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An altered processing of negative salient stimuli has been suggested to play a central role in the pathophysiology of major depression (MD). Besides negative affective and social stimuli, physical pain as a subtype of negative sensory stimulation has been investigated in this context. However, the few neuroimaging studies on unpleasant sensory stimulation or pain processing in MD report heterogeneous findings. Here, we investigated 47 young females, 22 with MD and 25 healthy controls (HC) using fMRI (3.0 T). Four levels of increasingly unpleasant electrical stimulation were applied. Ratings of stimulus intensity were assessed by a visual analogue scale. fMRI-data were analyzed using a 2 × 4 ANOVA. Behavioral results revealed no group differences regarding accuracy of unpleasant stimulation level ratings and sensitivity to stimulation. Regarding neural activation related to increasing levels of unpleasant stimulation, we observed increasing activation of brain regions related to the pain and salient stimulus processing corresponding to increasingly unpleasant stimulation in controls. This modulation was significantly smaller in MD compared to controls, particularly in the dorsal anterior cingulate cortex, the somatosensory cortex, and the posterior insula. Overall, brain regions associated with the processing of unpleasant sensory stimulation, but also associated with the salience network, were highly reactive but less modulated in female patients with MD. These results support and extent findings on altered processing of salience and of negative sensory stimuli even of a non-painful quality in female patients with MD. Electronic supplementary material The online version of this article (10.1007/s00406-020-01123-0) contains supplementary material, which is available to authorized users.

Stress underlies the development of various psychiatric disorders. Rodent studies suggest an involvement of the endocannabinoid system in the modulation of the stress response, which needs to be translated to humans. In this study, 22 healthy males (mean age: M = 22.7 years) were exposed to a thermal heat stressor in a fear conditioning paradigm and blood samples of the circulating endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG) were assessed. Additionally, electrodermal activity (EDA), task-related anxiety ratings and data on critical life experiences (CLE) were recorded. Interestingly, increases in 2-AG from pre-to-post stress correlated with: smaller stress responses (EDA), by trend more CLE, and greater conditioned anxiety. Smaller stress responses correlated with more CLE. We demonstrate a relation between endocannabinoid level changes from pre-to-post acute stress and the stress response. Our results suggest that investigating the role of 2-AG in the response to stress could be promising in finding treatments in the immediate aftermath of traumatic events.

Gold standard treatments for anxiety- and trauma-related disorders focus on exposure therapy promoting extinction learning and extinction retention. However, its efficacy is limited. Preclinical and particularly animal research has been able to demonstrate that homozygosity for the fatty acid amide hydrolase (FAAH) C385A allele, similar to FAAH inhibition, is associated with elevated concentrations of anandamide (AEA) and facilitates extinction learning and extinction recall. However, in humans, the underlying neurobiological processes are less well understood, and further knowledge might enhance the development of more effective therapies. In this functional magnetic resonance imaging (fMRI) study, a fear conditioning, fear extinction and extinction recall paradigm was conducted with 55 healthy male adults. They were genotyped for the FAAH single-nucleotide polymorphism (SNP) rs324420 to investigate differences related to extinction recall in neural activation and State–Trait Anxiety Inventory (STAI) ratings between AC heterozygotes and CC homozygotes (FAAH C385A SNP). Differential brain activation upon an unextinguished relative to an extinguished stimulus, was greater in AC heterozygotes as compared to CC homozygotes in core neural structures previously related to extinction recall, such as the medial superior frontal gyrus, the dorsal anterior cingulate and the anterior and middle insular cortex. Furthermore, AC heterozygotes displayed higher AEA levels and lower STAI-state ratings. Our data can be interpreted in line with previous suggestions of more successful extinction recall in A-allele carriers with elevated AEA levels. Data corroborate the hypothesis that the endocannabinoid system, particularly AEA, plays a modulatory role in the extinction of aversive memory.

Background: Investigating adolescents and young adults may provide a unique opportunity to understand developmental aspects of the neurobiology of depression. During adolescence, a considerable physiologic reorganization of both grey and white matter of the brain takes place, and it has been suggested that differences in grey-matter volumes during adolescence may reflect different maturational processes. Methods: We investigated grey-matter volumes in a comparatively large sample (n = 103) of adolescents and young adults (aged 12 to 27 years), 60 of them with a diagnosis of current depression. Results: Replicating previous studies, we found a clear whole-brain effect of age: the older the participants, the lower their global grey-matter volumes, particularly in the paracingulate and prefrontal cortices. Contrasting depressed and healthy youth in a whole-brain approach, we found greater grey-matter volumes in the dorsolateral prefrontal cortex of those with depression. Furthermore, a region-of-interest analysis indicated lower grey-matter volumes in the hippocampus in participants with depression compared with healthy controls. Limitations: The present study was limited because of a skewed sex distribution, its cross-sectional design and the fact that some participants were taking an antidepressant. Conclusion: During adolescence, restructuring of the brain is characterized by marked decreases in prefrontal grey-matter volumes, interpreted as a correlate of brain maturation. Findings of greater volumes in the prefrontal cortex, particularly in younger adolescents with depression, may suggest that these participants were more prone to delayed brain maturation or increased neuroplasticity. This finding may represent a risk factor for depression or constitute an effect of developing depression.

Human sexual behavior is mediated by a complex interplay of cerebral and spinal centers, as well as hormonal, peripheral, and autonomic functions. Neuroimaging studies identified central neural signatures of human sexual responses comprising neural emotional, motivational, autonomic, and cognitive components. However, empirical evidence regarding the neuromodulation of these neural signatures of human sexual responses was scarce for decades. Pharmacological functional magnetic resonance imaging (fMRI) provides a valuable tool to examine the interaction between neuromodulator systems and functional network anatomy relevant for human sexual behavior. In addition, this approach enables the examination of potential neural mechanisms regarding treatment-related sexual dysfunction under psychopharmacological agents. In this article, we introduce common neurobiological concepts regarding cerebral sexual responses based on neuroimaging findings and we discuss challenges and findings regarding investigating the neuromodulation of neural sexual stimulus processing. In particular, we summarize findings from our research program investigating how neural correlates of sexual stimulus processing are modulated by serotonergic, dopaminergic, and noradrenergic antidepressant medication in healthy males.

Humans engage in social interactions and have a fundamental need and motivation to establish and maintain social connections. Neuroimaging studies particularly focused on the neural substrates of social exclusion in healthy subjects (HC), borderline personality disorder (BPD), and major depression (MD). However, there is evidence regarding neural alterations also during social inclusion in BPD that we intended to elucidate in our study. Considering that patients with BPD often have comorbid MD, we investigated patients with BPD, and comorbid MD, patients with MD without BPD, and a sample of HC. By investigating these two clinical samples within one study design, we attempted to disentangle potential confounds arising by psychiatric disorder or medication and to relate neural alterations under social inclusion specifically to BPD. We investigated 48 females (15 BPD and MD, 16 MD, and 17 HC) aged between 18 and 40 years by fMRI (3T), using the established cyberball paradigm with social exclusion, inclusion, and passive watching conditions. Significant group-by-condition interaction effects (p < 0.05, FWE-corrected on cluster level) were observed within the dorsolateral (dlPFC) and dorsomedial prefrontal cortex (dmPFC), the temporo-parietal junction (TPJ), the posterior cingulate cortex (PCC), and the precuneus. Comparisons of estimated neural activations revealed that significant interaction effects were related to a relative increase in neural activations during social inclusion in BPD. In detail, we observed a significant increase in differential (social inclusion vs. passive watching) neural activation within the dmPFC and the PCC in BPD compared to both, MD and HC. However, significant interaction effects within the dlPFC and the TPJ could not specifically be linked to BPD considering that they did not differ significantly between the two clinical groups in post-hoc comparisons. Our study supports previous results on effects of social and inclusion in BPD, and provides further evidence regarding disorder specific neural alterations in BPD for brain regions associated with self-referential and mentalizing processes during social inclusion.

In adults, trauma imagery has proven to be a useful tool to assess the neural mechanisms of psychological trauma processing. In adolescents, heterogeneous results could be found for other tasks, however, a trauma imagery paradigm has not been evaluated. For this purpose, we investigated a trauma imagery paradigm with control scripts to assess neural correlates of traumatic experiences in youth. 15 adolescents, who had experienced a traumatic interpersonal event in the past and have developed clinically relevant symptoms, underwent an fMRI scan while listening to their individual trauma- versus two control scripts (positive/negative). We analysed a parametric contrast of the imagery phases (trauma > negative > positive) which revealed activity in the thalamus, dorsal anterior cingulate cortex, cuneus, dorsomedial prefrontal cortex and amygdala. Additionally, amygdala-activity correlated positively with depression-symptom-severity. Our data provide evidence for the feasibility of fMRI during a trauma imagery task in adolescents to investigate networks previously related to hyperarousal in adults with PTSD. Further, we demonstrate the specificity of the activated networks for trauma imagery as compared to imagery of other emotional situations. The task might be particularly useful to evaluate neural correlates of treatment in adolescents when hyperarousal is a target symptom.

Borderline Personality Disorder (BPD) is clinically characterized by emotional instability, interpersonal disturbances and dysfunctional behavior such as non-suicidal self-injury (NSSI). During NSSI, patients with BPD typically report analgesic or hypoalgesic phenomena, and pain perception and pain processing in BPD have been repeatedly investigated. Most of the studies so far focused on affective-motivational and cognitive-evaluative neural components of pain within categorial study designs. By contrast, rather basic somatosensory aspects such as neural intensity-encoding of somatosensory stimuli were not examined in further details. Thus, we investigated patients with BPD and healthy controls (HC) by functional magnetic resonance imaging (fMRI) during an unpleasant sensory stimulation task with parametrically increasing stimulus intensities. 15 females diagnosed with BPD and 15 HCs were investigated with fMRI during four individually adjusted levels of electrical stimulus intensities. Ratings of stimulus intensity were assessed by button presses during fMRI. fMRI-data were analyzed by analyses of variances (ANOVA) at a statistical threshold of p < 0.05 FWE-corrected on cluster level. Subjective ratings of stimulus intensities were alike between BPD and HC, and intensity levels identified with equal accuracy. Significant intensity-encoding neural activations were observed within the primary and secondary somtasensory cortex, the posterior insula, the posterior midcingulate cortex (pMCC) and the supplementary motor area (SMA) in both, HC and BPD. Notably, there were no significant between-groups differences in intensity-encoding neural activations, even at lowered significance thresholds. Present results suggest a similar neural somatosensory stimulus intensity encoding in BPD as previously observed on a behavioral level. The alterations in neural affective-motivational or cognitive-evaluative components reported so far may be restricted to pain rather than unpleasant stimulus processing and were absent in our study.

Introduction Non-suicidal self-injury (NSSI) is a symptom of borderline personality disorder (BPD). However, NSSI often occurs independently of BPD. Altered neural processing of social exclusion has been shown in adolescents with NSSI and adults with BPD with additional alterations during social inclusion in BPD patients. Aims of this study were to investigate differences in neural processing of social inclusion and exclusion situations between adolescents with NSSI and young adults with BPD and NSSI. Methods Using fMRI, neural processing of positive and negative social situations (paradigm: “Cyberball”) was explored. Participants were 14 adolescents with NSSI, but without BPD (Mage = 15.4; SD = 1.9), 15 adults with BPD and NSSI (Mage = 23.3; SD = 4.1), as well as 15 healthy adolescents (Mage = 14.5; SD = 1.7), and 16 healthy adults (Mage = 23.2; SD = 4.4). Results Behavioral results showed enhanced feelings of social exclusion in both patient groups as compared to healthy controls but only the NSSI group showed enhanced activation during social exclusion versus inclusion compared to the other groups. While both NSSI and BPD groups showed enhanced activation in the ventral anterior cingulate cortex during social exclusion as compared to their age-matched controls, enhanced activation during social inclusion as compared to a passive watching condition was mainly observed in the BPD group in the dorsolateral and dorsomedial prefrontal cortex, and the anterior insula. Discussion While neural processing of social exclusion was pronounced in adolescents with NSSI, BPD patients also showed increased activity in a per se positive social situation. These results might point toward a higher responsiveness to social exclusion in adolescents with NSSI, which might then develop into a generalized increased sensitivity to all kinds of social situations in adults with BPD.

Due to the physiological coupling with metabolism, brain perfusion is a potential aid in understanding the effects of medication on neural activity in vivo. In this study, arterial spin labeling (ASL) was used to quantify the effect of seven days of administration of paroxetine (20 mg), bupropion (150 mg) on cerebral blood flow levels at rest in a double-blind, placebo-controlled crossover design in N = 21 healthy participants. Paroxetine administration was associated with diffuse cortical perfusion decrements, more marked in the prefrontal region, and with decrements in the striatum, caudate and the basal forebrain. The effect of bupropion on the cortex was similar but less conspicuous. In the brainstem, there was suggestive evidence of perfusion decrements in the main serotonergic and noradrenergic nuclei. These results demonstrate the existence of effects on rest perfusion of antidepressant medication of potential use in monitoring its action. The observed perfusion reductions may be related to compensatory decrements of monoaminergic neural activity in the initial phases of treatment that are observed under both drugs following the increase in extracellular concentration of transmitters.

Recently, functional interactions between anteroventral prefrontal cortex and nucleus accumbens (NAcc) have been shown to relate to behavior counteracting reward-desiring (Diekhof and Gruber, 2010). Downregulation of the reward system by serotonin has also been suggested as the mode of action accounting for unsatisfactory effects of serotonin reuptake inhibitors (SSRIs) such as insufficient alleviation or even increase of anhedonia, and loss of interest. However, understanding of thein vivomechanisms of SSRI-related alteration of the human reward system is still incomplete. Using functional magnetic resonance imaging (fMRI) within a double-blind cross-over within-subjects study design and administering the SSRI paroxetine, the dopamine/norepinephrine reuptake inhibitor bupropione, and placebo for 7 d each, we investigated a group of 18 healthy male subjects. Under paroxetine, subjects showed significantly decreased activation of the bilateral NAcc during processing of primary rewards (erotic videos), but not under bupropion. Similar to the previous study, analysis of psychophysiological interactions revealed that this downregulation relied on negative interactions between left and right NAcc fMRI signals and the bilateral anteroventral prefrontal cortex that now were significantly enhanced under paroxetine and reduced under bupropion. Individual drug-dependent modulations of interacting brain regions were significantly associated with individual expressions of impulsivity as a personality trait. Our results corroborate and extend previous insights on interregional crosstalk from secondary to primary rewards and demonstrate parallels between active inhibitory control of and serotonergic effects on the dopaminergic reward system's activity.

Sexual dysfunction is a common side effect of selective serotonin reuptake inhibitors (SSRIs) like paroxetine in the treatment of depression, imposing a considerable risk on medication adherence and hence therapeutic success. Bupropion, a norepinephrine and dopamine reuptake inhibitor, is recommended as an alternative treatment without adverse effects concerning sexual arousal and libido. We investigated the neural bases of paroxetine-related subjective sexual dysfunction when compared with bupropion and placebo. We scanned 18 healthy, heterosexual males in a randomized, double-blind, within-subject design while watching video clips of erotic and nonerotic content under steady-state conditions after taking 20 mg of paroxetine, 150 mg of bupropion, and placebo for 7 days each. Under paroxetine, ratings of subjective sexual dysfunction increased compared with placebo or bupropion. Activation along the anterior cingulate cortex (ACC), including subgenual, pregenual, and midcingulate cortices, in the ventral striatum and midbrain was decreased when compared with placebo. In contrast, bupropion let subjective ratings and ACC activations unchanged and increased activity of brain regions including posterior midcingulate cortex, mediodorsal thalamus, and extended amygdala relative to placebo and paroxetine. Brain regions that have been related to the processing of motivational (ventral striatum), emotional, and autonomic components of erotic stimulation (anterior cingulate) in previous studies showed reduced responsiveness under paroxetine in our study. Drug effects on these regions may be part of the mechanism underlying SSRI-related sexual dysfunction. Increased activation under bupropion may point to an opposite effect that may relate to the lack of impaired sexual functioning.

Treatment with dopamine receptor agonists has been associated with impulse control disorders and pathological gambling (PG) secondary to medication in previously unaffected patients with Parkinson's disease or restless legs syndrome (RLS). In a within-subjects design, we investigated the underlying neurobiology in RLS patients using functional magnetic resonance imaging. We scanned 12 female RLS patients without a history of PG. All patients were scanned twice: once whilst taking their regular medication with low dose dopamine receptor agonists and once after a washout phase interval. They performed an established gambling game task involving expectation and receipt or omission of monetary rewards at different levels of probabilities. Upon expectation of rewards, reliable ventral striatal activation was detected only when patients were on, but not when patients were off medication. Upon receipt or omission of rewards, the observed ventral striatal signal under medication differed markedly from its predicted pattern which by contrast was apparent when patients were off medication. Orbitofrontal activation was not affected by medication. Chronic dopamine receptor agonist medication changed the neural signalling of reward expectation predisposing the dopaminergic reward system to mediate an increased appetitive drive. Even without manifest PG, chronic medication with dopamine receptor agonists led to markedly changed neural processing of negative consequences probably mediating dysfunctional learning of contingencies. Intact orbitofrontal functioning, potentially moderating impulse control, may explain why none of the patients actually developed PG. Our results support the notion of a general medication effect in patients under dopamine receptor agonists in terms of a sensitization towards impulse control disorders.

Background: Impaired sexual function is increasingly recognized as a side effect of psychopharmacological treatment. However, underlying mechanisms of action of the different drugs on sexual processing are still to be explored. Using functional magnetic resonance imaging, we previously investigated effects of serotonergic (paroxetine) and dopaminergic (bupropion) antidepressants on sexual functioning (Abler et al., 2011). Here, we studied the impact of noradrenergic and antidopaminergic medication on neural correlates of visual sexual stimulation in a new sample of subjects. Methods: Nineteen healthy heterosexual males (mean age 24 years, SD 3.1) under subchronic intake (7 days) of the noradrenergic agent reboxetine (4 mg/d), the antidopaminergic agent amisulpride (200 mg/d), and placebo were included and studied with functional magnetic resonance imaging within a randomized, double-blind, placebo-controlled, within-subjects design during an established erotic video-clip task. Subjective sexual functioning was assessed using the Massachusetts General Hospital-Sexual Functioning Questionnaire. Results: Relative to placebo, subjective sexual functioning was attenuated under reboxetine along with diminished neural activations within the caudate nucleus. Altered neural activations correlated with decreased sexual interest. Under amisulpride, neural activations and subjective sexual functioning remained unchanged. Conclusions: In line with previous interpretations of the role of the caudate nucleus in the context of primary reward processing, attenuated caudate activation may reflect detrimental effects on motivational aspects of erotic stimulus processing under noradrenergic agents.

Functional compensation demonstrated as mechanism to offset neuronal loss in early Alzheimer disease may also occur in other adult-onset neurodegenerative diseases, particularly Huntington disease (HD) with its genetic determination and gradual changes in structural integrity. In HD, neurodegeneration typically initiates in the dorsal striatum, successively affecting ventral striatal areas. Investigating carriers of the HD mutation with evident dorsal, but only minimal or no ventral striatal atrophy, we expected to find evidence for compensation of ventral striatal functioning. We investigated 14 pre- or early symptomatic carriers of the mutation leading to HD and 18 matched healthy controls. Participants underwent structural T1 magnetic resonance imaging (MRI) and functional MRI during a reward task that probes ventral striatal functioning. Motor functioning and attention were assessed with reaction time (RT) tasks. Structural images confirmed a specific decrease of dorsal striatal but only marginal ventral striatal volume in HD relative to control subjects, paralleling prolonged RT in the motor response tasks. While behavioral performance in the reward task during fMRI scanning was unimpaired, reward-related fMRI signaling in the HD group was differentially enhanced in the bilateral ventral striatum and in bilateral orbitofrontal cortex/anterior insula, as another region sensitive to reward processing. We provide evidence for the concept of functional compensation in premanifest HD which may suggest a defense mechanism in neurodegeneration. Given the so far inevitable course of HD with its genetically determined endpoint, this disease may provide another model to study the different aspects of the concept of functional compensation.

Background Eye Movement Desensitisation and Reprocessing (EMDR) is a method in psychotherapy effective in treating symptoms of posttraumatic stress disorder. The client attends to alternating bilateral visual, auditory or sensory stimulation while confronted with emotionally disturbing material. It is thought that the bilateral stimulation as a specific element of EMDR facilitates accessing and processing of negative material while presumably creating new associative links. We hypothesized that the putatively facilitated access should be reflected in increased activation of the amygdala upon bilateral EMDR stimulation even in healthy subjects. Methods We investigated 22 healthy female university students (mean 23.5 years) with fMRI. Subjects were scanned while confronted with blocks of disgusting and neutral picture stimuli. One third of the blocks was presented without any additional stimulation, one third with bilateral simultaneous auditory stimulation, and one third with bilateral alternating auditory stimulation as used in EMDR. Results Contrasting disgusting vs. neutral picture stimuli confirmed the expected robust effect of amygdala activation for all auditory stimulation conditions. The interaction analysis with the type of auditory stimulation revealed a specific increase in activation of the right amygdala for the bilateral alternating auditory stimulation. Activation of the left dorsolateral prefrontal cortex showed the opposite effect with decreased activation. Conclusions We demonstrate first time evidence for a putative neurobiological basis of the bilateral alternating stimulation as used in the EMDR method. The increase in limbic processing along with decreased frontal activation is in line with theoretical models of how bilateral alternating stimulation could help with therapeutic reintegration of information, and present findings may pave the way for future research on EMDR in the context of posttraumatic stress disorder.

While antidepressants are supposed to exert similar effects on mood and drive via various mechanisms of action, diverging effects are observed regarding side-effects and accordingly on neural correlates of motivation, emotion, reward and salient stimuli processing as a function of the drugs impact on neurotransmission. In the context of erotic stimulation, a unidirectional modulation of attentional functioning despite opposite effects on sexual arousal has been suggested for the selective serotonin reuptake-inhibitor (SSRI) paroxetine and the selective dopamine and noradrenaline reuptake-inhibitor (SDNRI) bupropion. To further elucidate the effects of antidepressant-related alterations of neural attention networks, we investigated 18 healthy males under subchronic administration (7 d) of paroxetine (20 mg), bupropion (150 mg) and placebo within a randomized placebo-controlled cross-over double-blind functional magnetic resonance imaging (fMRI) design during an established preceding attention task. Neuropsychological effects beyond the fMRI-paradigm were assessed by measuring alertness and divided attention. Comparing preceding attention periods of salient vs. neutral pictures, we revealed congruent effects of both drugs vs. placebo within the anterior midcingulate cortex, dorsolateral prefrontal cortex, anterior prefrontal cortex, superior temporal gyrus, anterior insula and the thalamus. Relatively decreased activation in this network was paralleled by slower reaction times in the divided attention task in both verum conditions compared to placebo. Our results suggest similar effects of antidepressant treatments on behavioural and neural attentional functioning by diverging neurochemical pathways. Concurrent alterations of brain regions within a fronto-parietal and cingulo-opercular attention network for top-down control could point to basic neural mechanisms of antidepressant action irrespective of receptor profiles.

Previous studies have demonstrated variable influences of sexual hormonal states on female brain activation and the necessity to control for these in neuroimaging studies. However, systematic investigations of these influences, particularly those of hormonal contraceptives as compared to the physiological menstrual cycle are scarce. In the present study, we investigated the hormonal modulation of neural correlates of erotic processing in a group of females under hormonal contraceptives (C group; N = 12), and a different group of females (nC group; N = 12) not taking contraceptives during their mid-follicular and mid-luteal phases of the cycle. We used functional magnetic resonance imaging to measure hemodynamic responses as an estimate of brain activation during three different experimental conditions of visual erotic stimulation: dynamic videos, static erotic pictures, and expectation of erotic pictures. Plasma estrogen and progesterone levels were assessed in all subjects. No strong hormonally modulating effect was detected upon more direct and explicit stimulation (viewing of videos or pictures) with significant activations in cortical and subcortical brain regions previously linked to erotic stimulation consistent across hormonal levels and stimulation type. Upon less direct and less explicit stimulation (expectation), activation patterns varied between the different hormonal conditions with various, predominantly frontal brain regions showing significant within- or between-group differences. Activation in the precentral gyrus during the follicular phase in the nC group was found elevated compared to the C group and positively correlated with estrogen levels. From the results we conclude that effects of hormonal influences on brain activation during erotic stimulation are weak if stimulation is direct and explicit but that female sexual hormones may modulate more subtle aspects of sexual arousal and behaviour as involved in sexual expectation. Results may provide a basis for future imaging studies on sexual processing in females, especially in the context of less explicit erotic stimulation.

The goal of this research was to examine the measurement invariance of the Emotion Regulation Questionnaire (ERQ; Gross & John, 2003) across two European nations. Participants were Italian and German undergraduate students. First, confirmatory factor analysis was used to test for the two-factor structure of the ERQ; subsequently, measurement invariance was analysed. The results showed acceptable fit indices for the German and Italian sample; however, results with regard to the Italian sample showed lower fit indices than results regarding the German one. Measurement invariance of the ERQ across Italy and Germany was confirmed. Despite the fact that we assumed measurement invariance of the ERQ, future research is needed to deal with the lower fit regarding the Italian version. http://dx.doi.org/10.1080/17405629.2012.690604 http://www.tandfonline.com/doi/pdf/10.1080/17405629.2012.690604

Thalamocortical loops, connecting functionally segregated, higher order cortical regions and basal ganglia, have been proposed not only for well described motor and sensory regions, but also for limbic and prefrontal areas relevant for affective and cognitive processes. These functions are, however, more specific to humans, rendering most invasive neuroanatomical approaches impossible and interspecies translations difficult. In contrast, non invasive imaging of functional neuroanatomy using fMRI allows for the development of elaborate task paradigms capable of testing the specific functionalities proposed for these circuits. Until recently, spatial resolution largely limited the anatomical definition of functional clusters at the level of distinct thalamic nuclei. Since their anatomical distinction seems crucial not only for the segregation of cognitive and limbic loops but also for the detection of their functional interaction during cognitive-emotional integration, we applied high resolution fMRI on 7 Tesla.Using an event related design, we could isolate thalamic effects for preceding attention as well as experience of erotic stimuli. We could demonstrate specific thalamic effects of general emotional arousal in mediodorsal nucleus and effects specific to preceding attention and expectancy in intralaminar centromedian/parafascicular complex (CM/PF). These thalamic effects were paralleled by specific coactivations in the head of caudate nucleus as well as segregated portions of rostral or caudal cingulate cortex and anterior insula supporting distinct thalamo-striato-cortical loops. In addition to predescribed effects of sexual arousal in hypothalamus and ventral striatum, high resolution fMRI could extent this network to paraventricular thalamus encompassing laterodorsal and parataenial nuclei. We could lend evidence to segregated subcortical loops which integrate cognitive and emotional aspects of basic human behaviour such as sexual processing.

In addiction, loss of prefrontal inhibitory control is believed to contribute to impulsivity. To improve cognitive therapy approaches, it is important to determine whether cognitive control strategies can generally influence reward processing at the neural level. We investigated the effects of one such strategy--namely, reappraisal (distancing from feelings)--on neural reward processing in 16 healthy subjects by utilizing event-related functional magnetic resonance imaging (fMRI). In a monetary incentive delay task, expected reward value (expecting to win 0.50 euro vs. 0.10 euro) and outcome valence (win vs. omission) were varied. An attenuation of expected value and a modulation of prediction error (PE) coding caused by distancing were found in right vs. left ventral striatum (VST) in the expectation vs. outcome period, respectively. Distancing from reward feelings recruited a right hemispheric fronto-parietal network. Moreover, self-reported reappraisal success (decrease of feelings by distancing) showed a trend toward positive correlation with activation in the rostral cingulate zone and the lateral orbitofrontal cortex, both part of the regulation network. Our results expand upon recent findings by showing that cognitive control over reward processing impacts not only the expectation period but also the reward signals in the outcome period. Moreover, increased recruitment of prefrontal reflective subsystems might enhance deliberate control over both reward processing and hedonic experience.

Transmission of reward signals is a function of dopamine, a neurotransmitter known to be involved in the mechanism of psychosis. Using functional magnetic resonance imaging (fMRI), we investigated how expectation and receipt of monetary rewards modulate brain activation in patients with bipolar mania and schizophrenia. We studied 12 acutely manic patients with a history of bipolar disorder, 12 patients with a current episode of schizoaffective disorder or schizophrenia and 12 healthy subjects. All patients were treated with dopamine antagonists at the time of the study. Subjects performed a delayed incentive paradigm with monetary reward in the scanner that allowed for investigating effects of expectation, receipt, and omission of rewards. Patients with schizophrenia and healthy control subjects showed the expected activation of dopaminergic brain areas, that is, ventral tegmentum activation upon expectation of monetary rewards and nucleus accumbens activation during receipt vs omission of rewards. In manic patients, however, we did not find a similar pattern of brain activation and the differential signal in the nucleus accumbens upon receipt vs omission of rewards was significantly lower compared to the healthy control subjects. Our findings provide evidence for abnormal function of the dopamine system during receipt or omission of expected rewards in bipolar disorder. These deficits in prediction error processing in acute mania may help to explain symptoms of disinhibition and abnormal goal pursuit regulation.

Strategies of cognitive control are helpful in reducing anxiety experienced during anticipation of unpleasant or potentially unpleasant events. We investigated the associated cerebral information processing underlying the use of a specific cognitive control strategy during the anticipation of affect-laden events. Using functional magnetic resonance imaging, we examined differential brain activity during anticipation of events of unknown and negative emotional valence in a group of eighteen healthy subjects that used a cognitive control strategy, similar to "reality checking" as used in psychotherapy, compared with a group of sixteen subjects that did not exert cognitive control. While expecting unpleasant stimuli, the "cognitive control" group showed higher activity in left medial and dorsolateral prefrontal cortex areas but reduced activity in the left extended amygdala, pulvinar/lateral geniculate nucleus and fusiform gyrus. Cognitive control during the "unknown" expectation was associated with reduced amygdalar activity as well and further with reduced insular and thalamic activity. The amygdala activations associated with cognitive control correlated negatively with the reappraisal scores of an emotion regulation questionnaire. The results indicate that cognitive control of particularly unpleasant emotions is associated with elevated prefrontal cortex activity that may serve to attenuate emotion processing in for instance amygdala, and, notably, in perception related brain areas.

Background: Various psychiatric populations are currently investigated with resting state fMRI, with the aim of individualizing diagnostics and treatment options and improving treatment outcomes. Many of these studies are conducted in large naturalistic samples, providing rich insights regarding disease-related neural alterations, but with the common psychopharmacological medication limiting interpretations of the results. We therefore investigated the effects of common noradrenergic and anti-dopaminergic medications on local and global resting state activity (rs-activity) in healthy volunteers to further the understanding of the respective effects independent from disease-related alterations. Methods: Within a randomized, double-blind, placebo-controlled crossover design, we investigated 19 healthy male subjects by resting state fMRI after the intake of reboxetine (4mg/d), amisulpride (200mg/d), and placebo for 7 days each. Treatment-related differences in local and global rs-activity were measured by the fractional amplitude of low frequency fluctuations (fALFF) and resting state functional connectivity (rs-FC). Results: fALFF revealed alterations of local rs-activity within regions of the core noradrenergic pathway, including the locus coeruleus under reboxetine, correlated with its plasma levels. Moreover, reboxetine led to increased rs-FC between regions within this pathway, i.e. the locus coeruleus, tectum, thalamus, and amygdala. Amisulpride modulated local rs-activity of regions within the dopaminergic pathway, with the altered signal in the putamen correlating with amisulpride plasma levels. Correspondingly, amisulpride increased rs-FC between regions of the dopaminergic pathway comprising the substantia nigra and putamen. Conclusion: Our data provide evidence of how psychopharmacological agents alter local and global rs-activity within the respective neuroanatomical pathways in healthy subjects, which may help with interpreting data in psychiatric populations.

Localization of cognitive processes is a strength of functional neuroimaging. However, information about functional interactions between brain areas is crucial for a deeper understanding of brain function. We applied vector autoregressive modeling in the context of Granger causality as a method to analyze directed connectivity in a standard event-related fMRI study using a simple auditory-motor paradigm. The basic idea is to use temporal information in stochastic time series of a brain region in order to predict signal time courses in other brain regions. Thus, we predicted that the method should demonstrate causal influence of the auditory cortex and the supplementary motor area (SMA) on primary motor cortex. Eleven right-handed healthy female subjects were instructed to press a ball with either their left or their right hand when hearing the command "Ieft" or "right" in the scanner. Influence to the left motor cortex was found from bilateral auditory cortex as well as from the SMA in 9 of I I subjects. Granger causality to the right motor cortex existed from bilateral auditory cortex in 5 and from SMA in 6 subjects. Granger causality to the SMA existed from right auditory cortex in 7 subjects and from left auditory cortex in 8 subjects. Our findings in a simple task show that even under suboptimal circumstances (a relatively long TR of 2440 ms), Granger causality can be a useful tool to explore effective connectivity. Temporally optimized scanning should increase that potential.

Summary:: Transcranial magnetic stimulation (TMS) is increasingly used as a research tool for functional brain mapping in cognitive neuroscience. Despite being mostly tolerable, side effects of TMS could influence task performance in behavioural TMS studies. In order to test this issue, healthy subjects assessed the discomfort caused by the stimulation during a verbal working memory task. We investigated the relation between subjective disturbance and task performance. Subjects were stimulated during the delay period of a delayed-match-to-sample task above cortical areas that had been identified before to be involved in working memory. Task performance and subjective disturbance due to side effects were monitored. The subjects' grade of discomfort correlated with the error rates: the higher the discomfort, the more errors were made. Conclusively, TMS side effects may bias task performance in cognitive neuroscience studies and may thereby lead to misinterpretation of results. We emphasize the importance of controlling side effects of the stimulation as a source of biasing effects in TMS studies

In neuroeconomics, reward and social interaction are central concepts to understand what motivates human behaviour. Both concepts are investigated in humans using neuroimaging methods. In this paper, we provide an overview about these results and discuss their relevance for economic behaviour. For reward it has been shown that a system exists in humans that is involved in predicting rewards and thus guides behaviour, involving a circuit including the striatum, the orbitofrontal cortex and the amygdala. Recent studies on social interaction revealed a mentalizing system representing the mental states of others. A central part of this system is the medial prefrontal cortex, in particular the anterior paracingulate cortex. The reward as well as the mentalizing system is engaged in economic decision-making. We will discuss implications of this study for neuromarketing as well as general implications of these results that may help to provide deeper insights into the motivating forces of human behaviour.

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Phonological rehearsal helps to keep selected information consciously in mind for further processing. This part of short-term storage takes place during the delay period of verbal working memory tasks and involves a frontoparietal network as functional magnetic resonance imaging (fMRI) studies have shown. The involved cortical areas can be further investigated by interfering with the local information processing using transcranial magnetic stimulation (TMS). On a single subject level, we identified predominantly left-sided premotor, prefrontal, and parietal areas active during the delay period of a verbal working memory task using event-related fMRI. In a pilot approach, TMS was neuronavigated to the individually active areas by using a stereotaxic device. Then, TMS was applied during the delay period of similar tasks as in fMRI. Error rates increased significantly upon stimulating left premotor cortex, but not upon parietal or prefrontal stimulation. The contribution of the premotor cortex to storage and rehearsal is discussed as an active top-down storage process within the frontoparietal network.

Non-suicidal self-injury (NSSI) is highly prevalent in adolescence and has been suggested as an autonomous diagnosis in the Diagnostic and Statistical Manual (DSM-5). Social rejection is as potential risk-factor for NSSI and depression in adolescence. Objectives of this study were to identify differences in neural processing of social rejection in depressed adolescents with and without co-morbid NSSI and healthy controls. Participants were 28 depressed adolescents (14 with co-morbid NSSI, 79% females) and 15 healthy controls, with an average age of 15.2 years (SD=1.8). Social exclusion was implemented using the Cyberball paradigm ‘Cyberball’ during functional magnetic resonance imaging (fMRI). All participants reported feelings of social exclusion after fMRI scanning. Investigating the effects of NSSI, we found that depressed adolescents with NSSI showed relatively enhanced activation of the medial prefrontal cortex (mPFC) and the ventrolateral prefrontal cortex (vlPFC) compared to depressed adolescents without NSSI and also compared to healthy controls. Results point towards divergent processing of social exclusion in depressed adolescents with NSSI as compared to adolescents with mere depression in brain regions previously related to the processing of social exclusion. This finding of distinct neurophysiological responses may stimulate further research on individual treatment approaches.

Background Reward value and uncertainty are represented by dopamine neurons in monkeys by distinct phasic and tonic firing rates. Knowledge about the underlying differential dopaminergic pathways is crucial for a better understanding of dopamine-related processes. Using functional magnetic resonance blood-oxygen level dependent (BOLD) imaging we analyzed brain activation in 15 healthy, male subjects performing a gambling task, upon expectation of potential monetary rewards at different reward values and levels of uncertainty. Results Consistent with previous studies, ventral striatal activation was related to both reward magnitudes and values. Activation in medial and lateral orbitofrontal brain areas was best predicted by reward uncertainty. Moreover, late BOLD responses relative to trial onset were due to expectation of different reward values and likely to represent phasic dopaminergic signaling. Early BOLD responses were due to different levels of reward uncertainty and likely to represent tonic dopaminergic signals. Conclusions We conclude that differential dopaminergic signaling as revealed in animal studies is not only represented locally by involvement of distinct brain regions but also by distinct BOLD signal characteristics.