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Placebos can reduce pain by inducing beliefs in the effectiveness of an actually inert treatment. Such top-down effects on pain typically engage lateral and medial prefrontal regions, the insula, somatosensory cortex, as well as the thalamus and brainstem during pain anticipation or perception. Considering the level of large-scale brain networks, these regions spatially align with fronto-parietal/executive control, salience, and sensory-motor networks, but it is unclear if and how placebos alter interactions between them during rest. Here, we investigated how placebo analgesia affected intrinsic network coupling. Ninety-nine human participants were randomly assigned to a placebo or control group and underwent resting-state fMRI after pain processing. Results revealed inverse coupling between two resting-state networks in placebo but not control participants. Specifically, networks comprised the bilateral somatosensory cortex and posterior insula, as well as the brainstem, thalamus, striatal regions, dorsal and rostral anterior cingulate cortex, and the anterior insula, respectively. Across participants, more negative between-network coupling was associated with lower individual pain intensity as assessed during a preceding pain task, and there was no significant relation with expectations of medication effectiveness in the placebo group. Altogether, these findings provide initial evidence that placebo analgesia affects the intrinsic communication between large-scale brain networks, even in the absence of pain. We suggest a theoretical model where placebo analgesia might affect processing within a descending pain-modulatory network, potentially segregating it from somatosensory regions that may code for painful experiences.

Sex steroid hormones such as estradiol and testosterone are known to have organizing, as well as activating effects on neural tissue in animals and humans. This study investigated the effects of transgender hormone replacement therapy on white matter microstructure using diffusion tensor imaging. Female-to-male and male-to-female transgender participants were measured at baseline, four weeks and four months past treatment start and compared to female and male controls. We observed androgenization-related reductions in mean diffusivity and increases in fractional anisotropy. We also observed feminization-related increases in mean diffusivity and reductions in fractional anisotropy. In both transgender participants and controls, hormonal fluctuations were correlated with changes in white matter microstructure. Although the present study does not preclude regression to the mean as a potential contributing factor, the results indicate that sex hormones are - at least in part - responsible for white matter variability in the human brain. Studies investigating the effects of sex hormones on adult human brain structure may be an important route for greater understanding of the psychological differences between females and males.

Placebos can reduce pain by inducing beliefs in the effectiveness of an actually inert treatment. Such top-down effects on pain typically engage lateral and medial prefrontal regions, the insula, somatosensory cortex, as well as the thalamus and brainstem during pain anticipation or perception. Considering the level of large-scale brain networks, these regions spatially align with fronto-parietal/executive control, salience, and sensory-motor networks, but it is unclear if and how placebos alter interactions between them during rest. Here, we investigated how placebo analgesia affected intrinsic network coupling. Ninety-nine human participants were randomly assigned to a placebo or control group and underwent resting-state fMRI after pain processing. Results revealed inverse coupling between sensory-motor and salience-like networks in placebo but not control participants. Specifically, networks were centered on the bilateral somatosensory cortex, as well as on the brainstem, thalamus, striatal regions, dorsal and rostral anterior cingulate cortex, and the insula, respectively. Across participants, more negative between-network coupling was associated with lower individual pain intensity as assessed during a preceding pain task, but was unrelated to expectations of medication effectiveness in the placebo group. Altogether, these findings provide initial evidence that placebo analgesia affects the intrinsic communication between large-scale brain networks, even in the absence of pain. We suggest a model where placebo analgesia increases activation within a descending pain-modulatory network, segregating it from somatosensory regions that might code for painful experiences.HighlightsPlacebo analgesia affects resting-state connectivity between networks.Salience-related and somatosensory regions are negatively coupled at rest.This coupling is negative following placebo, but not in control participants.More negative between-network coupling is related to lower pain intensity.

Sex-steroid hormones are primarily involved in sexual differentiation and development and are thought to underlie processes related to cognition and emotion. However, divergent results have been reported concerning the effects of hormone administration on brain structure including side effects like brain atrophy and dementia. Cross-sex hormone therapy in transgender subjects offers a unique model for studying the effects of sex hormones on the living human brain. In this study, 25 Female-to-Male (FtM) and 14 Male-to-Female (MtF) subjects underwent MRI examinations at baseline and after a period of at least 4-months of continuous cross-sex hormone administration. While MtFs received estradiol and anti-androgens, FtM subjects underwent high-dose testosterone treatment. The longitudinal processing stream of the FreeSurfer software suite was used for the automated assessment and delineation of brain volumes to assess the structural changes over the treatment period of cross-sex hormone administration. Most prominent results were found for MtFs receiving estradiol and anti-androgens in the form of significant decreases in the hippocampal region. Further analysis revealed that these decreases were reflected by increases in the ventricles. Additionally, changes in progesterone levels correlated with changes in gray matter structures in MtF subjects. In line with prior studies, our results indicate hormonal influences on subcortical structures related to memory and emotional processing. Additionally, this study adds valuable knowledge that progesterone may play an important role in this process.

Engaging in mentalizing, i.e., reflecting on others' thoughts, beliefs and feelings, is known to facilitate later empathy and prosocial behavior. Activation in dorsomedial prefrontal (dmPFC) areas during mentalizing has been shown to predict the extent of prosocial behavior. It is unclear, however, what cognitive process drives these effects: a simulation process in which the own mental states are used as a proxy for those of others (self-projection) or an effortful other-enhancement process in which one's own perspective is overridden. In this fMRI study we examined the effects of mentalizing with similar and dissimilar others on behavioral and brain measures of empathy and prosocial behavior, to assess which cognitive process mediates the facilitative effects of mentalizing. Participants had to mentalize with two fictitious target persons, one of whom was manipulated to have similar thoughts and beliefs as the participant, while the other had dissimilar mental states. We then assessed participants' behavioral and neural responses during an empathy for pain task and a prosocial behavior task. Similarity between participant and target person increased empathy and affiliation ratings, and mentalizing with dissimilar persons evoked increased activation in ventrolateral prefrontal cortex, the extent of which was inversely related with bias towards the similar person in empathy. Responses in two dmPFC regions were also predictive of later variations in subsequent empathy and prosocial behavior, either predicting overall prosociality and empathic concern (lateral dmPFC), or predicting reduced empathic bias towards the similar person and a lower response to self-related stressors in pain matrix areas (medial dmPFC). This pattern of results suggests that generating and enhancing other-related representations while overcoming one's own perspective, rather than enhanced recruitment of self-projection processes, is driving the facilitative effects of mentalizing on later empathic and prosocial responses.

Functional MRI enables the acquisition of a retinotopic map that relates regions of the visual field to neural populations in the visual cortex. During such a "population receptive field" (PRF) experiment, stable gaze fixation is of utmost importance in order to correctly link the presented stimulus patterns to stimulated retinal regions and the resulting Blood Oxygen Level Dependent (BOLD) response of the appropriate region within the visual cortex. A method is described that compensates for unstable gaze fixation by recording gaze position via an eyetracker and subsequently modifies the input stimulus underlying the PRF analysis according to the eyetracking measures. Here we show that PRF maps greatly improve when the method is applied to data acquired with either saccadic or smooth eye movements. We conclude that the technique presented herein is useful for studies involving subjects with unstable gaze fixation, particularly elderly patient populations.

International audience; People often spontaneously engage in copying each other's postures and mannerisms, a phenomenon referred to as behavioral mimicry. Social psychology experiments indicate that mimicry denotes an implicit affiliative signal flexibly regulated in response to social requirements. Yet, the mediating processes and neural underpinnings of such regulation are largely unexplored. The present functional magnetic resonance imaging (fMRI) study examined mimicry regulation by combining an automatic imitation task with facial stimuli, varied on two social-affective dimensions: emotional expression (angry vs happy) and ethnic group membership (in-vs out-group). Behavioral data revealed increased mimicry when happy and when out-group faces were shown. Imaging results revealed that mimicry regulation in response to happy faces was associated with increased activation in the right temporo-parietal junction (TPJ), right dorsal premotor cortex (dPMC), and right superior parietal lobule (SPL). Mimicry regulation in response to out-group faces was related to increased activation in the left ventral premotor cortex (vPMC) and inferior pa-rietal lobule (IPL), bilateral anterior insula, and mid-cingulate cortex (MCC). We suggest that mimicry in response to happy and to out-group faces is driven by distinct affiliative goals, and that mimicry regulation to attain these goals is mediated by distinct neuro-cognitive processes. Higher mimicry in response to happy faces seems to denote reciprocation of an affiliative signal. Higher mimicry in response to out-group faces, reflects an appeasement attempt towards an interaction partner perceived as threatening (an interpretation supported by implicit measures showing that out-group members are more strongly associated with threat). Our findings show that subtle social cues can result in the implicit regulation of mimicry. This regulation serves to achieve distinct affiliative goals, is mediated by different regulatory processes, and relies on distinct parts of an overarching network of task-related brain areas. Our findings shed new light on the neural mechanisms underlying the interplay between implicit action control and social cognition.

Citalopram and Escitalopram are gold standard pharmaceutical treatment options for affective, anxiety, and other psychiatric disorders. However, their neurophysiologic function on cortico-limbic circuits is incompletely characterized. Here we studied the neuropharmacological influence of Citalopram and Escitalopram on cortico-limbic regulatory processes by assessing the effective connectivity between orbitofrontal cortex (OFC) and amygdala using dynamic causal modeling (DCM) applied to functional MRI data. We investigated a cohort of 15 healthy subjects in a randomized, crossover, double-blind design after 10days of Escitalopram (10mg/d (S)-citalopram), Citalopram (10mg/d (S)-citalopram and 10mg/d (R)-citalopram), or placebo. Subjects performed an emotional face discrimination task, while undergoing functional magnetic resonance imaging (fMRI) scanning at 3 Tesla. As hypothesized, the OFC, in the context of the emotional face discrimination task, exhibited a down-regulatory effect on amygdala activation. This modulatory effect was significantly increased by (S)-citalopram, but not (R)-citalopram. For the first time, this study shows that (1) the differential effects of the two enantiomers (S)- and (R)-citalopram on cortico-limbic connections can be demonstrated by modeling effective connectivity methods, and (2) one of their mechanisms can be linked to an increased inhibition of amygdala activation by the orbitofrontal cortex.

PurposeThe present study describes retinotopic mapping of the primary visual cortex using functional MRI (fMRI) in patients with retinal disease. It addresses the relationship between fMRI data and data obtained by conventional assessment including microperimetry (MP) and structural imaging.MethodsInitial testing involved eight patients with central retinal disease (Stargardt disease, STGD) and eight with peripheral retinal disease (retinitis pigmentosa, RP), who were examined using fMRI and MP (Nidek MP-1). All had a secure clinical diagnosis supported by electrophysiological data. fMRI used population-receptive field (pRF) mapping to provide retinotopic data that were then compared with the results of MP, optical coherence tomography and fundus autofluorescence imaging.ResultsFull analysis, following assessment of fMRI data reliability criteria, was performed in five patients with STGD and seven patients with RP; unstable fixation was responsible for unreliable pRF measurements in three patients excluded from final analysis. The macular regions in patients with STGD with central visual field defects and outer retinal atrophy (ORA) at the macula correlated well with pRF coverage maps showing reduced density of activated voxels at the occipital pole. Patients with RP exhibited peripheral ORA and concentric visual field defects both on MP and pRF mapping. Anterior V1 voxels, corresponding to peripheral regions, showed no significant activation. Correspondence between MP and pRF mapping was quantified by calculating the simple matching coefficient.ConclusionRetinotopic maps acquired by fMRI provide a valuable adjunct in the assessment of retinal dysfunction. The addition of microperimetric data to pRF maps allowed better assessment of macular function than MP alone. Unlike MP, pRF mapping provides objective data independent of psychophysical perception from the patient.

Objectives: Anticipatory processes prepare the organism for upcoming experiences. The aim of this study was to investigate neural responses related to anticipation and processing of painful stimuli occurring with different levels of uncertainty. Experimental design: Twenty-five participants (13 females) took part in an electroencephalography and functional magnetic resonance imaging (fMRI) experiment at separate times. A visual cue announced the occurrence of an electrical painful or nonpainful stimulus, delivered with certainty or uncertainty (50% chance), at some point during the following 15 s. Principal observations: During the first 2 s of the anticipation phase, a strong effect of uncertainty was reflected in a pronounced frontal stimulus-preceding negativity (SPN) and increased fMRI activation in higher visual processing areas. In the last 2 s before stimulus delivery, we observed stimulus-specific preparatory processes indicated by a centroparietal SPN and posterior insula activation that was most pronounced for the certain pain condition. Uncertain anticipation was associated with attentional control processes. During stimulation, the results revealed that unexpected painful stimuli produced the strongest activation in the affective pain processing network and a more pronounced offset-P2. Conclusions: Our results reflect that during early anticipation uncertainty is strongly associated with affective mechanisms and seems to be a more salient event compared to certain anticipation. During the last 2 s before stimulation, attentional control mechanisms are initiated related to the increased salience of uncertainty. Furthermore, stimulus-specific preparatory mechanisms during certain anticipation also shaped the response to stimulation, underlining the adaptive value of stimulus-targeted preparatory activity which is less likely when facing an uncertain event. Hum Brain Mapp 36:744–755, 2015. © 2014 Wiley Periodicals, Inc.

The anticipation of favourable or unfavourable events is a key component in our daily life. However, the temporal dynamics of anticipation processes in relation to brain activation are still not fully understood. A modified version of the monetary incentive delay task was administered during separate functional magnetic resonance imaging (fMRI) and electroencephalogram (EEG) sessions in the same 25 participants to assess anticipatory processes with a multi-modal neuroimaging set-up. During fMRI, gain and loss anticipation were both associated with heightened activation in ventral striatum and reward-related areas. EEG revealed most pronounced P300 amplitudes for gain anticipation, whereas CNV amplitudes distinguished neutral from gain and loss anticipation. Importantly, P300, but not CNV amplitudes, were correlated to neural activation in the ventral striatum for both gain and loss anticipation. Larger P300 amplitudes indicated higher ventral striatum blood oxygen level dependent (BOLD) response. Early stimulus evaluation processes indexed by EEG seem to be positively related to higher activation levels in the ventral striatum, indexed by fMRI, which are usually associated with reward processing. The current results, however, point towards a more general motivational mechanism processing salient stimuli during anticipation., Highlights • Monetary incentive delay task was assessed in separate EEG and fMRI sessions. • Both gain and loss anticipation activated well known reward-related areas. • P300 amplitude differentiated reward cue from non-reward cues. • P300 amplitudes positively correlated with BOLD response in the ventral striatum. • Ventral striatum activation associated with general motivational processes.

Progressing from 3T to 7 T functional MRI enables marked improvements of human brain imaging in vivo. Although direct comparisons demonstrated advantages concerning blood oxygen level dependent (BOLD) signal response and spatial specificity, these mostly focused on single brain regions with rather simple tasks. Considering that physiological noise also increases with higher field strength, it is not entirely clear whether the advantages of 7T translate equally to the entire brain during tasks which elicit more complex neuronal processing. Therefore, we investigated the difference between 3T and 7 T in response to transcutaneous electrical painful and non-painful stimulation in 22 healthy subjects. For painful stimuli vs. baseline, stronger activations were observed at 7 T in several brain regions including the insula and supplementary motor area, but not the secondary somatosensory cortex (p

Biological causes underpinning the well known gender dimorphisms in human behavior, cognition, and emotion have received increased attention in recent years. The advent of diffusion-weighted magnetic resonance imaging has permitted the investigation of the white matter microstructure in unprecedented detail. Here, we aimed to study the potential influences of biological sex, gender identity, sex hormones, and sexual orientation on white matter microstructure by investigating transsexuals and healthy controls using diffusion tensor imaging (DTI). Twenty-three female-to-male (FtM) and 21 male-to-female (MtF) transsexuals, as well as 23 female (FC) and 22 male (MC) controls underwent DTI at 3 tesla. Fractional anisotropy, axial, radial, and mean diffusivity were calculated using tract-based spatial statistics (TBSS) and fiber tractography. Results showed widespread significant differences in mean diffusivity between groups in almost all white matter tracts. FCs had highest mean diffusivities, followed by FtM transsexuals with lower values, MtF transsexuals with further reduced values, and MCs with lowest values. Investigating axial and radial diffusivities showed that a transition in axial diffusivity accounted for mean diffusivity results. No significant differences in fractional anisotropy maps were found between groups. Plasma testosterone levels were strongly correlated with mean, axial, and radial diffusivities. However, controlling for individual estradiol, testosterone, or progesterone plasma levels or for subjects' sexual orientation did not change group differences. Our data harmonize with the hypothesis that fiber tract development is influenced by the hormonal environment during late prenatal and early postnatal brain development.

IntroductionSeveral fMRI and resting-state connectivity studies have demonstrated alterations in the limbic system and frontal areas in social anxiety disorder (SAD).AimsHere we used high-resolution whole-brain diffusion tensor imaging (DTI) to examine differences in anatomical connectivity between patients and controls in the white matter.MethodsWe examined 14 SAD patients (age 26.3 ± 9.0y) and 15 healthy controls (age 25.6 ± 3.3y) using DTI on a 3T Trio MRI scanner (Siemens, Germany). DTI acquisition with 1.6 mm isotropic resolution was performed in 30 directions and a maximum b-value of 800. Fractional anisotropy (FA) maps were obtained using FSL. Group analysis was performed in SPM8 (two sample t-test).ResultsThe figure shows a coronal slice through the uncinate fasciculus. Arrows point to areas where SAD patients show decreased FA-values compared to controls (p < 0.05). Note that these areas are limited to the uncinate fasciculus and are found bilaterally.ConclusionReduced FA-values indicate a reduction in anatomical connectivity strength. Our study thus clearly shows reduced connectivity strength in the uncinate fasciculus connecting frontal regions with limbic areas as the amygdalae and hippocampus. This reduced structural connectivity supports functional data demonstrating alterations of brain activation in the amygdala and prefrontal regions in social phobia.