Placebo Responses to Original vs. Generic ASA Brands During Exposure to Noxious Heat: A Pilot fMRI Study of Neurofunctional Correlates.

OBJECTIVE: We studied the expectation effects associated with brands by labeling placebo interventions (original and generic analgesic) and investigating the potential differences in efficacy between the two placebos in dealing with noxious heat pain, as well as exploring the neurometabolic correlates of the placebo response. DESIGN: We applied a two by two design with two identical placebo interventions that differed only in their labeling. One group was told that they received 500 mg of "Aspirin" (original brand) while the other group was told that they received a popular ASA generic (1A Pharma). After establishing the individual pain level of each subject, we measured pain intensities behaviorally before and after the intervention and looked for corresponding brain areas with increased hemodynamic response using functional magnetic resonance imaging. RESULTS: At the behavioral level, we found decreases in pain intensity from baseline to the intervention condition with the original brand only. At the neuronal level, we specifically observed activations of the anterior insulae under the baseline conditions, complemented by activations of the dorsomedial prefrontal cortex after the interventions. A direct comparison of the two placebo conditions revealed higher values of activation for the bilateral dorsolateral (as well as dorsomedial) prefrontal cortex for the original brand. CONCLUSION: Our data indicate a behavioral placebo response for the original brand only. Expectations by subjects appear to be triggered not only by the placebo treatment itself but also by the trusted brand, which thus serves as an enhanced placebo. Both processes appear to be based on fronto-cortical neural networks, as these areas showed significantly stronger activations with the original brand.

Neural correlates of moral judgments in first- and third-person perspectives: implications for neuroethics and beyond.

BACKGROUND: There appears to be an inconsistency in experimental paradigms used in fMRI research on moral judgments. As stimuli, moral dilemmas or moral statements/ pictures that induce emotional reactions are usually employed; a main difference between these stimuli is the perspective of the participants reflecting first-person (moral dilemmas) or third-person perspective (moral reactions). The present study employed functional magnetic resonance imaging (fMRI) in order to investigate the neural correlates of moral judgments in either first- or third-person perspective. RESULTS: Our results indicate that different neural mechanisms appear to be involved in these perspectives. Although conjunction analysis revealed common activation in the anterior medial prefrontal cortex, third person-perspective elicited unique activations in hippocampus and visual cortex. The common activation can be explained by the role the anterior medial prefrontal cortex may play in integrating different information types and also by its involvement in theory of mind. Our results also indicate that the so-called "actor-observer bias" affects moral evaluation in the third-person perspective, possibly due to the involvement of the hippocampus. We suggest two possible ways in which the hippocampus may support the process of moral judgment: by the engagement of episodic memory and its role in understanding the behaviors and emotions of others. CONCLUSION: We posit that these findings demonstrate that first or third person perspectives in moral cognition involve distinct neural processes, that are important to different aspects of moral judgments. These results are important to a deepened understanding of neural correlates of moral cognition-the so-called "first tradition" of neuroethics, with the caveat that any results must be interpreted and employed with prudence, so as to heed neuroethics "second tradition" that sustains the pragmatic evaluation of outcomes, capabilities and limitations of neuroscientific techniques and technologies.

Self processing in the brain: a paradigmatic fMRI case study with a professional singer.

Understanding the mechanisms involved in perception and conception of oneself is a fundamental psychological topic with high relevance for psychiatric and neurological issues, and it is one of the great challenges in neuroscientific research. The paradigmatic single-case study presented here aimed to investigate different components of self- and other-processes and to elucidate corresponding neurobiological underpinnings. An eminent professional opera singer with profound performance experience has undergone functional magnetic resonance imaging and was exposed to excerpts of Mozart arias, sung by herself or another singer. The results indicate a distinction between self- and other conditions in cortical midline structures, differentially involved in self-related and self-referential processing. This lends further support to the assumption of cortical midline structures being involved in the neural processing of self-specific stimuli and also confirms the power of single case studies as a research tool.

Neurocognitive processing of body representations in artistic and photographic images.

Visual art because of its artistic context can be related to the general idea of providing alternative perceptual experiences. However, research examining the neural basis of art beyond the paradigm of beauty has been neglected. This study seeks to determine how the perception of a body in an artwork can be distinguished from the perception of a body in a non-artistic photography. While viewing different body representations in both artworks and photographs, subjects were required to evaluate the appeal of the portrayed persons. By using functional magnetic resonance imaging (fMRI) we show that the perception of a body within the context of art leads to a higher activation in the right parietal cortex and the extrastriate cortex bilaterally. Relating this result to concepts from previous research, we suggest that the perception of art is linked to visuo-spatial coding and also motor mapping. In contrast, the higher activity in the ventromedial prefrontal cortex and the primary visual cortex during the perception of a body in a non-artistic frame of reference, i.e. in a photograph, can be linked to processes of person evaluation. Possibly, the task to judge the appeal of a person in a photograph might be more daunting and, thus, cause emotional and even moral challenges being reflected in the ventromedial prefrontal activity. Taken together, perceptual experiences within an artistic vs. a non-artistic frame of reference are based on distinct patterns of neuronal activity.

Classifying fMRI-derived resting-state connectivity patterns according to their daily rhythmicity.

The vast majority of biological functions express rhythmic fluctuations across the 24-hour day. We investigated the degree of daily modulation across fMRI (functional Magnetic Resonance Imaging) derived resting-state data in 15 subjects by evaluating the time courses of 20 connectivity patterns over 8h (4 sessions). For each subject, we determined the chronotype, which describes the relationship between the individual circadian rhythm and the local time. We could therefore analyze the daily time course of the connectivity patterns controlling for internal time. Furthermore, as the participants' scan times were staggered as a function of their chronotype, we prevented sleep deprivation and kept time awake constant across subjects. Individual functional connectivity within each connectivity pattern was defined at each session as connectivity strength measured by a mean z-value and, in addition, as the spatial extent expressed by the number of activated voxels. Highly rhythmic connectivity patterns included two sub-systems of the Default-Mode Network (DMN) and a network extending over sensori-motor regions. The network characterized as the most stable across the day is mainly associated with processing of executive control. We conclude that the degree of daily modulation largely varies across fMRI derived resting-state connectivity patterns, ranging from highly rhythmic to stable. This finding should be considered when interpreting results from fMRI studies.

fMRI correlates of inhibition of return in perifoveal and peripheral visual field.

When a target appears in the same peripheral location as a previous cue, responding is typically delayed if the cue-target interval is relatively long. This phenomenon is termed inhibition of return (IOR) and has been suggested to reflect an attentional bias in favour of novel visual space. It has been demonstrated recently that IOR is much stronger in the far periphery than in the perifoveal visual field. The present study further investigated the neural mechanisms underlying this eccentricity effect of IOR with an event-related fMRI technique. The results demonstrated a stronger activation in visual cortex for perifoveal processing and a broader activation in multiple brain areas for peripheral processing. When IOR effects were compared between these two areas, a stronger activation of the fronto-parietal network was evidenced for perifoveal versus peripheral IOR, while the prefrontal cortex was more strongly involved in the peripheral IOR versus perifoveal IOR. These results suggest that different neural mechanisms are mediating the dissociable inhibitory functions between the perifoveal and peripheral visual field.

A disembodied man: A case of somatopsychic depersonalization in schizotypal disorder.

In the general concept of self-disturbances in schizophrenia and schizophrenia spectrum disorders, somatopsychic depersonalization (SPD) occupies a special place as it constitutes a syndrome that comprises feelings of detachment from one's own body and mental processes. However, apart from clinical descriptions, to date the pathophysiology of SPD is not fully understood due to the rareness of the syndrome and a lack of experimental studies. In a case study of one patient with schizotypal disorder, we applied a multimodal approach to understanding the SPD phenomena. The patient's clinical profile was identified as disruption of implicit bodily function, accompanied by depressive symptoms. On a neuropsychological level, the patient exhibited impairment in executive functioning, intact tactile perception and kinesthetic praxis. Behavioral tests revealed an altered sense of time but unimpaired self-agency. Furthermore, the patient exhibited a lack of empathy and he had autistic traits, although with a sufficient ability to verbalize his feelings. On the neurobiological level using an active and passive touch paradigm during functional magnetic resonance imaging (fMRI), we found a hyperconnectivity of the default-mode network and salience network and a hypoconnectivity of the central executive brain networks in the performance of the touch task as well as intact perceptual touch processing emerging from the direct comparisons of the touch conditions. Our data provide evidence for the important role of altered large-brain network functioning in SPD that corresponds to the specific behavioral and neurocognitive phenomena.

Neurofunctional correlates of environmental cognition: an FMRI study with images from episodic memory.

This study capitalizes on individual episodic memories to investigate the question, how dif-ferent environments affect us on a neural level. Instead of using predefined environmental stimuli, this study relied on individual representations of beauty and pleasure. Drawing upon episodic memories we conducted two experiments. Healthy subjects imagined pleasant and non-pleasant environments, as well as beautiful and non-beautiful environments while neural activity was measured by using functional Magnetic Resonance Imaging. Although subjects found the different conditions equally simple to visualize, our results revealed more distribut-ed brain activations for non-pleasant and non-beautiful environments than for pleasant and beautiful environments. The additional regions activated in non-pleasant (left lateral prefrontal cortex) and non-beautiful environments (supplementary motor area, anterior cortical midline structures) are involved in self-regulation and top-down cognitive control. Taken together, the results show that perceptual experiences and emotional evaluations of environments within a positive and a negative frame of reference are based on distinct patterns of neural activity. We interpret the data in terms of a different cognitive and processing load placed by exposure to different environments. The results hint at the efficiency of subject-generated representations as stimulus material.

Sadness is unique: neural processing of emotions in speech prosody in musicians and non-musicians.

Musical training has been shown to have positive effects on several aspects of speech processing, however, the effects of musical training on the neural processing of speech prosody conveying distinct emotions are yet to be better understood. We used functional magnetic resonance imaging (fMRI) to investigate whether the neural responses to speech prosody conveying happiness, sadness, and fear differ between musicians and non-musicians. Differences in processing of emotional speech prosody between the two groups were only observed when sadness was expressed. Musicians showed increased activation in the middle frontal gyrus, the anterior medial prefrontal cortex, the posterior cingulate cortex and the retrosplenial cortex. Our results suggest an increased sensitivity of emotional processing in musicians with respect to sadness expressed in speech, possibly reflecting empathic processes.

Differences between musicians and non-musicians in neuro-affective processing of sadness and fear expressed in music.

Music is known to convey and evoke emotional states. Musical training has been argued to lead to changes in neural architecture and enhanced processing of emotions. It is not clear, however, whether musical training is also associated with changes in behavioral and neural responses to musically conveyed discrete emotions. Using functional magnetic resonance imaging, we investigated the responses to three musically conveyed emotions (happiness, sadness, fear) in a group of musicians and a group of non-musicians. We find that musicians rate sadness and fear as significantly more arousing than non-musicians, and that musical training is associated with specific neural activations: In response to sadness expressed in music, musicians show activation increases in the right prefrontal cortex, specifically in the superior and middle frontal gyri. In response to fear, musicians show activation increases in the right parietal cortex, specifically in the supramarginal and inferior parietal gyri. No specific activations were observed in response to happiness. Our results highlight the strong association between musical training and altered processing of "negative" emotions on both the behavioral and on the neural level.

Existential neuroscience: effects of mortality salience on the neurocognitive processing of attractive opposite-sex faces.

Being reminded of the inherently finite nature of human existence has been demonstrated to elicit strivings for sexual reproduction and the formation and maintenance of intimate relationships. Recently, it has been proposed that the perception of potential mating partners is influenced by mortality salience. Using functional magnetic resonance imaging, we investigated the neurocognitive processing of attractive opposite-sex faces after priming with death-related words for heterosexual men and women. Significant modulations of behavioral and neural responses were found when participants were requested to decide whether they would like to meet the presented person. Men were more in favor of meeting attractive women after being primed with death-related words compared to a no-prime condition. Increased neural activation could be found under mortality salience in the left anterior insula and the adjacent lateral prefrontal cortex (lPFC) for both men and women. As previously suggested, we believe that the lPFC activation reflects an approach-motivated defense mechanism to overcome concerns that are induced by being reminded of death and dying. Our results provide insight on a neurocognitive level that approach motivation in general, and mating motivation in particular is modulated by mortality salience.

Dysregulated daily rhythmicity of neuronal resting-state networks in MCI patients.

In young healthy participants, the degree of daily rhythmicity largely varies across different neuronal resting-state networks (RSNs), while it is to date unknown whether this temporal pattern of activity is conserved in healthy and pathological aging. Twelve healthy elderly (mean age=65.1±5.7 years) and 12 patients with amnestic mild cognitive impairment (aMCI; mean age=69.6±6.2 years) underwent four resting-state functional magnetic resonance imaging scans at fixed 2.5 h intervals throughout a day. Time courses of a RSN were extracted by a connectivity strength and a spatial extent approach performed individually for each participant. Highly rhythmic RSNs included a sensorimotor, a cerebellar and a visual network in healthy elderly; the least rhythmic RSNs in this group included a network associated with executive control and an orbitofrontal network. The degree of daily rhythmicity in aMCI patients was reduced and dysregulated. For healthy elderly, the findings are in accordance with results reported for young healthy participants suggesting a comparable distribution of daily rhythmicity across RSNs during healthy aging. In contrast, the reduction and dysregulation of daily rhythmicity observed in aMCI patients is presumably indicative of underlying neurodegenerative processes in this group.

Neurofunctional correlates of esthetic and moral judgments.

Recent neuroimaging studies indicate that there may be common ground for esthetic and moral judgments. However, because previous studies focused on either esthetic or moral judgments and did not compare the two directly, the issue remains open whether a common ground actually exists. We employed functional magnetic resonance imaging in order to study, in a within-subjects design, the potential equivalence of esthetic and moral judgments. One-line verses from poems and short moral statements were used as stimuli. Our results suggest a common basis for the two judgment categories, revealing comparable neural networks mainly the orbitomedial prefrontal cortex. However, additional activations were found in the moral judgment condition, that is, in the posterior cingulate cortex, the precuneus, and the temporoparietal junction. These regions have been related to understanding the minds of others.

Personality traits modulate neural responses to emotions expressed in music.

Music communicates and evokes emotions. The number of studies on the neural correlates of musical emotion processing is increasing but few have investigated the factors that modulate these neural activations. Previous research has shown that personality traits account for individual variability of neural responses. In this study, we used functional magnetic resonance imaging (fMRI) to investigate how the dimensions Extraversion and Neuroticism are related to differences in brain reactivity to musical stimuli expressing the emotions happiness, sadness and fear. 12 participants (7 female, M=20.33 years) completed the NEO-Five Factor Inventory (NEO-FFI) and were scanned while performing a passive listening task. Neurofunctional analyses revealed significant positive correlations between Neuroticism scores and activations in bilateral basal ganglia, insula and orbitofrontal cortex in response to music expressing happiness. Extraversion scores were marginally negatively correlated with activations in the right amygdala in response to music expressing fear. Our findings show that subjects' personality may have a predictive power in the neural correlates of musical emotion processing and should be considered in the context of experimental group homogeneity.

Culture and its neurofunctional correlates when death is in mind.

The human fear of death is marked by specific psychological reactions that affirm cultural belonging. Terror management theory explains this phenomenon with the symbolic immortality provided by collective meaning in culture. This coping has also been explained with the motive of maintaining a meaningful representation of the world. Here we show that neural patterns of activations corresponding to cultural worldview defense processes differed when images that affirmed participants' cultural heritage were preceded by death-related verbal primes versus verbal primes threatening meaning. Cultural content was drawn upon distinctly on a neural basis when facing death-related cognitions. The neural representation of cultural coping sheds light on the immediate mechanisms in compensating the human fear of death.

Matching reality in the arts: self-referential neural processing of naturalistic compared to surrealistic images.

How are works of art that present scenes that match potential expectations processed in the brain, in contrast to such scenes that can never occur in real life because they would violate physical laws? Using functional magnetic resonance imaging, we investigated the processing of surrealistic and naturalistic images in visual artworks. Looking at naturalistic paintings leads to a significantly higher activation in the visual cortex and in the precuneus. Humans apparently own a sensitive mechanism even for artistic representations of the visual world to separate the impossible from what potentially matches physical reality. The observation reported here also suggests that sensory input corresponding to a realistic representation of the visual world elicits higher self-referential processing.

Chronotype predicts activity patterns in the neural underpinnings of the motor system during the day.

Neuroimaging is increasingly used to study the motor system in vivo. Despite many reports of time-of-day influences on motor function at the behavioral level, little is known about these influences on neural motor networks and their activations recorded in neuroimaging. Using functional magnetic resonance imaging (fMRI), the authors studied 15 healthy subjects (9 females; mean ± SD age: 23 ± 3 yrs) performing a self-paced finger-tapping task at different times of day (morning, midday, afternoon, and evening). Blood-oxygenation-level-dependent signal showed systematic differences across the day in task-related motor areas of the brain, specifically in the supplementary motor area, parietal cortex, and rolandic operculum (p(corr)< .0125). The authors found that these time-of-day-dependent hemodynamic modulations are associated with chronotype and not with homeostatic sleep pressure. These results show that consideration of time-of-day for the analysis of fMRI studies is imperative.

Functional neuroimaging of duration discrimination on two different time scales.

Analyses of neural mechanisms of duration processing are essential for the understanding of psychological phenomena which evolve in time. Different mechanisms are presumably responsible for the processing of shorter (below 500 ms) and longer (above 500 ms) events but have not yet been a subject of an investigation with functional magnetic resonance imaging (fMRI). In the present study, we show a greater involvement of several brain regions - including right-hemispheric midline structures and left-hemispheric lateral regions - in the processing of visual stimuli of shorter as compared to longer duration. We propose a greater involvement of lower-level cognitive mechanisms in the processing of shorter events as opposed to higher-level mechanisms of cognitive control involved in longer events.