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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.

Several studies provide empirical evidence for the association between impulsivity and time perception. However, little is known about the neural substrates underlying this function. This investigation examined the influence of impulsivity on neural activation patterns during the encoding and reproduction of intervals with durations of 3, 9 and 18s using event-related functional magnetic resonance imaging (fMRI). Twenty-seven subjects participated in this study, including 15 high impulsive subjects that were classified based on their self-rating. FMRI activation during the duration reproduction task was correlated with measures of two self-report questionnaires related to the concept of impulsivity (Barratt Impulsiveness Scale, BIS; Zimbardo Time Perspective Inventory, ZTPI). Behaviorally, those individuals who under-reproduced temporal intervals also showed lower scores on the ZTPI future perspective subscale and higher scores on the BIS. FMRI activation revealed an accumulating pattern of neural activity peaking at the end of the 9- and 18-s intervals within right posterior insula. Activations of brain regions during the reproduction phase of the timing task, such as those related to motor execution as well as to the 'core control network' - encompassing the inferior frontal and medial frontal cortices, the anterior insula as well as the inferior parietal cortex - were significantly correlated with reproduced duration, as well as with BIS and ZTPI subscales. In particular, the greater activation in these regions the shorter were the reproduced intervals, the more impulsive was an individual and the less pronounced the future perspective. Activation in the core control network, thus, may form a biological marker for cognitive time management and for impulsiveness.

Event-related functional magnetic resonance imaging was applied to identify cortical areas involved in maintaining target information in working memory used for an upcoming grasping action. Participants had to grasp with their thumb and index finger of the dominant right hand three-dimensional objects of different size and orientation. Reaching-to-grasp movements were performed without visual feedback either immediately after object presentation or after a variable delay of 2-12 s. The right inferior parietal cortex demonstrated sustained neural activity throughout the delay, which overlapped with activity observed during encoding of the grasp target. Immediate and delayed grasping activated similar motor-related brain areas and showed no differential activity. The results suggest that the right inferior parietal cortex plays an important functional role in working memory maintenance of grasp-related information. Moreover, our findings confirm the assumption that brain areas engaged in maintaining information are also involved in encoding the same information, and thus extend previous findings on working memory function of the posterior parietal cortex in saccadic behavior to reach-to-grasp movements.

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.

Phobic responses are strong emotional reactions towards phobic objects, which can be described as a deficit in the automatic regulation of emotions. Difficulties in the voluntary cognitive control of these emotions suggest a further phobia-specific deficit in effortful emotion regulation mechanisms. The actual study is based on this emotion regulation conceptualization of specific phobias. The aim is to investigate the neural correlates of these two emotion regulation deficits in spider phobics. Sixteen spider phobic females participated in a functional magnetic resonance imaging (fMRI) study in which they were asked to voluntarily up- and down-regulate their emotions elicited by spider and generally aversive pictures with a reappraisal strategy. In line with the hypothesis concerning an automatic emotion regulation deficit, increased activity in the insula and reduced activity in the ventromedial prefrontal cortex was observed. Furthermore, phobia-specific effortful regulation within phobics was associated with altered activity in medial prefrontal cortex areas. Altogether, these results suggest that spider phobic subjects are indeed characterized by a deficit in the automatic as well as the effortful regulation of emotions elicited by phobic compared with aversive stimuli. These two forms of phobic emotion regulation deficits are associated with altered activity in different medial prefrontal cortex subregions.

OBJECTIVE: The quality of averaged gradient artifact subtraction from EEG recorded during fMRI is highly dependent on the accuracy of gradient artifact sampling. Even small sampling shifts (e.g. a single datapoint at 5kHz) increase the variance of the sampled gradient artifacts because of very steep slopes in the signal time course. Hence, although principally gradient artifacts are invariant signals because of their technical origin, variance attributed to sampling errors attenuates the effect of artifact removal. Recently, it has been shown that synchronizing the EEG-amplifier clock to the MR-scanner control-device clock improves artifact reduction by subtraction. METHODS: In order to investigate the synchronized measurement of combined EEG-fMRI, we used simulated EEG by measuring function generator signals in the MR-scanner. Only the usage of known signals allows an assessment of the improvement in accuracy of artifact recording by synchronized compared to non-synchronized measurement, since the signal is identical in both conditions. RESULTS: After averaged gradient artifact subtraction synchronized recorded signals were apparently less distorted than non-synchronized recorded signals. Spectral analyses revealed that especially artifact frequencies above 50Hz had less power in restored synchronized compared to restored non-synchronized recorded signals. Computed total signal variances were not always less in restored synchronized compared to restored non-synchronized recorded signals. CONCLUSIONS: Taken together, synchronizing simultaneous EEG-fMRI measurement is a useful enhancement for averaged gradient artifact subtraction although post-correction filtering is still necessary. SIGNIFICANCE: Our results support the recent finding that synchronization improves the quality of averaged gradient artifact subtraction. However, quantitatively we could not verify a systematic benefit of recording electrical signals during fMRI synchronously rather than non-synchronously to the MR-scanner control-device clock.

Functional magnetic resonance imaging studies have examined neural correlates of disgust imagery, but have never taken into account the moderating effects of personality traits. Twenty-four women first viewed and subsequently visualized pictures with disgust-inducing and happiness-inducing content. Relative to the picture perception, disgust, and happiness imagery provoked activation of the insula, anterior cingulate cortex, and parietal cortex. Trait disgust was negatively correlated with localized brain activation (e.g. insula, amygdala, parietal cortex, anterior cingulate cortex) during disgust imagery. This study provides first evidence that disgust propensity is associated with brain activation during imagery of repulsive scenes.

This study investigated differences in brain activation during meditation between meditators and non-meditators. Fifteen Vipassana meditators (mean practice: 7.9 years, 2h daily) and fifteen non-meditators, matched for sex, age, education, and handedness, participated in a block-design fMRI study that included mindfulness of breathing and mental arithmetic conditions. For the meditation condition (contrasted to arithmetic), meditators showed stronger activations in the rostral anterior cingulate cortex and the dorsal medial prefrontal cortex bilaterally, compared to controls. Greater rostral anterior cingulate cortex activation in meditators may reflect stronger processing of distracting events. The increased activation in the medial prefrontal cortex may reflect that meditators are stronger engaged in emotional processing.

Dopamine is known as the main neurotransmitter modulating the activation of the reward system of the brain. The DRD2 TaqIA polymorphism is associated with dopamine D2 receptor density which plays an important role in the context of reward. Persons carrying an A1 allele have a lower D2 receptor density and a higher risk to show substance abuse. The present study was designed to investigate the influence of the DRD2 TaqIA polymorphism and the selective D2 receptor agonist bromociptine on the activation of the reward system by means of functional magnetic resonance imaging (fMRI). In a double-blind crossover study with 24 participants we found an increase of reward system activation from placebo to bromocriptine only in subjects carrying the A1 allele. Furthermore, only A1 carrier showed an increase of performance under bromocriptine. The results are interpreted as reflecting a specific sensitivity for dopamine agonists in persons carrying an A1 allele and may complement actual data and theories of the development of addiction disorders postulating a higher genetic risk for substance abuse in carrier of the A1 allele.

We examined whether males and females differ in the intensity and laterality of their hemodynamic responses towards visual disgust and fear stimuli. Forty-one female, and 51 male subjects viewed disgust-inducing, fear-inducing and neutral pictures in an fMRI block design. Self-report data indicated that the target emotions had been elicited successfully with women responding stronger than men. While viewing the fear pictures, which depicted attacks by humans or animals, men exhibited greater activation in the bilateral amygdala and the left fusiform gyrus than women. This response pattern may reflect greater attention from males to cues of aggression in their environment. Further, the lateralization of brain activation was comparable in the two genders during both aversive picture conditions.

The majority of neuroimaging studies on affective processing have indicated that there are specific brain structures, which are selectively responsive to fear and disgust. Whereas the amygdala is assumed to be fear-related, the insular cortex is most likely involved in disgust processing. Since these findings are mainly a result of studies focusing exclusively either on fear, or on disgust, but rarely on both emotions together, the present experiment explored the neural effects of viewing disgusting and fear-inducing pictures in contrast to neutral pictures. This was done by means of functional magnetic resonance imaging (fMRI) with 19 subjects (nine males, ten females), who also gave affective ratings for the presented pictures. The fear and the disgust pictures were able to induce the target emotions and they received comparable valence and arousal ratings. The processing of both aversive picture types was associated with an increased brain activation in the occipital-temporal lobe, in the prefrontal cortex, and in the thalamus. The amygdala was significantly activated by disgusting, but not by fear-inducing, pictures. Thus, our data are in contrast with the idea of highly emotion-specific brain structures and rather suggest the existence of a common affective circuit.