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This study addresses the controversy over how motor maps are organized during action simulation by examining whether action simulation states, that is, motor imagery and action observation, run on either effector-specific and/or action-specific motor maps. Subjects had to observe or imagine three types of movements effected by the right hand or the right foot with different action goals. The functional magnetic resonance imaging results showed an action-specific organization within premotor and posterior parietal areas of both hemispheres during action simulation, especially during action observation. There were also less pronounced effector-specific activation sites during both simulation processes. It is concluded that the premotor and parietal areas contain multiple motor maps rather than a single, continuous map of the body. The forms of simulation (observation, imagery), the task contexts (movements related to an object, with usual/unusual effector), and the underlying reason for performing the simulation (rate your subjective success afterwards) lead to the specific use of different representational motor maps within both regions. In our experimental setting, action-specific maps are dominant especially, during action observation, whereas effector-specific maps are recruited to only a lesser degree.

We investigated the impact of sexual stimuli and the influence of sexual motivation on the performance in a dot-probe task and a line-orientation task in a large sample of males and females. All pictures (neutral, erotic) were rated on the dimensions of valence, arousal, disgust, and sexual arousal. Additionally, questionnaires measuring sexual interest/desire/motivation were employed. The ratings of the sexual stimuli point to a successful picture selection because sexual arousal did not differ between the sexes. The stimuli were equally arousing for men and women. Higher scores in the employed questionnaires measuring sexual interest/desire/motivation led to higher sexual arousal ratings of the sex pictures. Attentional bias towards sex pictures was observed in both experimental tasks. The attentional biases measured by the dot-probe and the line-orientation task were moderately intercorrelated suggesting attentional bias as a possible marker for a sex-attention trait. Finally, only the sexual sensation seeking score correlated with the attentional biases of the two tasks. Future research is needed to increase the predictive power of these indirect measures of sexual interest.

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.

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.

BACKGROUND: Extinction learning is proposed to be one key mechanism of action underlying exposure-based cognitive-behavioral therapy (CBT) in specific phobia. Beyond that, cognitive reappraisal, one important strategy to regulate negative emotions, is a crucial component of CBT interventions, but has been disregarded in previous studies investigating neural change processes in specific phobia. The aim of this study was to investigate the association of individual differences in habitual/dispositional cognitive reappraisal usage and the time course of brain activation during phobic stimulation in specific phobia. METHODS: Dental phobic patients and healthy control subjects participated in a functional magnetic resonance imaging (fMRI) study whilst being confronted with phobic, disgust, fear and neutral pictures. Individual differences in cognitive reappraisal usage were assessed via a self-report questionnaire and correlated with activation decreases over the course of time. RESULTS: Phobic individuals with higher dispositional cognitive reappraisal scores showed a more pronounced activation decline in the right dorsomedial prefrontal cortex (dmPFC) which might be associated with a diminution of explicit cognitive emotion regulation over the course of time. Less decrease of activation in the right ventromedial prefrontal cortex (vmPFC) and the lateral orbitofrontal cortex (lOFC) over time in subjects with higher cognitive reappraisal scores might be related to a stronger automatic regulation of emotions or even emotional relearning. Additionally, phobic subjects compared with healthy controls showed a stronger habituation of the left dmPFC over the course of symptom provocation. CONCLUSIONS: The results of this study show for the first time that individual differences in cognitive reappraisal usage are associated with the time course of brain activation during symptom provocation in specific phobia. Additionally, the present study gives first indications for the importance of considering individual differences in cognitive reappraisal usage in the treatment of specific phobia.

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.

INTRODUCTION: Few studies so far have directly compared the neural processing of visual sexual stimuli in men and women. Also, most of these studies only compared sexual with neutral stimuli, making it difficult to disentangle sexual stimulus processing from general emotional processing. AIM: The current study aimed to explore gender commonalities and differences in neural activity associated with the processing of visual sexual stimuli in a large sample of 50 men and 50 women. In order to disentangle effects of sexual processing from those of general emotional processing, we employed sexual, neutral, positive, and negative emotional pictures. METHODS: Subjects passively viewed sexual, neutral, positive, and negative emotional pictures during a functional magnetic resonance imaging (fMRI) session. Pictures were presented in 24 blocks of five pictures each. Every block was rated immediately after its presentation with respect to valence, arousal, and sexual arousal. MAIN OUTCOME MEASURES: Blood oxygen level dependent responses measured by fMRI and subjective ratings. RESULTS: fMRI analysis revealed a distributed network for the neural processing of sexual stimuli comprising the hypothalamus, the nucleus accumbens, as well as orbitofrontal, occipital, and parietal areas. This network could be identified (i) for both men and women, with men showing overall stronger activations than women and (ii) independent of general emotional arousal or valence effects. CONCLUSION: Our data speak in favor of a common neural network associated with the processing of visual sexual stimuli in men and women. Apart from the observed gender commonalities, overall stronger responses in men were observed that might indicate stronger sexual responsivity in men.

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.

Aversive social learning experiences might play a significant role in the aetiology of social anxiety disorder. Therefore, we investigated emotional learning and unlearning processes in healthy humans using a social conditioning paradigm. Forty-nine healthy subjects participated in a 2-day fMRI differential conditioning protocol. Acquisition and extinction were conducted on Day 1 and extinction recall on Day 2. BOLD responses, ratings and skin conductance responses were collected. Our data indicate successful conditioning and extinction on the neural and subjective level. As a main result, we observed a positive correlation of social anxiety and conditioning responses on the subjective level (valence and fear) as well as on the neural level with significant CS(+)/CS(-) differentiation in the left amygdala and the left hippocampus. Further, significant CS(+)/CS(-) differentiation in the left amygdala was found during extinction and was associated with lower scores in social anxiety. During extinction recall, we found a tendentially negative correlation of social anxiety and CS(+)/CS(-) differentiation in the vmPFC. In sum, we were able to show that social anxiety is related to conditionability with socially threatening stimuli. This could point to an important aspect in the aetiology of social anxiety disorder.

Jeannerod (2001) hypothesized that action execution, imagery, and observation are functionally equivalent. This led to the major prediction that these motor states are based on the same action-specific and even effector-specific motor representations. The present study examined whether hand and foot movements are represented in a somatotopic manner during action execution, imagery, and action observation. The experiment contained ten conditions: three execution conditions, three imagery conditions, three observation conditions, and one baseline condition. In the nine experimental conditions, participants had to execute, observe, or imagine right-hand extension/flexion movements or right-foot extension/flexion movements. The fMRI results showed a somatotopic organization within the contralateral premotor and primary motor cortex during motor imagery and motor execution. However, there was no clear somatotopic organization of action observation in the given regions of interest within the contralateral hemisphere, although observation of these movements activated these areas significantly.

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.

BACKGROUND: Patients with obsessive-compulsive disorder (OCD) have highly idiosyncratic triggers. To fully understand which role this idiosyncrasy plays in the neurobiological mechanisms behind OCD, it is necessary to elucidate the impact of individualization regarding the applied investigation methods. This functional magnetic resonance imaging (fMRI) study explores the neural correlates of contamination/washing-related OCD with a highly individualized symptom provocation paradigm. Additionally, it is the first study to directly compare individualized and standardized symptom provocation. METHODS: Nineteen patients with washing compulsions created individual OCD hierarchies, which later served as instructions to photograph their own individualized stimulus sets. The patients and 19 case-by-case matched healthy controls participated in a symptom provocation fMRI experiment with individualized and standardized stimulus sets created for each patient. RESULTS: OCD patients compared to healthy controls displayed stronger activation in the basal ganglia (nucleus accumbens, nucleus caudatus, pallidum) for individualized symptom provocation. Using standardized symptom provocation, this group comparison led to stronger activation in the nucleus caudatus. The direct comparison of between-group effects for both symptom provocation approaches revealed stronger activation of the orbitofronto-striatal network for individualized symptom provocation. CONCLUSIONS: The present study provides insight into the differential impact of individualized and standardized symptom provocation on the orbitofronto-striatal network of OCD washers. Behavioral and neural responses imply a higher symptom-specificity of individualized symptom provocation.

Mindfulness training aims to impact emotion regulation. Generalized anxiety disorder (GAD) symptoms can be successfully addressed through mindfulness-based interventions. This preliminary study is the first to investigate neural mechanisms of symptom improvements in GAD following mindfulness training. Furthermore, we compared brain activation between GAD patients and healthy participants at baseline. 26 patients with a current DSM-IV GAD diagnosis were randomized to an 8-week Mindfulness Based Stress Reduction (MBSR, N = 15) or a stress management education (SME, N = 11) active control program. 26 healthy participants were included for baseline comparisons. BOLD response was assessed with fMRI during affect labeling of angry and neutral facial expressions. At baseline, GAD patients showed higher amygdala activation than healthy participants in response to neutral, but not angry faces, suggesting that ambiguous stimuli reveal stronger reactivity in GAD patients. In patients, amygdala activation in response to neutral faces decreased following both interventions. BOLD response in ventrolateral prefrontal regions (VLPFC) showed greater increase in MBSR than SME participants. Functional connectivity between amygdala and PFC regions increased significantly pre- to post-intervention within the MBSR, but not SME group. Both, change in VLPFC activation and amygdala-prefrontal connectivity were correlated with change in Beck Anxiety Inventory (BAI) scores, suggesting clinical relevance of these changes. Amygdala-prefrontal connectivity turned from negative coupling (typically seen in down-regulation of emotions), to positive coupling; potentially suggesting a unique mechanism of mindfulness. Findings suggest that in GAD, mindfulness training leads to changes in fronto-limbic areas crucial for the regulation of emotion; these changes correspond with reported symptom improvements.

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.

Pain can be modulated by several cognitive techniques, typically involving increased cognitive control and decreased sensory processing. Recently, it has been demonstrated that pain can also be attenuated by mindfulness. Here, we investigate the underlying brain mechanisms by which the state of mindfulness reduces pain. Mindfulness practitioners and controls received unpleasant electric stimuli in the functional magnetic resonance imaging scanner during a mindfulness and a control condition. Mindfulness practitioners, but not controls, were able to reduce pain unpleasantness by 22% and anticipatory anxiety by 29% during a mindful state. In the brain, this reduction was associated with decreased activation in the lateral prefrontal cortex and increased activation in the right posterior insula during stimulation and increased rostral anterior cingulate cortex activation during the anticipation of pain. These findings reveal a unique mechanism of pain modulation, comprising increased sensory processing and decreased cognitive control, and are in sharp contrast to established pain modulation mechanisms.

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.

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.

RATIONALE: Biased processing of drug-associated stimuli is believed to be a crucial feature of addiction. Particularly, an attentional bias seems to contribute to the disorder's maintenance. Recent studies suggest differential effects for stimuli associated with the beginning (BEGIN-smoking-stimuli) or the terminal stage of the smoking ritual (END-smoking-stimuli), with the former but not the later evoking high cue-reactivity. OBJECTIVE: The current study investigated the neuronal network underlying an attentional bias to BEGIN-smoking-stimuli and END-smoking-stimuli in smokers and tested the hypothesis that the attentional bias is greater for BEGIN-smoking-stimuli. METHODS: Sixteen non-deprived smokers and 16 non-smoking controls participated in an fMRI study. Drug pictures (BEGIN-smoking-stimuli, END-smoking-stimuli) and control pictures were overlaid with geometrical figures and presented for 300 ms. Subjects had to identify picture content (identification-task) or figure orientation (distraction-task). The distraction-task was intended to demonstrate attentional bias. RESULTS: Behavioral data revealed an attentional bias to BEGIN-smoking-stimuli but not to END-smoking-stimuli in both groups. However, only smokers showed mesocorticolimbic deactivations in the distraction-task with BEGIN-smoking-stimuli. Importantly, these deactivations were significantly stronger for BEGIN- than for END-smoking-stimuli and correlated with the attentional bias score. CONCLUSIONS: Several explanations may account for missing group differences in behavioral data. Brain data suggest smokers using regulatory strategies in response to BEGIN-smoking-stimuli to prevent the elicitation of motivational responses interfering with distraction-task performance. These strategies could be reflected in the observed deactivations and might lead to a performance level in smokers that is similar to that of non-smokers.

BACKGROUND: Gene by environment (G×E) interaction between genetic variation in the promoter region of the serotonin transporter gene (serotonin transporter-linked polymorphic region [5-HTTLPR]) and stressful life events (SLEs) has been extensively studied in the context of depression. Recent findings suggest increased neural and endocrine stress sensitivity as a possible mechanism conveying elevated vulnerability to psychopathology. Furthermore, these G×E mediated alterations very likely reflect interrelated biological processes. METHODS: In the present functional magnetic resonance imaging study, amygdala reactivity to fearful stimuli was assessed in healthy male adults (n = 44), who were previously found to differ with regard to endocrine stress reactivity as a function of 5-HTTLPR × SLEs. Furthermore, functional connectivity between the amygdala and the hypothalamus was measured as a potential mechanism linking elevated neural and endocrine responses during stressful/threatening situations. The study sample was carefully preselected regarding 5-HTTLPR genotype and SLEs. RESULTS: We report significant G×E interaction on neural response patterns and functional amygdala-hypothalamus connectivity. Specifically, homozygous carriers of the 5-HTTLPR S' allele with a history of SLEs (S'S'/high SLEs group) displayed elevated bilateral amygdala activation in response to fearful faces. Within the same sample, a comparable G×E interaction effect has previously been demonstrated regarding increased cortisol reactivity, indicating a cross-validation of heightened biological stress sensitivity. Furthermore, S'S'/high SLEs subjects were characterized by an increased functional coupling between the right amygdala and the hypothalamus, thus indicating a potential link between neural and endocrine hyperreactivity. CONCLUSIONS: The present findings contribute to the ongoing debate on 5-HTTLPR × SLEs interaction and are discussed with respect to clinical implications.