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.

Oscillatory and non-oscillatory brain activity reflects fear expression in an immediate and delayed fear extinction task.

Fear extinction is pivotal for inhibiting fear responding to former threat-predictive stimuli. In rodents, short intervals between fear acquisition and extinction impair extinction recall compared to long intervals. This is called Immediate Extinction Deficit (IED). Importantly, human studies of the IED are sparse and its neurophysiological correlates have not been examined in humans. We, therefore, investigated the IED by recording electroencephalography (EEG), skin conductance responses (SCRs), an electrocardiogram (ECG), and subjective ratings of valence and arousal. Forty male participants were randomly assigned to extinction learning either 10 min after fear acquisition (immediate extinction) or 24 h afterward (delayed extinction). Fear and extinction recall were assessed 24 h after extinction learning. We observed evidence for an IED in SCR responses, but not in the ECG, subjective ratings, or in any assessed neurophysiological marker of fear expression. Irrespective of extinction timing (immediate vs. delayed), fear conditioning caused a tilt of the non-oscillatory background spectrum with decreased low-frequency power (<30 Hz) for threat-predictive stimuli. When controlling for this tilt, we observed a suppression of theta and alpha oscillations to threat-predictive stimuli, especially pronounced during fear acquisition. In sum, our data show that delayed extinction might be partially advantageous over immediate extinction in reducing sympathetic arousal (as assessed via SCR) to former threat-predictive stimuli. However, this effect was limited to SCR responses since all other fear measures were not affected by extinction timing. Additionally, we demonstrate that oscillatory and non-oscillatory activity is sensitive to fear conditioning, which has important implications for fear conditioning studies examining neural oscillations.

Role of noradrenergic arousal for fear extinction processes in rodents and humans.

Fear extinction is a learning mechanism that is pivotal for the inhibition of fear responses towards cues or contexts that no longer predict the occurrence of a threat. Failure of fear extinction leads to fear expression under safe conditions and is regarded to be a cardinal characteristic of many anxiety-related disorders and posttraumatic stress disorder. Importantly, the neurotransmitter noradrenaline was shown to be a potent modulator of fear extinction. Rodent studies demonstrated that excessive noradrenaline transmission after acute stress opens a time window of vulnerability, in which fear extinction learning results in attenuated long-term extinction success. In contrast, when excessive noradrenergic transmission subsides, well-coordinated noradrenaline transmission is necessary for the formation of a long-lasting extinction memory. In addition, emerging evidence suggests that the neuropeptide corticotropin releasing hormone (CRF), which strongly regulates noradrenaline transmission under conditions of acute stress, also impedes long-term extinction success. Recent rodent work - using sophisticated methods - provides evidence for a hypothetical mechanistic framework of how noradrenaline and CRF dynamically orchestrate the neural fear and extinction circuitry to attenuate or to improve fear extinction and extinction recall. Accordingly, we review the evidence from rodent studies linking noradrenaline and CRF to fear extinction learning and recall and derive the hypothetical mechanistic framework of how different levels of noradrenaline and CRF may create a time window of vulnerability which impedes successful long-term fear extinction. We also address evidence from human studies linking noradrenaline and fear extinction success. Moreover, we accumulate emerging approaches to non-invasively measure and manipulate the noradrenergic system in healthy humans. Finally, we emphasize the importance of future studies to account for sex (hormone) differences when examining the interaction between fear extinction, noradrenaline, and CRF. To conclude, NA's effects on fear extinction recall strongly depend on the arousal levels at the onset of fear extinction learning. Our review aimed at compiling the available (mainly rodent) data in a neurobiological framework, suited to derive testable hypotheses for future work in humans.

Phase-Synchronized Stimulus Presentation Augments Contingency Knowledge and Affective Evaluation in a Fear-Conditioning Task.

Memory often combines information from different sensory modalities. Animal studies show that synchronized neuronal activity in the theta band (4-8 Hz) binds multimodal associations. Studies with human participants have likewise established that theta-phase synchronization augments the formation of declarative video-tone pair memories. Another form of associative learning, classical fear conditioning, models nondeclarative, emotional memory with distinct neuronal mechanisms. Typical fear-conditioning tasks pair a conditioned stimulus (CS) in one modality with an aversive unconditioned stimulus (US) in another. The present study examines the effects of CS-US synchronization in the theta band on fear memory formation in humans. In a fear generalization procedure, we paired one of five visual gratings of varying orientation (CS) with an aversive auditory US. We modulated the luminance of the CS and the volume of the US at a rate of 4 Hz. To manipulate the synchrony between visual and auditory input during fear acquisition, one group (N = 20) received synchronous CS-US pairing, whereas the control group (N = 20) received the CS-US pairs out of phase. Phase synchronization improved CS-US contingency knowledge and facilitated CS discrimination in terms of rated valence and arousal, resulting in narrower generalization across the CS gratings compared with the out-of-phase group. In contrast, synchronization did not amplify conditioned responding in physiological arousal (skin conductance) and visuocortical engagement (steady-state visually evoked potentials) during acquisition, although both measures demonstrated tuning toward the CS+ Together, these data support a causal role of theta-phase synchronization in affective evaluation and contingency report during fear acquisition.

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.

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 17ß-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.

Sex-hormone status and emotional processing in healthy women.

Fluctuations of sex hormones across the menstrual cycle allow investigating the role of 17-ß estradiol and progesterone in emotional processing. We examined emotional memory, empathy-related measures, as well as mimic and skin-conductance responses to affective stimuli in 72 women either in the mid-cycle (MC-group: moderate to high estradiol, low progesterone), the later cycle (LC-group: high progesterone, moderate estradiol), or during oral contraceptive use (OC-group: low endogenous ovarian-hormone levels). In the first session, affective pictures were presented (memory encoding) while recording mimic and skin-conductance responses. Additionally, participants were exposed to a post-encoding stressor (cold pressor test). After 24 h, we tested surprise recall as well as empathy-related performance. Emotional memory was not affected by the hormone-status group, stressor, or salivary hormone levels. For the cognitive empathy-related measure, hormone status interacted with the protagonist gender. Women in the LC- and OC-groups identified emotions more accurately if depicted by female protagonists, yet the MC-group identified emotions depicted by men and women equally well. Correspondingly, the number of correctly identified emotions from male protagonists correlated positively with estradiol levels. In the affective empathy-related ratings, the OC-group showed a negativity bias, rating negative (vs. positive) emotions higher, although not associated with hormone levels. Mimic responses were not modulated by hormone-status group or related to hormone levels. Skin-conductance responses to negative pictures were heightened in the LC-group and correlated positively with progesterone levels. These data suggest a differential impact of female sex hormones on emotional processing, i.e., empathy-related performance and affective sympathetic reactivity, but not in emotional memory or affective mimic reactivity.

Prefrontal Theta Oscillations Are Modulated by Estradiol Status During Fear Recall and Extinction Recall.

BACKGROUND: Emerging human studies demonstrate that theta oscillations in the dorsal anterior cingulate cortex are enhanced during fear recall (enhanced fear expression) and reduced during successful extinction recall (reduced fear expression). Although evidence suggests sex differences in fear recall and extinction recall, there are currently no human studies examining the oscillatory foundations of these memory processes separately in men and women. METHODS: Because previous studies suggest that estradiol partially mediates these sex differences, we examined 20 men (low estradiol and low progesterone), 20 women using oral contraceptives (low estradiol and low progesterone), and 20 free-cycling women during midcycle (high estradiol and low progesterone). We used a fear-conditioning procedure, allowing us to separately assess fear recall and extinction recall 24 hours after fear and extinction learning. Skin conductance responses and electroencephalography were recorded during fear recall and extinction recall, and prefrontal oscillations were source localized. RESULTS: We found elevated fear expression during fear recall and impaired extinction recall, as indicated by increased peripheral arousal (skin conductance responses) and fronto-central theta oscillations, source localized in the dorsal anterior cingulate cortex and dorsomedial prefrontal cortex. Importantly, peripheral arousal and dorsal anterior cingulate cortex theta oscillations were stronger in men and women on oral contraceptives than in women from the midcycle group. CONCLUSIONS: Our data show that neural oscillatory and peripheral correlates of heightened fear expression during fear recall and (impaired) extinction recall do not simply differ between sexes but depend on hormonal fluctuations within women.

The role of olfaction and sex-hormone status in empathy-related measures.

Reports of a female advantage in empathy-related measures suggest a role for sex hormones, although the data are inconsistent. Studies also report similar sex differences in human olfactory perception. In rodents, olfaction is involved in detecting and integrating socially relevant information and is modulated by the brain actions of estrogens. We hypothesized that olfaction may untangle the mixed evidence on the relationship between sex hormones and empathy-related measures (cognitive and affective) in humans. To test this, we examined 60 healthy participants in three sex-hormone-status groups: free-cycling women tested in cycle phases with higher 17-ß estradiol and progesterone, oral-contraceptive users (low estradiol and progesterone), and men. We assessed empathy-related measures, facial mimicry (from zygomaticus and corrugator muscle activity), and odor discrimination ability. In the empathy-related measures and facial mimicry, we did not find overall group effects or meaningful associations with salivary levels of estradiol, progesterone, or testosterone. Free-cycling women only outperformed men in the recognition of emotions from pictures of the eye region, but sex hormones were unrelated to emotion recognition performance. Oral contraceptive users showed higher scores in the affective empathy-related measure when viewing negative emotions, with no relation to hormone levels. Free-cycling women exhibited the strongest facial mimicry (viewing female, but not male protagonists), positively associated with progesterone. Finally, the groups differed in odor discrimination, with free-cycling women outperforming men. However, odor discrimination ability and empathy-related performance were not correlated. Our results support a role of sex hormones in odor perception and in empathy-related measures, to a certain extent. However, no common underlying mechanism was found.

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.

Women with high estradiol status are protected against declarative memory impairment by pre-learning stress.

Stress is a potent modulator of learning and memory. Factors contributing to whether stress aids or impairs memory are timing of the stressor, memory stage, form of memory studied, and sex of the subjects. The female sex hormone 17-beta-estradiol (E2) has widespread effects in the brain and affects hippocampus-dependent memory in animals. In humans, the interaction between stress effects and E2 has not been widely studied. We report data from a healthy sample divided into 3 hormone-status groups: free-cycling women in the early follicular phase (EF: low E2, low progesterone [P4]), or during midcycle (MC: high E2, low P4), and men. Participants within each hormone-status group were randomly assigned to a psychosocial stressor or a control treatment 37 min before encoding a short story of neutral content. We found a Hormone status × Stress × Time (immediate, 35-min, 24-h delayed recall) interaction. Irrespective of time, hormone status mattered only after stress treatment: stressed early follicular women had poorer recall compared to stressed men and midcycle women. Only in the early follicular group, recall was negatively correlated with increases in salivary cortisol, but not with blood levels of E2 and P4. To uncover changes beyond immediate recall, we computed the individual percent change relative to immediate recall and repeated the analysis for these adjusted 35-min and 24-h data. Despite the lack of a stress effect in raw data, memory in stressed men was more stable over time (35-min and 24-h delay) than in unstressed men. In contrast, stressed EF-women (vs. control) recalled less at the 35-min and (as a trend) at the 24-h delay. Stressed MC-women (vs. control) showed less recall only at the 35-min delay while compensating this stress effect after a 24-h consolidation interval. Overall, results suggest that women in high-E2 midcycle phase could be less vulnerable to effects of pre-learning stress on declarative memory encoding and consolidation.

Overshadowing and latent inhibition in nausea-based context conditioning in humans: Theoretical and practical implications.

Volunteer participants underwent nausea-inducing body rotation in a distinctive context, and the acquired ability of the contextual cues to evoke nausea was subsequently assessed by a symptom rating scale. One group received prior exposure to the context (a latent inhibition procedure); a second consumed a novel flavour prior to rotation (an overshadowing procedure); a third group experienced both procedures; and a control group received neither. When tested in the context in the absence of rotation, all groups reported an increase in nausea-related symptoms at the time when rotation had previously occurred, an outcome consistent with the occurrence of conditioned nausea. The magnitude of this increase did not differ across the groups, but the overall level of responsiveness (the degree to which nausea-related symptoms were reported) was enhanced in the latent inhibition and reduced in the overshadowing condition. Cortisol levels showed the same pattern. The implications of these findings for the proposal that overshadowing and latent inhibition procedures might be used to control the development of anticipatory nausea in patients undergoing chemotherapy is considered.

Cold pressor test improves fear extinction in healthy men.

Fear extinction is an important paradigm to study the neural basis of anxiety and trauma- and stressor-related disorders and for modeling features of extinction learning and exposure-based psychotherapy. To date the effects of acute stress on extinction learning in humans are not well understood. Models of stress effects on emotional memory suggest that learning during the so-called first wave of the stress response will be enhanced. The first wave includes (among others) increases of noradrenaline in the brain and increased sympathetic tone, adrenaline and noradrenaline in the periphery while the second wave includes genomic glucocorticoid-actions. The cold pressor test (CPT) is a valid way to induce the first wave of the stress response. We thus hypothesized that the CPT will facilitate extinction. In a 2-day fear-conditioning procedure with 40 healthy men, using differential skin conductance responses as a measure of conditioned fear, we placed the CPT versus a control procedure prior to extinction training on Day 1. We tested for extinction learning on Day 1 and extinction retrieval on Day 2. During extinction training (Day 1) only the CPT-group showed a significant reduction in differential responding. This was still evident on Day 2, where the CPT group had less differential responding during early trials (retrieval) and a higher extinction retention index. This is the first human study to show that a simple procedure, triggering the first-wave stress response--the CPT--can effectively enhance fear extinction in humans.

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.

Stress exposure prior to fear acquisition interacts with estradiol status to alter recall of fear extinction in humans.

Classical fear acquisition and extinction are important models for the etiology and treatment of anxiety disorders such as posttraumatic stress disorder (PTSD). Women are at a higher risk for PTSD than men. Levels of circulating 17-ß estradiol (E2) in women have been linked to deficits in fear extinction and extinction recall. In PTSD, fear learning coincides with acute traumatic stress. However, little is known about the possible interaction between stress exposure and hormone status on fear acquisition and extinction learning. In a 2-day, 2×3 between-subjects design with healthy participants, we examined the effects of stress (psychosocial stressor vs. control, placed 45 min prior to conditioning) and natural E2-status on differential fear conditioning, covering fear acquisition, immediate extinction (Day 1), and 24h-delayed extinction recall (Day 2). To operationalize E2-status, we compared women in the early follicular phase (EF) of their menstrual cycle (low E2, low progesterone plasma levels), women in the midcycle phase (MC, high E2, low progesterone), and men. Conditioning was indicated by differential skin conductance responses. We found an interaction between stress exposure and natural E2-status in women only: In MC-women, extinction recall on Day 2 (24h after initial extinction training) was better when fear acquisition had been preceded by stress. In EF-women, the inverse was true. We show that extinction recall of conditioned fear acquired after stress depends on estrogen status in women. Therefore, extinction-based exposure therapy in free-cycling female anxiety patients should take cycle status into account.

Effects of overshadowing on conditioned and unconditioned nausea in a rotation paradigm with humans.

We examine whether overshadowing by salient stimuli is effective in reducing the ability of a certain environment (the putative conditioned stimulus) to evoke conditioned nausea in healthy humans that experience nausea-evoking rotation (as the unconditioned stimulus, US) in that environment. Twenty-four rotation-susceptible subjects (12 males, 12 females) were randomly assigned to receive either overshadowing by salient tasting beverages (OS+), or a control treatment (a familiar beverage, water; OS-) prior to rotation on three consecutive days (acquisition). To control for taste experiences, the alternative beverage was consumed 12 h later in the home environment (OS+: water, OS-: salient beverage). At Day 4 (test), all subjects drank the familiar beverage (water) prior to rotation (US). Rotation was standardized as 2 × 1-min rotation/day. Nausea was determined by a 7-item symptom scale measuring symptom number (SN) prior to (anticipatory), immediately after, and 15 and 30 min after rotation and by the Nausea Profile (NP) questionnaire immediately after rotation. Cortisol and tumour necrosis factor (TNF)-α in saliva were sampled at the same time-points. SN and cortisol were also measured at home. Overshadowing reduced anticipatory (conditioned) SN. Post-rotation nausea (i.e. the unconditioned response) measured by the NP decreased within the OS+ group only. Anticipatory cortisol and TNF-α were not affected by overshadowing. Treatment × gender interactions manifested for post-rotation cortisol and TNF-α. Groups did not differ in SN and cortisol at home. Overshadowing is effective in reducing symptoms of anticipatory nausea and rotation-induced unconditioned nausea; its effect on endocrine and immunological parameters is gender specific. Its application in alleviation of anticipatory nausea in cancer patients is considered.

Differential impact of the first and second wave of a stress response on subsequent fear conditioning in healthy men.

Stress is a process of multiple neuroendocrine changes over time. We examined effects of the first-wave and second-wave stress response on acquisition and immediate extinction of differential fear conditioning, assessed by skin conductance responses. In Experiment 1, we placed acquisition either close to the (second-wave) salivary cortisol peak, induced by a psychosocial stressor (experimental group, EG), or after non-stressful pretreatment (control group, CG). Contrary to predictions, groups did not differ in differential responding. In the EG only, mean differential responding was negatively correlated with cortisol increases. In Experiment 2, we placed conditioning near the first-wave stress response, induced by a cold pressor test (CPT), or after a warm-water condition (CG). CPT-stress increased extinction resistance. Moreover, acquisition performance after CPT was positively correlated with first-wave blood pressure increases. Data suggest that mediators of the first-wave stress response enhance fear maintenance whereas second-wave cortisol responsivity to stress might attenuate fear learning.

Unconditioned and conditioned effects of intravenous insulin and glucose on heart rate variability in healthy men.

We examined whether an injection of intravenous insulin and intravenous glucose would affect frequency-domain measures of heart rate variability (HRV), i.e., the high-frequency (HF-) band and the ratio of the low frequency (LF-) to the HF-band in healthy humans. Using a classical conditioning protocol, we also assessed whether the measures of HRV are subject to classical conditioning. Thirty healthy men were divided into three groups, given a conditioned stimulus (CS) and an intravenous injection of either insulin (0.05IU/kg) in Group 1, glucose (15%, 0.5g/kg) in Group 2, or placebo (physiological saline [0.9%]) in Group 3 during the 4-day acquisition phase. All subjects were given an olfactory CS (rosewood-peppermint smell) and placebo injection on day 5 (test). Due to their high inter-individual variability, HF and LF/HF-ratio were analysed by intragroup comparisons, using a pre-injection baseline interval (min -15 to -5), and three functional post-injection intervals: a) the interval to the maximum insulin level, i. e. insulin peak (min 0-5) in Groups 1 and 2, b) the interval to the maximum of insulin-induced hypoglycaemia (min 20-25) in Group 1, and c) the end of the session (min 70-75). On days 1 to 4, we found significant increases of the HF-band from baseline to interval min 0-5 in Group 1, and an even more pronounced increase in the glucose-treated Group 2. At the test (Day 5), both experimental groups responded with an HF-increase in the interval of the former insulin peak, and also at the other measurement intervals, reflecting some general increase of vagal activity remaining as a conditioned response. On days 1 to 4, the HF-band was positively correlated with the change of peripheral insulin levels in Group 1, reaching statistical significance on days 3 and 4. This pattern only emerged in tendency on Day 4 in Group 2. In conclusion, insulin triggers an increase in parasympathetic tone at maximum hyperinsulinaemia, and our data support the notion that this response pattern can become classically conditioned.

Endocrine and psychological stress responses in a simulated emergency situation.

BACKGROUND: Several studies have assessed the effects of training using patient simulation systems on medical skills. However, endocrine and psychological stress responses in a patient simulation situation and the relationship between stress reactivity and medical performance have been studied rarely, so far. METHODS: Medical students (18 males and 16 females) who had completed at least two months anaesthesiology training participated in the study. In a counterbalanced cross-over design they were subjected to three conditions: rest, laboratory stress (LS; public speaking), and simulated emergency situation (SIM; myocardial ischemia and ventricular fibrillation). Salivary cortisol and psychological responses (visual analogue scales, VAS) were assessed every 15 min from 15 min prior to until 60 min after intervention. Differences between stress and rest conditions were analysed. Medical performance was assessed according to the European Resuscitation Council's Guidelines for Resuscitation. RESULTS: As compared to rest, cortisol increased significantly in both stress conditions with different time courses in LS and SIM. Psychological responses in SIM exceeded those in LS. Cortisol increase in LS (r(s)=.486; p=.019) but not in SIM (r(s)=.106; p=.631) correlated significantly with medical performance. DISCUSSION: A simulated emergency situation is a profound stressor. The positive relationship between endocrine stress responsiveness in a standard laboratory situation and medical performance in a simulated emergency situation indicates that high stress responsiveness might be a predictor of good performance. At the same time the high stress response might counteract educational efforts associated with training using high-fidelity patient simulation.

Role of classical conditioning in learning gastrointestinal symptoms.

Nausea and/or vomiting are aversive gastrointestinal (GI) symptoms. Nausea and vomiting manifest unconditionally after a nauseogenic experience. However, there is correlative, quasiexperimental and experimental evidence that nausea and vomiting can also be learned via classical (Pavlovian) conditioning and might occur in anticipation of the nauseogenic event. Classical conditioning of nausea can develop with chemotherapy in cancer patients. Initially, nausea and vomiting occur during and after the administration of cytotoxic drugs (post-treatment nausea and vomiting) as unconditioned responses (UR). In addition, 20%-30% of cancer patients receiving chemotherapy report these side effects, despite antiemetic medication, when being re-exposed to the stimuli that usually signal the chemotherapy session and its drug infusion. These symptoms are called anticipatory nausea (AN) and/or anticipatory vomiting (ANV) and are explained by classical conditioning. Moreover, there is recent evidence for the assumption that post-chemotherapy nausea is at least partly influenced by learning. After summarizing the relevant assumptions of the conditioning model, revealing that a context can become a conditioned stimulus (CS), the present paper summarizes data that nausea and/or vomiting is acquired by classical conditioning and, consequently, may be alleviated by conditioning techniques. Our own research has focussed on two aspects and is emphasized here. First, a conditioned nausea model was established in healthy humans using body rotation as the nausea-inducing treatment. The validity of this motion-sickness model to examine conditioning mechanisms in the acquisition and alleviation of conditioned nausea and associated endocrine and immunological responses is summarized. Results from the rotation-induced motion sickness model showed that gender is an important moderator variable to be considered in further studies. This paper concludes with a review of the application of the demonstrated conditioning principles as interventions to ameliorate distressing AN/ANV in cancer patients undergoing chemotherapy, which is the second focus of our work.