same paradigm, we will not only address the effect of synchronization in the theta-range, but also use in-phase vs. out-of-phase stimulation in a slower delta-frequency band (1.7 Hz). We aim to replicate the effects in the theta-band in an online setting and confirm the frequency-specificity of phase-synchronization

Visuocortical tuning to a threat-related feature persists after extinction and consolidation of conditioned fear

Neurons in the visual cortex sharpen their orientation tuning as humans learn aversive contingencies. A stimulus orientation (CS+) that reliably predicts an aversive noise (unconditioned stimulus: US) is selectively enhanced in lower-tier visual cortex, while similar unpaired orientations (CS−) are inhibited. Here, we examine in male volunteers how sharpened visual processing is affected by fear extinction learning (where no US is presented), and how fear and extinction memory undergo consolidation one day after the original learning episode. Using steady-state visually evoked potentials from electroencephalography in a fear generalization task, we found that extinction learning prompted rapid changes in orientation tuning: Both conditioned visuocortical and skin conductance responses to the CS+ were strongly reduced. Next-day re-testing (delayed recall) revealed a brief but precise return-of-tuning to the CS+ in visual cortex accompanied by a brief, more generalized return-of-fear in skin conductance. Explorative analyses also showed persistent tuning to the threat cue in higher visual areas, 24 h after successful extinction, outlasting peripheral responding. Together, experience-based changes in the sensitivity of visual neurons show response patterns consistent with memory consolidation and spontaneous recovery, the hallmarks of long-term neural plasticity

You See What You Smell: Preferential Processing of Chemosensory Satiety Cues and Its Impact on Body Shape Perception

The current study examines neural responses to satiety- and fasting-related volatiles and their effect on the processing of body shapes. Axillary sweat was sampled with cotton pads from 10 individuals after 12 h of fasting, and after having consumed a standard breakfast. Pure cotton pads served as the control. The chemosensory stimuli were presented to 20 participants (via a constant-flow olfactometer) exclusively, and additionally as context to images of overweight and underweight avatars. EEG was recorded (61 electrodes), and chemosensory (CSERPs; P1, N1, P2, P3) and visual event-related potentials (VERPs; N1, P2, P3a, P3b) were analyzed. The amplitudes of all positive CSERP components differed more strongly from cotton in response to chemosensory satiety cues as compared to fasting cues (P1: p = 0.023, P2: p = 0.083, P3: p = 0.031), paralleled by activity within the middle frontal and temporal gyrus. Overweight compared to underweight body shapes tended to elicit larger VERP P2 amplitudes (p = 0.068), and chemosensory satiety cues amplified the VERP amplitudes in response to any body shape (P2, P3a, P3b; all ps ≤ 0.017) as compared to the cotton control. The results indicate that chemosensory satiety cues transmit complex social information, overriding the processing of analogous visual input