Differential modulation of emotion processing brain regions by noradrenergic and serotonergic antidepressants

Rationale: Most widely used antidepressant drugs affect the serotonergic and noradrenergic pathways. However, there are currently no neurobiological criteria for selecting between these targets and predicting the treatment response in individual depressed patients. Objectives: The current study is aimed at differentiating brain regions known to be pathophysiologically and functionally involved in depression-related emotion processing with respect to their susceptibility to serotonergic and noradrenergic modulation. Methods: In a single-blind pseudo-randomized crossover study, 16 healthy subjects (out of 21 enrolled) were included in analysis after ingesting a single dose of citalopram (a selective serotonin-reuptake inhibitor, 40mg), reboxetine (a selective noradrenaline-reuptake inhibitor, 8mg), or placebo at three time points prior to functional magnetic resonance imaging (fMRI). During fMRI, subjects anticipated and subsequently viewed emotional pictures. Effects of serotonergic and noradrenergic modulation versus placebo on brain activity during the perception of negative pictures were analyzed with a repeated measures ANOVA in the whole brain and in specific regions of interest relevant to depression. Results: Noradrenergic modulation by reboxetine increased brain activity in the thalamus, right dorsolateral prefrontal cortex and occipital regions during the perception of negative emotional stimuli. Citalopram primarily affected the ventrolateral prefrontal cortical regions. Conclusion: The brain regions involved in the processing of negative emotional stimuli were differentially modulated by selective noradrenergic and serotonergic drugs: thalamic activity was increased by reboxetine, whereas citalopram primarily affected ventrolateral prefrontal regions. Thus, dysfunction in these regions, which could be identified in depressed patients, may predict treatment responses to either noradrenergic or serotonergic antidepressant

Mirror neuron activity during contagious yawning—an fMRI study

Yawning is contagious. However, little research has been done to elucidate the neuronal representation of this phenomenon. Our study objective was to test the hypothesis that the human mirror neuron system (MNS) is activated by visually perceived yawning. We used functional magnetic resonance imaging to assess brain activity during contagious yawning (CY). Signal-dependent changes in blood oxygen levels were compared when subjects viewed videotapes of yawning faces as opposed to faces with a neutral expression. In response to yawning, subjects showed unilateral activation of their Brodmann's area 9 (BA 9) portion of the right inferior frontal gyrus, a region of the MNS. In this way, two individuals could share physiological and associated emotional states based on perceived motor patterns. This is one component of empathy (motor empathy) that underlies the development of cognitive empathy. The BA 9 is reportedly active in tasks requiring mentalizing abilities. Our results emphasize the connection between the MNS and higher cognitive empathic functions, including mentalizing. We conclude that CY is based on a functional substrate of empath

Neural correlates of personality dimensions and affective measures during the anticipation of emotional stimuli

Neuroticism and extraversion are proposed personality dimensions for individual emotion processing. Neuroticism is correlated with depression and anxiety disorders, implicating a common neurobiological basis. Extraversion is rather inversely correlated with anxiety and depression. We examined neural correlates of personality in relation to depressiveness and anxiety in healthy adult subjects with functional magnetic resonance imaging during the cued anticipation of emotional stimuli. Distributed particularly prefrontal but also other cortical regions and the thalamus were associated with extraversion. Parieto-occipital and temporal regions and subcortically the caudate were correlated with neuroticism and affective measures. Neuroticism-related regions were partially cross-correlated with anxiety and depression and vice versa. Extraversion-related activity was not correlated with the other measures. The neural correlates of extraversion compared with those of neuroticism and affective measures fit with concepts of different neurobiological bases of the personality dimensions and point at predispositions for affective disorder

Side Effects of Transcranial Magnetic Stimulation Biased Task Performance in a Cognitive Neuroscience Study

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 studie

SSRI Treatment Response Prediction in Depression Based on Brain Activation by Emotional Stimuli

Introduction: The prediction of antidepressant treatment response may improve outcome. Functional magnetic resonance imaging (fMRI) of emotion processing in major depressive disorder (MDD) may reveal regional brain function serving as predictors of response to treatment with selective serotonin reuptake inhibitor (SSRI). Methods: We examined the association between pre-treatment neural activity by means of fMRI during the perception of emotional stimuli in 22 patients with MDD and the treatment outcome after 6 weeks' medication with an SSRI. A whole brain correlation analysis with Beck Depression Inventory (BDI) change between pre- to post-treatment was conducted to identify neural regions associated with treatment response. Results: During the perception of positive stimuli, responders were characterized by more activation in posterior cingulate cortex (PCC), medial prefrontal cortex, and thalamus as well as middle temporal gyrus. During perception of negative stimuli, PCC, and pregenual anterior cingulate cortex showed the highest correlation with treatment response. Furthermore, responders exhibited higher activation to emotional stimuli than to neutral stimuli in all the above-mentioned regions, while non-responders demonstrated an attenuated neural response to emotional compared to neutral stimuli. Conclusion: Our data suggest that the activity of distinct brain regions is correlated with SSRI treatment outcome and may serve as treatment response predictor. While some regions, in which activity was correlated with treatment response, can be assigned to networks that have been implied in the pathophysiology of depression, most of our regions of interest could also be matched to the default mode network (DMN). Higher DMN activity has been associated with increased rumination as well as negative self-referential processing in previous studies. This may suggest our responders to SSRI to be characterized by such dysregulations and that SSRIs might modify the function associated with this network

Mirror neuron activity during contagious yawning-an fMRI study

Yawning is contagious. However, little research has been done to elucidate the neuronal representation of this phenomenon. Our study objective was to test the hypothesis that the human mirror neuron system (MNS) is activated by visually perceived yawning. We used functional magnetic resonance imaging to assess brain activity during contagious yawning (CY). Signal-dependent changes in blood oxygen levels were compared when subjects viewed videotapes of yawning faces as opposed to faces with a neutral expression. In response to yawning, subjects showed unilateral activation of their Brodmann's area 9 (BA 9) portion of the right inferior frontal gyrus, a region of the MNS. In this way, two individuals could share physiological and associated emotional states based on perceived motor patterns. This is one component of empathy (motor empathy) that underlies the development of cognitive empathy. The BA 9 is reportedly active in tasks requiring mentalizing abilities. Our results emphasize the connection between the MNS and higher cognitive empathic functions, including mentalizing. We conclude that CY is based on a functional substrate of empathy

Sham or real—Post hoc estimation of stimulation condition in a randomized transcranial magnetic stimulation trial

Selecting a suitable sham condition within the frame of repetitive transcranial magnetic stimulation (rTMS) treatment trials is a central issue. On the one hand, the ideal sham condition should not have a real stimulation effect; on the other hand, it should not be recognized as sham by patients, particularly when considering that real stimulation conditions come along with rTMS specific side effects. Within the course of a multi-centre trial assessing the antidepressant effects of rTMS, patients were randomized to sham or real stimulation, in both cases using a standard stimulation coil. In one centre, patients (n = 33) were asked about their impression whether they received the sham or the real treatment, and if they would recommend the treatment to others. 29 patients returned the questionnaires and were included into the analysis. From 15 subjects with real stimulation, 11 suggested to have obtained real, and 4 to have obtained sham. From 14 sham stimulated subjects, 9 suggested to have obtained the real condition and 5 to have been sham stimulated. This difference was not significant (p = 0.60, chi square test). In addition, the major part of patients in both stimulation conditions would recommend rTMS to others. In both conditions, real and sham, the majority of subjects believed to have obtained the real condition. This implies suitability of the sham condition used since subjects appeared not to be able to identify the condition. The results imply the feasibility of a valid sham condition with a “real” coil

Altered emotion processing circuits during the anticipation of emotional stimuli in women with borderline personality disorder

Borderline personality disorder (BPD) is associated with disturbed emotion processing, typically encompassing intense and fast emotional reactions toward affective stimuli. In this study, we were interested in whether emotional dysregulation in BPD occurs not only during the perception of emotional stimuli, but also during the anticipation of upcoming emotional pictures in the absence of concrete stimuli. Eighteen female patients with a diagnosis of BPD and 18 healthy control subjects anticipated cued visual stimuli with prior known emotional valence or prior unknown emotional content during functional magnetic resonance imaging. Brain activity during the anticipation of emotional stimuli was compared between both groups. When anticipating negative pictures, BPD patients demonstrated less signal change in the left dorsal anterior cingulate cortex (dACC) and left middle cingulate cortex (MCC), and enhanced activations in the left pregenual ACC, left posterior cingulate cortex (PCC) as well as in left visual cortical areas including the lingual gyrus. During the anticipation of ambiguously announced stimuli, brain activity in BPD was also reduced in the left MCC extending into the medial and bilateral dorsolateral prefrontal cortex. Results point out that deficient recruitment of brain areas related to cognitive-emotional interaction already during the anticipation phase may add to emotional dysregulation in BPD. Stronger activation of the PCC could correspond to an increased autobiographical reference in BPD. Moreover, increased preparatory visual activity during negative anticipation may contribute to hypersensitivity toward emotional cues in this disorder

Real-time Neurofeedback Using Functional MRI Could Improve Down-Regulation of Amygdala Activity During Emotional Stimulation: A Proof-of-Concept Study

The amygdala is a central target of emotion regulation. It is overactive and dysregulated in affective and anxiety disorders and amygdala activity normalizes with successful therapy of the symptoms. However, a considerable percentage of patients do not reach remission within acceptable duration of treatment. The amygdala could therefore represent a promising target for real-time functional magnetic resonance imaging (rtfMRI) neurofeedback. rtfMRI neurofeedback directly improves the voluntary regulation of localized brain activity. At present, most rtfMRI neurofeedback studies have trained participants to increase activity of a target, i.e. up-regulation. However, in the case of the amygdala, down-regulation is supposedly more clinically relevant. Therefore, we developed a task that trained participants to down-regulate activity of the right amygdala while being confronted with amygdala stimulation, i.e. negative emotional faces. The activity in the functionally-defined region was used as online visual feedback in six healthy subjects instructed to minimize this signal using reality checking as emotion regulation strategy. Over a period of four training sessions, participants significantly increased down-regulation of the right amygdala compared to a passive viewing condition to control for habilitation effects. This result supports the concept of using rtfMRI neurofeedback training to control brain activity during relevant stimulation, specifically in the case of emotion, and has implications towards clinical treatment of emotional disorders