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Increased amygdala reactivity might lead to negative bias during emotional processing that can be reversed by antidepressant drug treatment. However, little is known on how N-methyl-d-aspartate (NMDA) receptor antagonism with ketamine as a novel antidepressant drug target might modulate amygdala reactivity to emotional stimulation. Using functional magnetic resonance imaging (fMRI) and resting-state fMRI (rsfMRI), we assessed amygdalo-hippocampal reactivity at baseline and during pharmacological stimulation with ketamine (intravenous bolus of 0.12 mg/kg, followed by a continuous infusion of 0.25 mg/kg/h) in 23 healthy subjects that were presented with stimuli from the International Affective Picture System (IAPS). We found that ketamine reduced neural reactivity in the bilateral amygdalo-hippocampal complex during emotional stimulation. Reduced amygdala reactivity to negative pictures was correlated to resting-state connectivity to the pregenual anterior cingulate cortex. Interestingly, subjects experienced intensity of psychedelic alterations of consciousness during ketamine infusion predicted the reduction in neural responsivity to negative but not to positive or neutral stimuli. Our findings suggest that the pharmacological modulation of glutamate-responsive cerebral circuits, which is associated with a shift in emotional bias and a reduction of amygdalo-hippocampal reactivity to emotional stimuli, represents an early biomechanism to restore parts of the disrupted neurobehavioral homeostasis in MDD patients. Hum Brain Mapp 37:1941-1952, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Cognition-emotion interaction in the brain can be investigated by incorporating stimuli with emotional content into cognitive tasks. Emotional stimuli in the context of a working memory (WM) task yield increased activation in WM-related lateral prefrontal regions, whereas cognitive effort enhances deactivation in emotion-related cortical midline regions. N-methyl-d-aspartate glutamate receptors (NMDA-Rs) are critically involved in WM, and NMDA-R antagonists, such as ketamine, accordingly affect WM but also have a profound impact on emotional processing, as underscored by the rapid reduction of depressive symptoms after administration of a single dose of ketamine. The effect of ketamine on both cognitive and emotional processing therefore makes it a useful tool to further explore cognition-emotion interaction in the brain. Twenty-three healthy subjects were administered ketamine to investigate whether its effects on WM performance and brain reactivity depend on emotional content or emotional valence of stimuli. Furthermore, we aimed at investigating how ketamine affects the integration of emotion and WM processes in emotion-related cortical midline regions and WM-related lateral prefrontal regions. Results show that ketamine modulates cognition-emotion interaction in the brain by inducing lateralized and valence-specific effects in emotion-related cortical midline regions, WM-related lateral prefrontal regions and insula. In emotion-related cortical midline regions ketamine abolishes enhancement of deactivation normally observed during cognitive effort, while in the right DLPFC and the left insula the previously described pattern of increased activation due to emotional content is abrogated exclusively for negative stimuli. Our data therefore shows a specific effect of ketamine on cognition-emotion interaction in the brain and indicates that its effect on amelioration of negative biases in MDD patients might be related to less interference of cognitive processing by negative emotional content., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Patients with major depressive disorder (MDD) often show a tendency to strongly introspect and reflect upon their self, which has been described as increased self-focus. Although subcortical-cortical midline structures have been associated with reflection and introspection of oneself in healthy subjects, the neural correlates of the abnormally increased attribution of negative emotions to oneself, i.e. negative self-attribution, as hallmark of the increased self-focus in MDD remain unclear. The aim of the study was, therefore, to investigate the neural correlates during judgment of self-relatedness of positive and negative emotional stimuli thereby testing for emotional self-attribution. Using fMRI, we investigated 27 acute MDD patients and compared them with 25 healthy subjects employing a paradigm that focused on judgment of self-relatedness when compared with mere perception of the very same emotional stimuli. Behaviourally, patients with MDD showed significantly higher degrees of self-relatedness of specifically negative emotional stimuli when compared with healthy subjects. Neurally, patients with MDD showed significantly lower signal intensities in various subcortical and cortical midline regions like the dorsomedial prefrontal cortex (DMPFC), supragenual anterior cingulate cortex, precuneus, ventral striatum (VS), and the dorsomedial thalamus (DMT). Signal changes in the DMPFC correlated with depression severity and hopelessness whereas those in the VS and the DMT were related to judgment of self-relatedness of negative emotional stimuli. In conclusion, we present first evidence that the abnormally increased negative self-attribution as hallmark of the increased self-focus in MDD might be mediated by altered neural activity in subcortical-cortical midline structures., ((c) 2008 Wiley-Liss, Inc.)

Context: Major depressive disorder (MDD) is characterized by diverse metabolic and functional abnormalities that occur in, among other regions, the pregenual anterior cingulate cortex (pgACC), a cortical region linked to anhedonia., Objectives: To contextualize metabolic, functional, and clinical parameters and thus to reveal cellular mechanisms related to anhedonia., Design: The pgACC was investigated using a combined functional magnetic resonance imaging and magnetic resonance spectroscopic approach. Negative blood oxygenation level-dependent (BOLD) activations in the pgACC were assessed during emotional stimulation. Quantitative J-resolved magnetic resonance spectroscopy in the pgACC enabled simultaneous determination of glutamine, glutamate, N-acetylaspartate, glucose, and gamma-aminobutyric acid concentrations. Subjective emotional intensity ratings as well as various clinical parameters were determined., Setting: The patients were recruited and evaluated in the Department of Psychiatry, University of Zurich, while the measurements were performed in the Institute of Biomedical Engineering, University of Zurich and the Technical University Zurich., Participants: Nineteen unmedicated patients with MDD and 24 healthy subjects., Main Outcome Measures: Reduced glutamine levels and lower functional responses in pgACC in anhedonic depressed patients were expected to be the predominant effect of abnormal glutamatergic transmission. It was further tested if, among patients, the ratings of emotional intensity on visual stimulation predicted the amount of metabolic and functional alterations in terms of reduced relative metabolite concentrations and BOLD changes., Results: Patients with highly anhedonic MDD show decreased glutamine but normal glutamate and gamma-aminobutyric acid concentrations, with glutamine concentrations being dissociated from glucose concentrations. Glutamate and N-acetylaspartate concentrations in pgACC correlate with negative BOLD responses induced by emotional stimulation in MDD; whereas in healthy subjects, negative BOLD responses correlate with gamma-aminobutyric acid instead. Negative BOLD responses as well as glutamate and N-acetylaspartate concentrations correlate with emotional intensity ratings, an anhedonia surrogate, in those with MDD but not in healthy subjects., Conclusion: Aberrant neuronal activation patterns of the pgACC in anhedonic depression are related to deficits of glutamatergic metabolism.

Studies using functional magnetic resonance imaging (fMRI) show predominant negative blood oxygenation level-dependent (BOLD) responses (NBRs) in regions of the default-mode network such as the pregenual anterior cingulate cortex, the ventromedial prefrontal cortex, and the posterior cingulate cortex. Patients with major depressive disorder (MDD) show emotional-cognitive disturbances, which have been associated with alterations within the default-mode network. However, it remains unclear whether these default-mode network alterations are related to abnormalities in NBRs. We therefore investigated neural activity in the default-mode network during different emotional tasks in patients with MDD in an event-related fMRI design. MDD patients showed significantly reduced NBRs in several regions of the default-mode network. Decreased NBRs in MDD patients correlated with depression severity and feelings of hopelessness. In sum, our findings demonstrate that default-mode network NBRs are reduced in MDD and modulate these patients' abnormally negative emotions.

The human anterior cingulate cortex (ACC) is part of the default-mode network that shows predominant negative blood oxygen level-dependent (BOLD) responses in functional magnetic resonance imaging (fMRI). We combined fMRI during emotional processing and resting-state magnetic resonance spectroscopy measurements and observed that the concentration of GABA in the ACC specifically correlated with the amount of negative BOLD responses in the very same region. Our findings show that default-mode network negative BOLD responses during emotions are mediated by GABA.

Damasio proposes in his somatic marker theory that not only cognitive but also affective components are critical for decision making. Since affective judgment requires an interplay between affective and cognitive components, it might be considered a key process in decision making that has been linked to neural activity in ventromedial prefrontal cortex (VMPFC). Using functional magnetic resonance imaging (fMRI), we examined the relationship between VMPFC, emotionally (unexpected)- and cognitively (expected)-accentuated affective judgment, and beneficial decision making (Iowa Gambling Task; IGT) in healthy subjects. Neuronal activity in the VMPFC during unexpected affective judgment significantly correlated with both global and final performance in the IGT task. These findings suggest that the degree to which subjects recruit the VMPFC during affective judgment is related to beneficial performance in decision making in gambling., (2005 Wiley-Liss, Inc.)

Emotions are frequently characterized by distinct dimensions such as valence, intensity, and recognition. However, the exact neural representation of these dimensions in different prefrontal cortical regions remains unclear. One of the problems in revealing prefrontal cortical representation is that the very same regions are also involved in cognitive functions associated with emotion processing. We therefore conducted an fMRI study involving the viewing of emotional pictures (using the International Affective Picture System; IAPS) and controlled for associated cognitive processing like judgment and preceding attention. Functional activation was correlated with subjective post-scanning ratings of valence, intensity, and recognition. Valence significantly correlated with the functional response in ventromedial prefrontal cortex (VMPFC) and dorsolateral prefrontal cortex (DLPFC), intensity with activation in ventrolateral prefrontal cortex (VLPFC) and dorsomedial prefrontal cortex (DMPFC), and recognition with the functional response in perigenual anterior cingulate cortex (PACC). In conclusion, our results indicate segregated neural representation of the different emotion dimensions in different prefrontal cortical regions.

Objectives. Functional imaging studies in major depressive disorder (MDD) indicate abnormal resting state neural activity and negative blood oxygenation level-dependent (BOLD) responses (NBRs) in regions of the default-mode network (DMN). Methods. Since activity in DMN regions has been associated with self-relatedness, we investigated neural activity in these regions during self-related emotional judgement and passive picture viewing in 25 patients with MDD and 25 healthy controls in an event-related fMRI design. Results. Behaviourally, MDD subjects showed significantly higher ratings of self-relatedness that also correlated with depression symptoms such as hopelessness. Neuroimaging results in MDD patients showed significantly lower negative BOLD responses (NBRs) in anterior medial cortical regions during judgement of self-relatedness while posterior medial regions showed increased NBRs. Unlike in healthy subjects, the anterior medial cortical NBRs were no longer parametrically modulated by the degree of self-relatedness in MDD patients. Conclusions. Our findings suggest that reduced NBRs in the anterior regions of the default-mode network may signify decoupling from self-relatedness in MDD patients with the consecutive abnormal increase of self-focus. [ABSTRACT FROM AUTHOR]

Heinzel A, Northoff G, Boeker H, Boesiger P, Grimm S. Emotional processing and executive functions in major depressive disorder: dorsal prefrontal activity correlates with performance in the intra-extra dimensional set shift. Major depressive disorder (MDD) is characterised by predominately negatively valenced emotional symptoms that are often accompanied by cognitive impairments. We posited that cognitive impairments in MDD are related to altered emotional processing in prefrontal cortex. We compared 20 medication-free patients with MDD and 29 matched healthy controls. Both groups performed an emotional task during functional magnetic resonance imaging (fMRI). Furthermore, they completed the intra-extra dimensional set shift (IED) test probing for cognitive impairments. Then we correlated the results of the IED with the changes in fMRI BOLD signal in MDD patients and healthy subjects. The subcategory of the IED applying extradimensional shift (EDS) showed a divergent performance of the MDD group committing significantly more errors than the control group. Correlating the EDS errors with fMRI signal changes, the healthy subjects showed a positive correlation with the right ventrolateral prefrontal cortex and the right orbitofrontal cortex. MDD subjects, in contrast, showed a positive correlation in right dorsolateral prefrontal cortex (DLPFC) and a negative correlation in the left dorsomedial prefrontal cortex (DMPFC). We hypothesise that the differential correlation in healthy controls and MDD patients may reflect the use of different strategies in their performance. The impaired executive functions, as reflected by altered processing in right DLPFC and left DMPFC, may implicitly influence emotional processing in patients suffering from MDD. [ABSTRACT FROM AUTHOR]

Catatonia is a psychomotor syndrome characterized by concurrent emotional, behavioral, and motor anomalies. Pathophysiological mechanisms of psychomotor disturbances may be related to abnormal emotional-motor processing in prefrontal cortical networks. We therefore investigated prefrontal cortical activation and connectivity patterns during emotional-motor stimulation using functional magnetic resonance imaging (FMRI). We investigated 10 akinetic catatonic patients in a postacute state and compared them with 10 noncatatonic postacute psychiatric controls (age-, sex-, diagnosis-, and medication-matched) and 10 healthy controls. Positive and negative pictures from the International Affective Picture System were used for emotional stimulation. FMRI measurements covered the whole frontal lobe, activation signals in various frontal cortical regions were obtained, and functional connectivity between the different prefrontal cortical regions was investigated using structural equation modeling. Catatonic patients showed alterations in the orbitofrontal cortical activation pattern and in functional connectivity to the premotor cortex in negative and positive emotions compared to psychiatric and healthy controls. Catatonic behavioral and affective symptoms correlated significantly with orbitofrontal activity, whereas catatonic motor symptoms were rather related to medial prefrontal activity. It is concluded that catatonic symptoms may be closely related to dysfunction in the orbitofrontal cortex and consequent alteration in the prefrontal cortical network during emotional processing. Because we investigated postacute patients, orbitofrontal cortical alterations may be interpreted as a trait marker predisposing for development of catatonic syndrome in schizophrenic or affective psychosis. [ABSTRACT FROM PUBLISHER]

Background: Although recent neuroimaging and therapeutic transcranial magnetic cortex stimulation (TMS) studies suggest imbalance between left and right dorsolateral prefrontal cortex (DLPFC) in major depressive disorder (MDD) the fundamental neuropsychological characterization of left DLPFC hypoactivity and right DLPFC hyperactivity in MDD remains poorly understood. Methods: We used event-related functional magnetic resonance imaging (fMRI) to investigate neural activity in left and right DLPFC related to unattended (unexpected) and attended (expected) judgment of emotions. Participating in the study were 20 medication-free patients with MDD and 30 healthy subjects. Results: The MDD patients showed hypoactivity in the left DLPFC during both unattended and attended emotional judgment and hyperactivity in the right DLPFC during attended emotional judgment. In contrast to healthy subjects, left DLPFC activity during emotional judgment was not parametrically modulated by negative emotional valence and was inversely modulated by positive emotional valence in MDD patients. Hyperactivity in the right DLPFC correlated with depression severity. Conclusions: Results demonstrate that left DLPFC hypoactivity is associated with negative emotional judgment rather than with emotional perception or attention while right DLPFC hyperactivity is linked to attentional modulation. Left–right DLPFC imbalance is characterized in neuropsychological regard, which bridges the gap from resting metabolism and therapeutic repetitive transcranial magnetic stimulation effects to functional neuroanatomy of altered emotional–cognitive interaction in MDD. [Copyright &y& Elsevier]