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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.

Patients suffering from obsessive-compulsive disorder (OCD) are characterized by dysregulated neuronal processing of disorder-specific and also unspecific affective stimuli. In the present study, we investigated whether generic fear-inducing, disgust-inducing, and neutral stimuli can be decoded from brain patterns of single fMRI time samples of individual OCD patients and healthy controls. Furthermore, we tested whether differences in the underlying encoding provide information to classify subjects into groups (OCD patients or healthy controls). Two pattern classification analyses were conducted. In analysis 1, we used a classifier to decode the category of a currently viewed picture from extended fMRI patterns of single time samples (TR=3s) in individual subjects for several pairs of categories. In analysis 2, we used a searchlight approach to predict subjects' diagnostic status based on local brain patterns. In analysis 1, we obtained significant accuracies for the separation of fear-eliciting from neutral pictures in OCD patients and healthy controls. Separation of disgust-inducing from neutral pictures was significant in healthy controls. In analysis 2, we identified diagnostic information for the presence of OCD in the orbitofrontal cortex, and in the caudate nucleus. Accuracy obtained in these regions was 100% (p<10(-6)). To summarize our findings, by using multivariate pattern classification techniques we were able to identify neurobiological markers providing reliable diagnostic information about OCD. The classifier-based fMRI paradigms proposed here might be integrated in future diagnostic procedures and treatment concepts.

The understanding of individual differences in responses to disgusting stimuli is important to gain more insight into the development of certain psychiatric disorders. The aim of this study was to investigate conditioned disgust responses, its potential overlap with conditioned fear responses (CRs) and the influence of disgust sensitivity on blood oxygen level-dependent responses. Yet even though current studies report evidence that disgust sensitivity is a vulnerability factor, the knowledge about the underlying neural mechanisms remains very limited. Two groups were exposed either to a disgust- or a fear-conditioning paradigm. Using functional magnetic resonance imaging, we identified a conjoint activated network including the cingulate cortex, the nucleus accumbens, the orbitofrontal cortex, and the occipital cortex within the disgust- and the fear-conditioning group. Moreover, we report evidence of increased insula activation in the disgust-conditioning group. In addition, functional connectivity analysis revealed increased interconnections, most pronounced within the insula in the high disgust sensitivity group compared with the low disgust sensitivity group. The conjunction results suggest that the conditioned responses in disgust and fear conditioning recruit the same neural network, implicating that different conditioned responses of aversive learning depend on a common neural network. Increased insula activation within the disgust-conditioning group might be attributable to heightened interoceptive processes, which might be more pronounced in disgust. Finally, the findings regarding disgust sensitivity are discussed with respect to vulnerability factors for certain psychiatric disorders.

Remembering something that has not in fact been experienced is commonly referred to as false memory. The Deese-Roediger-McDermott (DRM) paradigm is a well-elaborated approach to this phenomenon. This study attempts to investigate the peripheral physiology of false memories induced in a visual DRM paradigm. The main research question is whether false recognition is different from true recognition in terms of accompanying physiological responses.Sixty subjects participated in the experiment, which included a study phase with visual scenes each showing a group of interrelated items in social contexts. Subjects were divided into an experimental group undergoing a classical DRM design and a control group without DRM manipulation. The control group was implemented in order to statistically control for possible biases produced by memorability differences between stimulus types. After a short retention interval, a pictorial recognition phase was conducted in the manner of a Concealed Information Test. Simultaneous recordings of electrodermal activity, respiration line length, phasic heart rate, and finger pulse waveform length were used. Results yielded a significant Group by Item Type interaction, showing that true recognition is accompanied by greater electrodermal activity than false recognition.Results are discussed in the light of Sokolov's Orienting Reflex, the Preliminary Process Theory and the Concealed Information Test. Implications and restrictions of the introduced design features are critically discussed. This study demonstrates the applicability of measures of peripheral physiology to the field of false memory research.

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.

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.

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.

Physiological responses in the Concealed Information Test (CIT) are known to depend on the depth of encoding critical items; CIT questions commonly refer to knowledge about critical items. It is unclear to what extent (1) different modes of item handling in a mock-crime, and (2) alternative questioning formats, e.g. asking about participants' particular actions with the critical items, influence the physiological responses. In the presented mock-crime study with fifty-three participants, two questioning formats, i.e. "Did you see …?" (viewing questioning) and "Did you steal …?" (stealing questioning), were compared between subjects. The mode of encoding, stealing vs. merely viewing the critical objects, was varied within subject. Skin conductance, electrocardiogram, respiration, and finger pulse were recorded. For both questioning formats and each physiological measure, physiological responses to stolen as well as merely viewed objects differed from those to irrelevant objects. Considering viewing questioning, responses to stolen and merely viewed objects did not differ, with the exception of greater phasic decreases of heart rate for stolen objects. Considering stealing questioning, responses to stolen objects exceeded those to merely viewed objects with each physiological measure. The statistically proven interaction between mode of encoding a particular object and questioning format sheds light on the factors influencing the physiological responses in a CIT. The level of subjective significance of a particular item might emerge interactively from the mode of item handling and the questioning format.

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.

During observation of an ambiguous Necker cube, our percept changes spontaneously although the external stimulus does not. An EEG paradigm allowing time-resolved EEG measurement during endogenous perceptual reversals recently revealed a chain of ERP correlates beginning with an early occipital positivity at around 130 ms (Reversal Positivity, "RP"). In order to better understand the functional role of this RP, we investigated its relation to the P100, which is spatiotemporally close, typically occurring 100 ms after onset of a visual stimulus at occipital electrodes. We compared the relation of the ERP amplitudes to varying sizes of ambiguous Necker cubes. The main results are: (1) The P100 amplitude increases monotonically with stimulus size but is independent of the participants' percept. (2) The RP, in contrast, is percept-related and largely unaffected by stimulus size. (3) A similar pattern to RP was found for reaction times: They depend on the percept but not on stimulus size. We speculate that the P100 reflects processing of elementary visual features, while the RP is related to a processing conflict during 3D interpretation that precedes a reversal. The present results indicate that low-level visual processing (related to stimulus size) and (relative) high-level processing (related to perceptual reversal) occur in close spatial and temporal vicinity.

One approach to investigate psychophysiological processes occurring in the Concealed Information Test (CIT) is to use a parallel task, which engages specific mental activity in addition to the CIT. In the present study, the influence of an interfering n-back task on the physiological responses in a Concealed Information Test (CIT) was investigated. Forty participants underwent a mock-crime experiment with a modified CIT. In a within-subject design, the CIT was applied in blocks with and without an additional n-back task. Electrodermal activity (EDA), respiration line length (RLL), heart rate (HR), and finger pulse waveform length (FPWL) were registered. Reaction times in the n-back task and the CIT were recorded. The parallel task enhanced the differential EDA response to probe vs. irrelevant items, while it diminished the response differences for RLL and phasic HR. Results shed light upon working-memory-related processes in the CIT. The diverging effects of the interfering mental activity on electrodermal and cardiopulmonary measures, if replicable, might contribute to a better understanding of the psychophysiological responsiveness underlying the CIT.

Ambiguous figures induce sudden transitions between rivaling percepts. We investigated electroencephalogram frequency modulations of accompanying change-related de- and rebinding processes. Presenting the stimuli discontinously, we synchronized perceptual reversals with stimulus onset, which served as a time reference for averaging. The resultant gain in temporal resolution revealed a sequence of time-frequency correlates of the reversal process. Most conspicuous was a transient right-hemispheric gamma modulation preceding endogenous reversals by at least 200 ms. No such modulation occurred with exogenously induced reversals of unambiguous stimulus variants. Post-onset components were delayed for ambiguous compared to unambiguous stimuli. The time course of oscillatory activity differed in several respects from predictions based on binding-related hypotheses. The gamma modulation preceding endogenous reversals may indicate an unstable brain state, ready to switch.

Recent research suggests that our sense of time intervals in the range of seconds is directly related to activity in the insular cortex, which contains the primary sensory area for interoception. We therefore investigated whether performance in a duration reproduction task might correlate with individual interoceptive awareness and with measurable changes in autonomic activity during the task. Thirty-one healthy volunteers participated in an interoceptive (heartbeat) perception task and in repeated temporal reproduction trials using intervals of 8, 14, and 20s duration while skin conductance levels and cardiac and respiratory periods were recorded. We observed progressive increases in cardiac periods and decreases in skin conductance level during the encoding and (less reliably) the reproduction of these intervals. Notably, individuals' duration reproduction accuracy correlated positively both with the slope of cardiac slowing during the encoding intervals and with individual heartbeat perception scores. These results support the view that autonomic function and interoceptive awareness underpin our perception of time intervals in the range of seconds.

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.

Perceiving a first target stimulus (T1) in a rapid serial visual presentation stream results in a transient impairment in detecting a second target (T2). This "attentional blink" is modulated by the emotional relevance of T1 and T2. The present experiment examined the neural underpinnings of the emotional modulation of the attentional blink. Behaviorally, the attentional blink was reduced for emotional T2 while emotional T1 led to a prolonged attentional blink. Using functional magnetic resonance imaging, we observed amygdala activation associated with the reduced attentional blink for emotional T2 in the face of neutral T1. The prolonged attentional blink following emotional T1 was correlated with enhanced activity in a cortical network including the anterior cingulate cortex, the insula and the orbitofrontal cortex. These results suggest that brain areas previously implicated in rather reflexive emotional reactions are responsible for the reduced attentional blink for emotional T2 whereas neural structures previously related to higher level processing of emotional information mediate the prolonged attentional blink following emotional T1.

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.

The present study examined the neural basis of vivid motor imagery with parametrical functional magnetic resonance imaging. 22 participants performed motor imagery (MI) of six different right-hand movements that differed in terms of pointing accuracy needs and object involvement, i.e., either none, two big or two small squares had to be pointed at in alternation either with or without an object grasped with the fingers. After each imagery trial, they rated the perceived vividness of motor imagery on a 7-point scale. Results showed that increased perceived imagery vividness was parametrically associated with increasing neural activation within the left putamen, the left premotor cortex (PMC), the posterior parietal cortex of the left hemisphere, the left primary motor cortex, the left somatosensory cortex, and the left cerebellum. Within the right hemisphere, activation was found within the right cerebellum, the right putamen, and the right PMC. It is concluded that the perceived vividness of MI is parametrically associated with neural activity within sensorimotor areas. The results corroborate the hypothesis that MI is an outcome of neural computations based on movement representations located within motor areas.

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.

BACKGROUND: Action observation leads to neural activation of the human premotor cortex. This study examined how the level of motor expertise (expert vs. novice) in ballroom dancing and the visual viewpoint (internal vs. external viewpoint) influence this activation within different parts of this area of the brain. RESULTS: Sixteen dance experts and 16 novices observed ballroom dance videos from internal or external viewpoints while lying in a functional magnetic resonance imaging scanner. A conjunction analysis of all observation conditions showed that action observation activated distinct networks of premotor, parietal, and cerebellar structures. Experts revealed increased activation in the ventral premotor cortex compared to novices. An internal viewpoint led to higher activation of the dorsal premotor cortex. CONCLUSIONS: The present results suggest that the ventral and dorsal premotor cortex adopt differential roles during action observation depending on the level of motor expertise and the viewpoint.