No Sex Difference Found: Cues of Sexual Stimuli Activate the Reward System in both Sexes.

Sexually explicit material (SEM) is increasingly used in western societies. One reason for this high usage might be the rewarding property of SEM demonstrated in many brain imaging studies showing an activation of the reward system during the presentation of SEM. It is not yet well understood why women use SEM to a remarkably lesser extent than men. Maybe men react stronger to stimuli - so called SEM cues -, which signal the presentation of SEM and are therefore more vulnerable to use SEM than women. Therefore, the present study aimed at investigating the sex specific neural correlates towards SEM and SEM cues. We were further interested in whether person characteristics as trait sexual motivation, extent of SEM use in the last month, and age at onset of goal-oriented SEM use affect the neural responses to SEM and SEM cues. The trials of the fMRI experiment consisted of an expectation phase with SEM or neutral cues and a presentation phase with SEM or neutral stimuli, respectively. Analyses showed that the reward circuitry was activated by SEM, but also by SEM cues. There were some sex differences in hemodynamic responses to SEM during the presentation phase, but not during the expectation phase to SEM cues in any of the regions of interest. The influence of the investigated person characteristics was only small if existent. The results suggest that sex specific cue processing cannot explain sex differences in the use of SEM.

Neuroticism and extraversion moderate neural responses and effective connectivity during appetitive conditioning.

Classical appetitive conditioning constitutes a basic learning process through which environmental stimuli can be associated with reward. Previous studies showed that individual differences in neuroticism and extraversion influence emotional processing and have been shown to modulate neural activity in subcortical and prefrontal areas in response to emotional stimuli. However, the role of individual differences in appetitive conditioning has so far not been investigated in detail. The aim of this study was to assess the association between neuroticism and extraversion with neural activity and connectivity during appetitive conditioning. The conditioned stimulus (CS) was either a picture of a dish or a cup. One stimulus (CS+) was paired with a monetary reward and the other stimulus (CS-) was associated with its absence while hemodynamic activity was measured by means of functional magnetic resonance imaging. A significant negative correlation of neuroticism scores with amygdala activity was observed during appetitive conditioning. Further, extraversion was positively associated with responses in the hippocampus and the thalamus. In addition, effective connectivity between the amygdala as a seed region and the anterior cingulate cortex, the insula, and the thalamus was negatively correlated with neuroticism scores and positively correlated with extraversion scores. The results may indicate a neural correlate for the deficits in appetitive learning in subjects with high neuroticism scores and point to a facilitating effect of extraversion on reward-related learning. Hum Brain Mapp 37:2992-3002, 2016. © 2016 Wiley Periodicals, Inc.

No evidence for blocking the return of fear by disrupting reconsolidation prior to extinction learning.

Fear extinction is a central model for the treatment of anxiety disorders. Initial research has reported that the single presentation of a conditioned stimulus prior to extinction learning can permanently block the return of fear. However, only few studies have explored this issue and could not always replicate the findings. The present study examined human fear extinction using a four-day design. On the first day, two neutral stimuli were paired with electrical stimulation (UCS), while a third stimulus (CS-) was not. Twenty-four hours later, one conditioned stimulus (CS+rem) and the CS- were reminded once, 10 min before extinction learning, while the other conditioned stimulus (CS+non-rem) was not presented prior to extinction learning. All stimuli were presented during extinction learning and during two re-extinction sessions (24 h and 6-months after extinction learning) without reinforcement. Blood oxygen level-dependent (BOLD) responses and skin conductance responses (SCRs) to both CS+ and the CS- were explored during acquisition, extinction, and in both re-extinction sessions. Regarding SCRs, the results showed that a single presentation of a conditioned stimulus did not block the return of fear during re-extinction: Fear recovery during re-extinction (24 h and 6-months after extinction learning) was observed for both CS+ compared with the CS- with no difference between CS+rem and CS+non-rem. Regarding BOLD-responses, no significant differences between CS+rem and CS+non-rem were found in region of interest (ROI)-analyses (amygdala, ventromedial prefrontal cortex) during extinction learning and both re-extinction sessions. Whole-brain analyses showed increased BOLD-responses to the CS+non-rem as compared to the CS+rem in several regions (e.g., middle frontal gyrus) during extinction learning and re-extinction (24 h after extinction learning). The present findings suggest that the effect of preventing the return of fear by disrupting reconsolidation seems to be a more labile phenomenon than previously assumed. Possible boundary conditions and implications are discussed.

Altered Appetitive Conditioning and Neural Connectivity in Subjects With Compulsive Sexual Behavior.

INTRODUCTION: There has been growing interest in a better understanding of the etiology of compulsive sexual behavior (CSB). It is assumed that facilitated appetitive conditioning might be an important mechanism for the development and maintenance of CSB, but no study thus far has investigated these processes. AIM: To explore group differences in neural activity associated with appetitive conditioning and connectivity in subjects with CSB and a healthy control group. METHODS: Two groups (20 subjects with CSB and 20 controls) were exposed to an appetitive conditioning paradigm during a functional magnetic resonance imaging experiment, in which a neutral stimulus (CS+) predicted visual sexual stimuli and a second stimulus (CS-) did not. MAIN OUTCOME MEASURES: Blood oxygen level-dependent responses and psychophysiologic interaction. RESULTS: As a main result, we found increased amygdala activity during appetitive conditioning for the CS+ vs the CS- and decreased coupling between the ventral striatum and prefrontal cortex in the CSB vs control group. CONCLUSION: The findings show that neural correlates of appetitive conditioning and neural connectivity are altered in patients with CSB. The increased amygdala activation might reflect facilitated conditioning processes in patients with CSB. In addition, the observed decreased coupling could be interpreted as a marker for impaired emotion regulation success in this group.

Increased skin conductance responses and neural activity during fear conditioning are associated with a repressive coping style.

The investigation of individual differences in coping styles in response to fear conditioning is an important issue for a better understanding of the etiology and treatment of psychiatric disorders. It has been assumed that an avoidant (repressive) coping style is characterized by increased emotion regulation efforts in context of fear stimuli as compared to a more vigilant coping style. However, no study so far has investigated the neural correlates of fear conditioning of repressors and sensitizers. In the present fMRI study, 76 participants were classified as repressors or as sensitizers and were exposed to a fear conditioning paradigm, in which the CS+ predicted electrical stimulation, while another neutral stimulus (CS-) did not. In addition, skin conductance responses (SCRs) were measured continuously. As the main findings, we found increased neural activity in repressors as compared to sensitizers in the ventromedial prefrontal cortex and the anterior cingulate cortex (ACC) during fear conditioning. In addition, elevated activity to the CS+ in amygdala, insula, occipital, and orbitofrontal cortex (OFC) as well as elevated conditioned SCRs were found in repressors. The present results demonstrate increased neural activations in structures linked to emotion down-regulation mechanisms like the ventromedial prefrontal cortex, which may reflect the increased coping effort in repressors. At the same time, repressors showed increased activations in arousal and evaluation-associated structures like the amygdala, the occipital cortex (OCC), and the OFC, which was mirrored in increased SCRs. The present results support recent assumptions about a two-process model of repression postulating a fast vigilant response to fear stimuli, and a second process associated with the down-regulation of emotional responses.

Impact of COMT Val158Met-polymorphism on appetitive conditioning and amygdala/prefrontal effective connectivity.

Appetitive conditioning is an important mechanism for the development, maintenance, and treatment of psychiatric disorders like substance abuse. Therefore, it is important to identify genetic variations, which impact appetitive conditioning. It has been suggested that the Val(158) Met-polymorphism in the Catechol-O-Methyl-Transferase (COMT) is associated with the alteration of neural processes of appetitive conditioning due to the central role of the dopaminergic system in reward processing. However, no study has so far investigated the relationship between variations in the COMT Val(158) Met-polymorphism and appetitive conditioning. In this fMRI study, an appetitive conditioning paradigm was applied, in which one neutral stimulus (CS+) predicted appetitive stimuli (UCS) while a second neutral stimulus (CS-) was never paired with the UCS. As a main result, we observed a significant association between the COMT Val(158) Met-genotype and appetitive conditioning: skin conductance responses (SCRs) revealed a significant difference between CS+ and CS- in Val/Val-allele carriers but not in the other genotype groups. Val/Val-allele carriers showed increased hemodynamic responses in the amygdala compared with the Met/Met-allele group in the contrast CS+ > CS-. In addition, psychophysiological-interaction analysis revealed increased effective amygdala/ventromedial prefrontal cortex connectivity in Met/Met-allele carriers. The increased amygdala activity points to facilitated appetitive conditioning in Val/Val-allele carriers while the amygdala/prefrontal connectivity results could be regarded as a marker for altered emotion regulation during conditioning, which potentially impacts appetitive learning sensitivity. The SCRs finding indicates a stronger conditioned response in the Val/Val-allele group and dovetails with the neural differences between the groups. These findings contribute to the current research on COMT in emotional processing.

The association between the 5-HTTLPR and neural correlates of fear conditioning and connectivity.

Strong evidence links the 5-HTTLPR genotype to the modulation of amygdala reactivity during fear conditioning, which is considered to convey the increased vulnerability for anxiety disorders in s-allele carriers. In addition to amygdala reactivity, the 5-HTTLPR has been shown to be related to alterations in structural and effective connectivity. The aim of this study was to investigate the effects of 5-HTTLPR genotype on amygdala reactivity and effective connectivity during fear conditioning, as well as structural connectivity [as measured by diffusion tensor imaging (DTI)]. To integrate different classification strategies, we used the bi-allelic (s-allele vs l/l-allele group) as well as the tri-allelic (low-functioning vs high-functioning) classification approach. S-allele carriers showed exaggerated amygdala reactivity and elevated amygdala-insula coupling during fear conditioning (CS + > CS-) compared with the l/l-allele group. In addition, DTI analysis showed increased fractional anisotropy values in s-allele carriers within the uncinate fasciculus. Using the tri-allelic classification approach, increased amygdala reactivity and amygdala insula coupling were observed in the low-functioning compared with the high-functioning group. No significant differences between the two groups were found in structural connectivity. The present results add to the current debate on the influence of the 5-HTTLPR on brain functioning. These differences between s-allele and l/l-allele carriers may contribute to altered vulnerability for psychiatric disorders.

Learning to like disgust: neuronal correlates of counterconditioning.

Converging lines of research suggest that exaggerated disgust responses play a crucial role in the development and maintenance of certain anxiety disorders. One strategy that might effectively alter disgust responses is counterconditioning. In this study, we used functional magnetic resonance imaging (fMRI) to examine if the neuronal bases of disgust responses are altered through a counterconditioning procedure. One disgust picture (conditioned stimulus: CS+disg) announced a monetary reward, while a second disgust picture (CS-disg) was never paired with the reward. Two neutral control pictures (CS+con/CS-con) were conditioned in the same manner. Analyses of evaluative conditioning showed that both CS+ were rated significantly more positive after conditioning as compared to the corresponding CS-. Thereby, the CS+disg and the CS+con received an equal increase in valence ratings. Regarding the fMRI data, ANOVA results showed main effects of the conditioning procedure (i.e., CS+ vs. CS-) in the dorsal anterior cingulate cortex. Further, main effects of the picture category (disgust vs. control) were found in the bilateral insula and the orbitofrontal cortex. No interaction effects were detected. In conclusion, the results imply that learning and anticipation of reward was not significantly influenced by the disgust content of the CS pictures. This suggests that the affect induced by the disgust pictures and the affect created by the anticipation of reward may not influence the processing of each other.

Dissociation of neuronal, electrodermal, and evaluative responses in disgust extinction.

Disgust extinction is an important mechanism relevant for the treatment of psychiatric disorders. However, only a few studies have investigated disgust extinction. Moreover, because disgust sensitivity (DS) is considered as a relevant factor for learning processes, this study also investigated the potential relationship between DS and disgust extinction learning. The aim of this study was to explore the neuronal correlates of disgust extinction, as well as changes in skin conductance responses (SCRs) and evaluative conditioning. Twenty subjects were exposed to a differential extinction paradigm, in which a previous conditioned, and now unreinforced, stimulus (conditioned stimulus, CS+) was compared to a second stimulus (CS-), which was previously not associated with the unconditioned stimulus (UCS). Extinction learning was measured on three different response levels (BOLD responses, SCRs, and evaluative conditioning). Regarding evaluative conditioning, the CS+ was rated as more unpleasant than the CS-. Interestingly, significantly increased amygdala responses and SCRs toward to the CS- were observed. Finally, a (negative) trend was found between DS scores and BOLD responses of the prefrontal cortex. The present findings showed a dissociation of different response levels. The increased CS- responses could be explained by the assumption that the increased amygdala activity may reflect a safety learning signal during the first extinction trials and the subjective focus may therefore shift from the CS+ to the CS-. The correlation finding supports previous studies postulating that DS hampers extinction processes. The present results point toward dissociations between the response levels in context of extinction processes.

Stress differentially affects fear conditioning in men and women.

Stress and fear conditioning processes are both important vulnerability factors in the development of psychiatric disorders. In behavioral studies considerable sex differences in fear learning have been observed after increases of the stress hormone cortisol. But neuroimaging experiments, which give insights into the neurobiological correlates of stress × sex interactions in fear conditioning, are lacking so far. In the current functional magnetic resonance imaging (fMRI) study, we tested whether a psychosocial stressor (Trier Social Stress Test) compared to a control condition influenced subsequent fear conditioning in 48 men and 48 women taking oral contraceptives (OCs). One of two pictures of a geometrical figure was always paired (conditioned stimulus, CS+) or never paired (CS-) with an electrical stimulation (unconditioned stimulus). BOLD responses as well as skin conductance responses were assessed. Sex-independently, stress enhanced the CS+/CS- differentiation in the hippocampus in early acquisition but attenuated conditioned responses in the medial frontal cortex in late acquisition. In early acquisition, stress reduced the CS+/CS- differentiation in the nucleus accumbens in men, but enhanced it in OC women. In late acquisition, the same pattern (reduction in men, enhancement in OC women) was found in the amygdala as well as in the anterior cingulate. Thus, psychosocial stress impaired the neuronal correlates of fear learning and expression in men, but facilitated them in OC women. A sex-specific modulation of fear conditioning after stress might contribute to the divergent prevalence of men and women in developing psychiatric disorders.

Individual differences in neural correlates of fear conditioning as a function of 5-HTTLPR and stressful life events.

Fear learning is a crucial process in the pathogeneses of psychiatric disorders, which highlights the need to identify specific factors contributing to interindividual variation. We hypothesized variation in the serotonin transporter gene (5-HTTLPR) and stressful life events (SLEs) to be associated with neural correlates of fear conditioning in a sample of healthy male adults (n = 47). Subjects were exposed to a differential fear conditioning paradigm after being preselected regarding 5-HTTLPR genotype and SLEs. Individual differences in brain activity as measured by functional magnetic resonance imaging (fMRI), skin conductance responses and preference ratings were assessed. We report significant variation in neural correlates of fear conditioning as a function of 5-HTTLPR genotype. Specifically, the conditioned stimulus (CS(+)) elicited elevated activity within the fear-network (amygdala, insula, thalamus, occipital cortex) in subjects carrying two copies of the 5-HTTLPR S' allele. Moreover, our results revealed preliminary evidence for a significant gene-by-environment interaction, such as homozygous carriers of the 5-HTTLPR S' allele with a history of SLEs demonstrated elevated reactivity to the CS(+) in the occipital cortex and the insula. Our findings contribute to the current debate on 5-HTTLPR x SLEs interaction by investigating crucial alterations on an intermediate phenotype level which may convey an elevated vulnerability for the development of psychopathology.

The 5-HTTLPR polymorphism is associated with altered hemodynamic responses during appetitive conditioning.

BACKGROUND: Current models suggest that a variation in the promoter region of the serotonin transporter gene (5-HTTLPR) is associated with altered amygdala reactivity not only towards negative but also towards positive stimuli, which has been neglected in the past. This association may possibly convey an elevated vulnerability for psychopathology like abuse, craving, and relapses. Since appetitive conditioning is a crucial mechanism in the pathogenesis of these psychiatric disorders, the identification of specific factors contributing to interindividual variation is important. METHODS: In the present study (N = 86), an appetitive conditioning paradigm was conducted, in which a neutral stimulus (CS+) was associated with appetitive stimuli, while a second stimulus (CS-) predicted their absence. Subjects were genotyped according to the 5-HTTLPR genotype. RESULTS: As the main result, we report a significant association between the 5-HTTLPR genotype and hemodynamic responses. Individuals with the s-allele displayed elevated conditioned bilateral amygdala activity in contrast to l/l-allele carriers. Further, increased hemodynamic responses in s-allele carriers were also found in the extended emotional network including the orbitofrontal cortex, the thalamus, and the ventral striatum. CONCLUSION: The present findings indicate an association of the 5-HTTLPR and altered conditioned responses in appetitive conditioning. Further, the findings contribute to the ongoing debate on 5-HTTLPR dependent hemodynamic response patterns by emphasizing that s-allele carriers are not exclusively biased towards fearful, but also towards positive stimuli. In conclusion, our results imply that s-allele carriers might be better described as hyper-reactive towards salient stimuli, which may convey vulnerability for the development of psychiatric disorders.

Oral contraceptive usage alters the effects of cortisol on implicit fear learning.

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.

Creativity and the brain: uncovering the neural signature of conceptual expansion.

Neurophysiological studies of creativity thus far have not allowed for clear conclusions to be made regarding the specific neural underpinnings of such complex cognition due to overgeneralizations concerning the creativity construct, heterogeneity in the type of creativity tasks used, and the questionable efficacy of the employed comparison tasks. A novel experimental design was developed in the present fMRI study which rendered it possible to investigate a critical facet of creative cognition - that of conceptual expansion - as distinct from general divergent thinking, working memory, or cognitive load. Brain regions involved in the retention, retrieval and integration of conceptual knowledge such as the anterior inferior frontal gyrus, the temporal poles and the lateral frontopolar cortex were found to be selectively involved during conceptual expansion. The findings go against generic ideas that argue for the dominance of the right hemisphere during creative thinking and indicate the necessity to reconsider the functions of regions such as the anterior cingulate cortex to include more abstract facets of cognitive control. This study represents a new direction in the investigation of creativity in that it highlights the necessity to adopt a process based perspective in which the multifaceted nature of creativity can be truly grasped.

Can clouds dance? Neural correlates of passive conceptual expansion using a metaphor processing task: Implications for creative cognition.

Creativity has emerged in the focus of neurocognitive research in the past decade. However, a heterogeneous pattern of brain areas has been implicated as underpinning the neural correlates of creativity. One explanation for these divergent findings lies in the fact that creativity is not usually investigated in terms of its many underlying cognitive processes. The present fMRI study focuses on the neural correlates of conceptual expansion, a central component of all creative processes. The study aims to avoid pitfalls of previous fMRI studies on creativity by employing a novel paradigm. Participants were presented with phrases and made judgments regarding both the unusualness and the appropriateness of the stimuli, corresponding to the two defining criteria of creativity. According to their respective evaluation, three subject-determined experimental conditions were obtained. Phrases judged as both unusual and appropriate were classified as indicating conceptual expansion in participants. The findings reveal the involvement of frontal and temporal regions when engaging in passive conceptual expansion as opposed to the information processing of mere unusualness (novelty) or appropriateness (relevance). Taking this new experimental approach to uncover specific processes involved in creative cognition revealed that frontal and temporal regions known to be involved in semantic cognition and relational reasoning play a role in passive conceptual expansion. Adopting a different vantage point on the investigation of creativity would allow for critical advances in future research on this topic.

Neuronal correlates of extinction learning are modulated by sex hormones.

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.

Weaving the (neuronal) web: fear learning in spider phobia.

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.

Influence of contingency awareness on neural, electrodermal and evaluative responses during fear conditioning.

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.

Cortisol enhances neural differentiation during fear acquisition and extinction in contingency aware young women.

Previously, we observed cortisol induced enhancement of neural fear acquisition in women. Yet, less is known about cortisol effects on neural fear extinction. Via differential fear conditioning, we explored cortisol effects on acquisition and extinction. Twenty contingency aware women taking monophasic oral contraceptives were included; 10 received placebo, 10 cortisol before conditioning. Group differences emerged in anterior cingulate cortex (ACC), hippocampus, and--as trend--in insula and thalamus during acquisition and in hippocampus, thalamus, and--as trend--in amygdala, insula, and ACC during extinction. During acquisition group differences were due to higher responses to the CS+ than to the CS- in the cortisol group. Notably, during extinction, group differences were due to higher responses to the CS- than to the CS+ in this group. Thus, cortisol induced a fear acquisition and extinction specific enhanced neural differentiation.

Investigating the impact of sex and cortisol on implicit fear conditioning with fMRI.

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.