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Fear acquisition and extinction are crucial mechanisms in the etiology and maintenance of anxiety disorders. Moreover, they might play a pivotal role in conveying the influence of genetic and environmental factors on the development of a (more or less) stronger proneness for, or resilience against psychopathology. There are only few insights in the neurobiology of genetically and environmentally based individual differences in fear learning and extinction. In this functional magnetic resonance imaging study, 74 healthy subjects were investigated. These were invited according to 5-HTTLPR/rs25531 (S+ vs. L(A)L(A); triallelic classification) and TPH2 (G(-703)T) (T+ vs. T-) genotype. The aim was to investigate the influence of genetic factors and traumatic life events on skin conductance responses (SCRs) and neural responses (amygdala, insula, dorsal anterior cingulate cortex (dACC) and ventromedial prefrontal cortex (vmPFC)) during acquisition and extinction learning in a differential fear conditioning paradigm. Fear acquisition was characterized by stronger late conditioned and unconditioned responses in the right insula in 5-HTTLPR S-allele carriers. During extinction traumatic life events were associated with reduced amygdala activation in S-allele carriers vs. non-carriers. Beyond that, T-allele carriers of the TPH2 (G(-703)T) polymorphism with a higher number of traumatic life events showed enhanced responsiveness in the amygdala during acquisition and in the vmPFC during extinction learning compared with non-carriers. Finally, a combined effect of the two polymorphisms with higher responses in S- and T-allele carriers was found in the dACC during extinction. The results indicate an increased expression of conditioned, but also unconditioned fear responses in the insula in 5-HTTLPR S-allele carriers. A combined effect of the two polymorphisms on dACC activation during extinction might be associated with prolonged fear expression. Gene-by-environment interactions in amygdala and vmPFC activation may reflect a neural endophenotype translating genetic and adverse environmental influences into vulnerability for or resilience against developing affective psychopathology.

INTRODUCTION: Studies investigating sexual arousal exist, yet there are diverging findings on the underlying neural mechanisms with regard to sexual orientation. Moreover, sexual arousal effects have often been confounded with general arousal effects. Hence, it is still unclear which structures underlie the sexual arousal response in homosexual and heterosexual men. AIM: Neural activity and subjective responses were investigated in order to disentangle sexual from general arousal. Considering sexual orientation, differential and conjoint neural activations were of interest. METHODS: The functional magnetic resonance imaging (fMRI) study focused on the neural networks involved in the processing of sexual stimuli in 21 male participants (11 homosexual, 10 heterosexual). Both groups viewed pictures with erotic content as well as aversive and neutral stimuli. The erotic pictures were subdivided into three categories (most sexually arousing, least sexually arousing, and rest) based on the individual subjective ratings of each participant. MAIN OUTCOME MEASURES: Blood oxygen level-dependent responses measured by fMRI and subjective ratings. RESULTS: A conjunction analysis revealed conjoint neural activation related to sexual arousal in thalamus, hypothalamus, occipital cortex, and nucleus accumbens. Increased insula, amygdala, and anterior cingulate gyrus activation could be linked to general arousal. Group differences emerged neither when viewing the most sexually arousing pictures compared with highly arousing aversive pictures nor compared with neutral pictures. CONCLUSION: Results suggest that a widespread neural network is activated by highly sexually arousing visual stimuli. A partly distinct network of structures underlies sexual and general arousal effects. The processing of preferred, highly sexually arousing stimuli recruited similar structures in homosexual and heterosexual males.

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.

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

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

An important feature of addiction is the high drug craving that may promote the continuation of consumption. Environmental stimuli classically conditioned to drug-intake have a strong motivational power for addicts and can elicit craving. However, addicts differ in the attitudes towards their own consumption behavior: some are content with drug taking (consonant users) whereas others are discontent (dissonant users). Such differences may be important for clinical practice because the experience of dissonance might enhance the likelihood to consider treatment. This fMRI study investigated in smokers whether these different attitudes influence subjective and neural responses to smoking stimuli. Based on self-characterization, smokers were divided into consonant and dissonant smokers. These two groups were presented smoking stimuli and neutral stimuli. Former studies have suggested differences in the impact of smoking stimuli depending on the temporal stage of the smoking ritual they are associated with. Therefore, we used stimuli associated with the beginning (BEGIN-smoking-stimuli) and stimuli associated with the terminal stage (END-smoking-stimuli) of the smoking ritual as distinct stimulus categories. Stimulus ratings did not differ between both groups. Brain data showed that BEGIN-smoking-stimuli led to enhanced mesolimbic responses (amygdala, hippocampus, insula) in dissonant compared to consonant smokers. In response to END-smoking-stimuli, dissonant smokers showed reduced mesocortical responses (orbitofrontal cortex, subcallosal cortex) compared to consonant smokers. These results suggest that smoking stimuli with a high incentive value (BEGIN-smoking-stimuli) are more appetitive for dissonant than consonant smokers at least on the neural level. To the contrary, smoking stimuli with low incentive value (END-smoking-stimuli) seem to be less appetitive for dissonant smokers than consonant smokers. These differences might be one reason why dissonant smokers experience difficulties in translating their attitudes into an actual behavior change.

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.

Findings from animal as well as human neuroimaging studies suggest that reward delivery is associated with the activation of subcortical limbic and prefrontal brain regions, including the thalamus, the striatum, the anterior cingulate and the prefrontal cortex. The aim of the present study was to explore if these reward-sensitive regions are also activated during the anticipation of reinforcers that vary with regard to their motivational value. A differential conditioning paradigm was performed, with the presentation of a rewarded reaction time task serving as the unconditioned stimulus (US). Depending on their reaction time, subjects were given (or not given) a monetary reward, or were presented with a verbal feedback consisting of being fast or slow. In a third control condition no task needed to be executed. Each of the three conditions was introduced by a different visual cue (CS). Brain activation of 27 subjects was recorded using event-related functional magnetic resonance imaging. The results showed significant activation of the substantia nigra, thalamic, striatal, and orbitofrontal brain regions as well as of the insula and the anterior cingulate during the presentation of a CS signalling a rewarded task. The anticipation of a monetary reward produced stronger activation in these regions than the anticipation of positive verbal feedback. The results are interpreted as reflecting the motivation-dependent reactivity of the brain reward system with highly motivating stimuli (monetary reward) leading to a stronger activation than those less motivating ones (verbal reward).

Many studies investigating music processing in adult musicians and nonmusicians point towards pronounced behavioral and neurophysiological differences between the two groups. Recent studies indicate that these differences can already be found in early childhood. Further, electro-encephalography studies using musical discrimination tasks have demonstrated that differences in music processing become more pronounced when explicitly rather than implicitly trained musical abilities are required. Exploring the functional neuroanatomy underlying the processing of different expectation violations in children and its association with musical training, we investigated neural responses to different melodic deviances in musically trained and untrained children. Using functional magnetic resonance imaging, children (aged 11-14 years) were examined while comparing pairs of short melodies that were either identical or differed with respect to four notes. The implemented deviances were either subtle (by inserting plausible in-key notes) or obvious (by inserting implausible out-of-key notes). Our results indicate a strong association between musical training and functional neuroanatomy of the brain. Similar to research on music processing in adults, the processing of obvious melodic deviances activated a network involving inferior frontal, premotor and anterior insula regions in musically trained and untrained children. By contrast, subtle deviances led to activation in the inferior frontal and premotor cortex, the anterior insula, the superior temporal gyrus, and the supramarginal gyrus in musically trained children only. Our work provides further insights into the functional neuroanatomy of melody processing and its association with musical training in children, providing the basis for further studies specifying distinct musical processes (e.g. contour and interval processing).

Findings from animal as well as human neuroimaging studies suggest that reward delivery is associated with the activation of subcortical limbic and prefrontal brain regions, including the thalamus, the striatum, the anterior cingulate and the prefrontal cortex. The aim of the present study was to explore if these reward-sensitive regions are also activated during the anticipation of reinforcers that vary with regard to their motivational value. A differential conditioning paradigm was performed, with the presentation of a rewarded reaction time task serving as the unconditioned stimulus (US). Depending on their reaction time, subjects were given (or not given) a monetary reward, or were presented with a verbal feedback consisting of being fast or slow. In a third control condition no task needed to be executed. Each of the three conditions was introduced by a different visual cue (CS). Brain activation of 27 subjects was recorded using event-related functional magnetic resonance imaging. The results showed significant activation of the substantia nigra, thalamic, striatal, and orbitofrontal brain regions as well as of the insula and the anterior cingulate during the presentation of a CS signalling a rewarded task. The anticipation of a monetary reward produced stronger activation in these regions than the anticipation of positive verbal feedback. The results are interpreted as reflecting the motivation-dependent reactivity of the brain reward system with highly motivating stimuli (monetary reward) leading to a stronger activation than those less motivating ones (verbal reward).

We investigated subjective and hemodynamic responses towards disgust-inducing, fear-inducing, and neutral pictures in a functional magnetic resonance imaging study. Within an interval of 1 week, 24 male subjects underwent the same block design twice in order to analyze possible response changes to the repeated picture presentation. The results showed that disgust-inducing and fear-inducing scenes provoked a similar activation pattern in comparison to neutral scenes. This included the thalamus, primary and secondary visual fields, the amygdala, the hippocampus, and various regions of the prefrontal cortex. During the retest, the affective ratings hardly changed. In contrast, most of the previously observed brain activations disappeared, with the exception of the temporo-occipital activation. An additional analysis, which compared the emotion-related activation patterns during the two presentations, showed that the responses to the fear-inducing pictures were more stable than the responses to the disgust-inducing ones.

We investigated subjective and hemodynamic responses towards disgust-inducing, fear-inducing, and neutral pictures in a functional magnetic resonance imaging study. Within an interval of 1 week, 24 male subjects underwent the same block design twice in order to analyze possible response changes to the repeated picture presentation. The results showed that disgust-inducing and fear-inducing scenes provoked a similar activation pattern in comparison to neutral scenes. This included the thalamus, primary and secondary visual fields, the amygdala, the hippocampus, and various regions of the prefrontal cortex. During the retest, the affective ratings hardly changed. In contrast, most of the previously observed brain activations disappeared, with the exception of the temporo-occipital activation. An additional analysis, which compared the emotion-related activation patterns during the two presentations, showed that the responses to the fear-inducing pictures were more stable than the responses to the disgust-inducing ones.

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 aim of this fMRI study was to explore brain structures that are involved in the processing of erotic and disgust-inducing pictures. The stimuli were chosen to trigger approach and withdrawal tendencies, respectively. By adding sadomasochistic (SM) scenes to the design and examining 12 subjects with and 12 subjects without sadomasochistic preferences, we introduced a picture category that induced erotic pleasure in one sample and disgust in the other sample. Since we also presented neutral pictures, all subjects viewed pictures of four different categories: neutral, disgust-inducing, erotic, and SM erotic pictures. The analysis indicated that several brain structures are commonly involved in the processing of disgust-inducing and erotic pictures (occipital cortex, hippocampus, thalamus, and the amygdala). The ventral striatum was specifically activated when subjects saw highly sexually arousing pictures. This indicates the involvement of the human reward system during the processing of visual erotica.

The aim of this fMRI study was to explore brain structures that are involved in the processing of erotic and disgust-inducing pictures. The stimuli were chosen to trigger approach and withdrawal tendencies, respectively. By adding sadomasochistic (SM) scenes to the design and examining 12 subjects with and 12 subjects without sadomasochistic preferences, we introduced a picture category that induced erotic pleasure in one sample and disgust in the other sample. Since we also presented neutral pictures, all subjects viewed pictures of four different categories: neutral, disgust-inducing, erotic, and SM erotic pictures. The analysis indicated that several brain structures are commonly involved in the processing of disgust-inducing and erotic pictures (occipital cortex, hippocampus, thalamus, and the amygdala). The ventral striatum was specifically activated when subjects saw highly sexually arousing pictures. This indicates the involvement of the human reward system during the processing of visual erotica.