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The effects of sex and stress hormones on classical fear conditioning have been subject of recent experimental studies. A correlation approach between basal cortisol concentrations and neuronal activation in fear-related structures seems to be a promising alternative approach in order to foster our understanding of how cortisol influences emotional learning. In this functional magnetic resonance imaging study, participants with varying sex hormone status (20 men, 15 women taking oral contraceptives, 15 women tested in the luteal phase) underwent an instructed fear conditioning protocol with geometrical figures as conditioned stimuli and an electrical stimulation as unconditioned stimulus. Salivary cortisol concentrations were measured and afterwards correlated with fear conditioned brain responses. Results revealed a positive correlation between basal cortisol levels and differential activation in the amygdala in men and OC women only. These results suggest that elevated endogenous cortisol levels are associated with enhanced fear anticipation depending on current sex hormone availability.

Facilitated detection of threatening visual cues is thought to be adaptive. In theory, detection of threat cues should activate the amygdala independently from allocation of attention. However, previous studies using emotional facial expressions as well as phobic cues yielded contradictory results. We used fMRI to examine whether the allocation of attention to components of superimposed spider and bird displays modulates amygdala activation. Nineteen spider-phobic women were instructed to identify either a moving or a stationary animal in briefly presented double-exposure displays. Amygdala activation followed a dose-response relationship: Compared to congruent neutral displays (two birds), amygdala activation was most pronounced in response to congruent phobic displays (two spiders) and less but still significant in response to mixed displays (spider and bird) when attention was focused on the phobic component. When attention was focused on the neutral component, mixed displays did not result in significant amygdala activation. This was confirmed in a significant parametric graduation of the amygdala activation in the order of congruent phobic displays, mixed displays with attention focus on the spider, mixed displays with focus on the bird and congruent neutral displays. These results challenge the notion that amygdala activation in response to briefly presented phobic cues is independent from attention.

An important feature of the human defense system comprises fear learning, which stress hormones can crucially modulate. However, stress hormones might influence men and women differently, in part because of interactions with sex hormones. In women, distinct stages of the menstrual cycle or the intake of oral contraceptives (OC) affect sex hormone levels. In this study, we used a differential fear conditioning paradigm with electrical stimulation as unconditioned stimulus (UCS) following one neutral stimulus (conditioned stimulus, CS+), but not another (CS-).To investigate implicit fear learning, participants were distracted from detecting the contingencies between CS and UCS. To address interaction effects of sex and stress hormones, 32 men, 30 women in the early follicular phase of the menstrual cycle (FO), 30 women in the luteal phase (LU), and 30 OC women received either 30 mg cortisol or a placebo. In the contrast CS+ minus CS-, an interaction between cortisol administration and sex hormone status emerged in the anterior parahippocampal gyrus and the hippocampus. Cortisol reduced fear learning in men, FO, and LU women, but enhanced it in OC women. Additionally, cortisol attenuated differential amygdala activation in the entire group. These results demonstrate that OC usage substantially modifies cortisol effects on emotional learning in women, particularly in memory-related medial temporal lobe regions. Further, a high dose of cortisol reduces amygdala differentiation pointing to a lowered learning ability of the defense system under high cortisol concentrations, irrespective of current sex hormone availability.

In emotional learning tasks, sex differences, stress effects and an interaction of these two moderators have often been observed. The sex hormones estradiol (E2) and progesterone (P4) vary over the menstrual cycle. We tested groups with different sex hormone status: 39 men, 30 women in the luteal phase (LU, high E2+P4) and 29 women taking oral contraceptives (OC, low E2+P4). They received either 30 mg cortisol or placebo prior to instructed differential fear conditioning consisting of neutral conditioned stimuli (CS) and an electrical stimulation (unconditioned stimulus; UCS). One figure (CS+) was paired with the UCS, the other figure (CS-) never. During extinction, no electrical stimulation was administered. Regarding fear acquisition, results showed higher skin conductance and higher brain responses to the CS+ compared to the CS- in several structures that were not modulated by cortisol or sex hormones. However, OC women exhibited higher CS+/CS- differentiations than men and LU women in the amygdala, thalamus, anterior cingulate and ventromedial prefrontal cortex during extinction. The suppression of endogenous sex hormones by OC seems to alter neuronal correlates of extinction. The observation that extinction is influenced by the current sex hormone availability is relevant for future studies and might also be clinically important.

In an fMRI study, effects of contingency awareness on conditioned responses were assessed in three groups comprising 118 subjects. A differential fear-conditioning paradigm with visual conditioned stimuli, an electrical unconditioned stimulus and two distractors was applied. The instructed aware group was informed about the contingencies, whereas the distractors prevented contingency detection in the unaware group. The third group (learned aware) was not informed about the contingencies, but learned them despite the distractors. Main effects of contingency awareness on conditioned responses emerged in several brain structures. Post hoc tests revealed differential dorsal anterior cingulate, insula and ventral striatum responses in aware conditioning only, whereas the amygdala was activated independent of contingency awareness. Differential responses of the hippocampus were specifically observed in learned aware subjects, indicating a role in the development of contingency awareness. The orbitofrontal cortex showed varying response patterns: lateral structures showed higher responses in instructed aware than unaware subjects, the opposite was true for medial parts. Conditioned subjective and electrodermal responses emerged only in the two aware groups. These results confirm the independence of conditioned amygdala responses from contingency awareness and indicate specific neural circuits for different aspects of fear acquisition in unaware, learned aware and instructed aware subjects.

Fear conditioning is influenced by stress but opposing effects in males and females have often been reported. In a previous human functional magnetic resonance imaging (fMRI) study, we observed acute effects of the stress hormone cortisol on prefrontal structures. Men showed evidence for impaired fear conditioning after cortisol treatment, while the opposite pattern was found for women. In the current experiment, we tested whether similar sex-dependent effects would occur on the neural level if contingency awareness was prevented experimentally to investigate implicit learning processes. A differential fear conditioning experiment with transcutaneous electrical stimulation as unconditioned stimulus and geometric figures as conditioned stimuli (CS) was conducted. One figure was always paired (CS+), whereas the other (CS-) was never paired with the UCS. Thirty-nine (19 female) subjects participated in this fMRI study, receiving either placebo or 30 mg cortisol (hydrocortisone) before conditioning. Dependent variables were skin conductance responses (SCRs) and neural activity (BOLD signal). In line with prior findings in unaware participants, no differential learning could be observed for the SCRs. However, a sex x cortisol interaction was detected with a reduced mean response to the CS after cortisol treatment in men, while the opposite pattern was observed in women (enhanced mean SCR under cortisol). In the contrast CS+ minus CS-, neural activity showed a sex x cortisol interaction in the insula and further trends in the hippocampus and the thalamus. In these regions, cortisol reduced the CS+/CS- differentiation in men but enhanced it in women. In contrast to these sex specific effects, differential amygdala activation was found in the placebo group but not in the cortisol group, irrespective of sex. Further, differential neural activity in the amygdala and thalamus were positively correlated with the SCRs in the placebo group only. The present study in contingency unaware participants illustrates that cortisol has in some brain regions sex specific effects on neural correlates of emotional learning. These effects might translate into a different vulnerability of the two sexes for anxiety disorders.

The ability to detect and learn contingencies between fearful stimuli and their predictive cues is an important capacity to cope with the environment. Contingency awareness refers to the ability to verbalize the relationships between conditioned and unconditioned stimuli. Although there is a heated debate about the influence of contingency awareness on conditioned fear responses, neural correlates behind the formation process of contingency awareness have gained only little attention in human fear conditioning. Recent animal studies indicate that the ventral striatum (VS) could be involved in this process, but in human studies the VS is mostly associated with positive emotions. To examine this question, we reanalyzed four recently published classical fear conditioning studies (n = 117) with respect to the VS at three distinct levels of contingency awareness: subjects, who did not learn the contingencies (unaware), subjects, who learned the contingencies during the experiment (learned aware) and subjects, who were informed about the contingencies in advance (instructed aware). The results showed significantly increased activations in the left and right VS in learned aware compared to unaware subjects. Interestingly, this activation pattern was only found in learned but not in instructed aware subjects. We assume that the VS is not involved when contingency awareness does not develop during conditioning or when contingency awareness is unambiguously induced already prior to conditioning. VS involvement seems to be important for the transition from a contingency unaware to a contingency aware state. Implications for fear conditioning models as well as for the contingency awareness debate are discussed.

Theories of specific phobias consider classical conditioning as a central mechanism in the pathogenesis and maintenance of the disorder. Although the neuronal network underlying human fear conditioning is understood in considerable detail, no study to date has examined the neuronal correlates of fear conditioning directly in patients with specific phobias. Using functional magnet resonance imaging (fMRI) we investigated conditioned responses using phobia-relevant and non-phobia-relevant unconditioned stimuli in patients with specific phobias (n=15) and healthy controls (n=14) by means of a differential picture-picture conditioning paradigm: three neutral geometric figures (conditioned stimuli) were followed by either pictures of spiders, highly aversive scenes or household items (unconditioned stimuli), respectively. Enhanced activations within the fear network (medial prefrontal cortex, anterior cingulate cortex, amygdala, insula and thalamus) were observed in response to the phobia-related conditioned stimulus. Further, spider phobic subjects displayed higher amygdala activation in response to the phobia-related conditioned stimulus than to the non-phobia-related conditioned stimulus. Moreover, no differences between patients and healthy controls emerged regarding the non-phobia-related conditioned stimulus. The results imply that learned phobic fear is based on exaggerated responses in structures belonging to the fear network and emphasize the importance of the amygdala in the processing of phobic fear. Further, altered responding of the fear network in patients was only observed in response to the phobia-related conditioned stimulus but not to the non-phobia-related conditioned stimulus indicating no differences in general conditionability between patients with specific phobias and healthy controls.

INTRODUCTION: Learning processes like classical conditioning are involved in mediating sexual behavior. Yet, the neural bases underlying these processes have not been investigated so far. AIM: The aim of this study was to explore neural activations of classical conditioning of sexual arousal with respect to sex differences and contingency awareness. METHODS: In the acquisition phase, a geometric figure (CS+) was presented for 8 seconds and was followed by highly sexual arousing pictures (UCS), whereas another figure (CS-) predicted neutral pictures. Ratings and contingency awareness were assessed after the entire conditioning procedure. Forty subjects (20 females) were classified into one of four groups according to their sex and the development of contingency awareness (aware females, aware males, unaware females, and unaware males). MAIN OUTCOME MEASURES: Blood oxygen level dependent (BOLD) responses measured by functional magnetic resonance imaging (fMRI), skin conductance responses (SCRs), and subjective ratings. RESULTS: fMRI analysis showed two effects (awareness and sex) when comparing CS+ with CS-: (i) aware compared to unaware subjects showed enhanced differentiation (e.g., ventral striatum, orbitofrontal cortex, occipital cortex); and (ii) men showed increased activity compared to women in the amygdala, thalamus, and brainstem. CS+ and CS- ratings differed in aware subjects only. However, no conditioned SCRs occurred in any group. CONCLUSION: The increased activity in men is in line with theories postulating that men are generally more prone to conditioning of sexual arousal. Further, contingency awareness seems to be an important factor in appetitive learning processes, which facilitates conditioning processes.