Christian J. Merz

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.

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.

Neural Activations of the Acquisition of Conditioned Sexual Arousal: Effects of Contingency Awareness and Sex

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.

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.

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.

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.

Don’t fear ‘fear conditioning’: Methodological considerations for the design and analysis of studies on human fear acquisition, extinction, and return of fear

HighlightsOriginates from discussions on replicability and researchers degrees of freedom.Aims at stimulating discussions on methods applied in fear conditioning research.Addresses critical issues on terminology, design, methods, analysis.Serves as comprehensive compendium and critical evaluation of read‐out measures.Highlights methodological considerations when studying individual differences. ABSTRACT The so‐called ‘replicability crisis’ has sparked methodological discussions in many areas of science in general, and in psychology in particular. This has led to recent endeavours to promote the transparency, rigour, and ultimately, replicability of research. Originating from this zeitgeist, the challenge to discuss critical issues on terminology, design, methods, and analysis considerations in fear conditioning research is taken up by this work, which involved representatives from fourteen of the major human fear conditioning laboratories in Europe. This compendium is intended to provide a basis for the development of a common procedural and terminology framework for the field of human fear conditioning. Whenever possible, we give general recommendations. When this is not feasible, we provide evidence‐based guidance for methodological decisions on study design, outcome measures, and analyses. Importantly, this work is also intended to raise awareness and initiate discussions on crucial questions with respect to data collection, processing, statistical analyses, the impact of subtle procedural changes, and data reporting specifically tailored to the research on fear conditioning.

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.

Stress Impairs Retrieval of Socially Relevant Information

Several studies have reported that stress impairs memory retrieval, even though findings are not unequivocal. Moreover, memory for socially relevant information was not previously investigated. The present study aimed to test the effects of stress on the retrieval of social memory (e.g., memory concerning names, birthdays, or biographies). In a randomized cross-over experiment, the cognitive performance of 29 subjects (15 women) was tested twice. Social memory was tested in a stress session, in which participants were exposed to a brief standardized psychosocial laboratory stressor between encoding and retrieval. Performance was compared with a stress-free control session. Stress exposure caused an increase in cortisol concentrations and changes in several mood measures. Social memory retrieval was reduced in the stress compared with the control session. An association between the cortisol stress response and poorer retrieval was significant in responders, that is, those participants displaying a cortisol rise after stress onset. Thus, similar to other forms of declarative memory, the retrieval of declarative memory for socially relevant information learned from biographical notes is impaired after acute stress exposure. This effect is linked to the stress-induced cortisol increase.

ADHD related behaviors are associated with brain activation in the reward system

Neuroimaging studies on attention-deficit/hyperactivity disorder (ADHD) suggest dysfunctional reward processing, with hypo-responsiveness during reward anticipation in the reward system including the nucleus accumbens (NAcc). In this study, we investigated the association between ADHD related behaviors and the reward system using functional magnetic resonance imaging in a non-clinical sample. Participants were 31 healthy, female undergraduate students with varying levels of self-reported ADHD related behaviors measured by the adult ADHD self-report scale. The anticipation of different types of reward was investigated: monetary reward, punishment avoidance, and verbal feedback. All three reward anticipation conditions were found to be associated with increased brain activation in the reward system, with the highest activation in the monetary reward anticipation condition, followed by the punishment avoidance anticipation condition, and the lowest activation in the verbal feedback anticipation condition. Most interestingly, in all three conditions, NAcc activation was negatively correlated with ADHD related behaviors. In conclusion, our results from a non-clinical sample are in accordance with reported deficits in the reward system in ADHD patients: the higher the number and severity of ADHD related behaviors, the lower the neural responses in the dopaminergic driven reward anticipation task. Thus, our data support current aetiological models of ADHD which assume that deficits in the reward system might be responsible for many of the ADHD related behaviors.