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Original Article |

Reduced Medial Prefrontal Responses to Social Interaction Images in Remitted Depression FREE

Rebecca Elliott, PhD; Karen Lythe, PhD; Rachel Lee, MBChB; Shane McKie, PhD; Gabriella Juhasz, MD, PhD; Emma J. Thomas, PhD; Darragh Downey, PhD; J. F. William Deakin, MBChB, PhD; Ian M. Anderson, MD, PhD
[+] Author Affiliations

Author Affiliations: Neuroscience and Psychiatry Unit, University of Manchester, and Manchester Academic Health Sciences Centre, Manchester, England.


Arch Gen Psychiatry. 2012;69(1):37-45. doi:10.1001/archgenpsychiatry.2011.139.
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Published online

Context Major depressive disorder is associated with impairments in processing emotional stimuli, and residual impairments are observed during remission, possibly indicating trait vulnerability. Stimuli with social context represent a distinct class of emotional stimuli, which in healthy volunteers are associated with specific neural substrates but have not previously been studied relative to vulnerability to depression.

Objective To explore whether individuals with remitted major depressive disorder had altered neuronal processing of social emotional stimuli.

Design Cross-sectional design using functional magnetic resonance imaging, combined with a cognitive activation task.

Setting General community of greater Manchester, England.

Participants Twenty-five unmedicated participants fully remitted from major depressive disorder and 29 age-matched control subjects.

Main Outcome Measures Neuronal responses to positive and negative social interaction images vs valence-matched images with less overt social context.

Results Participants with remitted depression showed attenuated frontopolar response relative to controls for positive and negative images depicting social interactions. For negative social images, participants with remitted depression also showed reduced latero-orbitofrontal response relative to controls.

Conclusions In the absence of current symptoms, individuals with remitted major depressive disorder showed reduced frontopolar processing of stimuli showing social interactions, a reduction not seen for stimuli showing individual successes and failures and, therefore, not simply an effect of emotional valence. These results suggest a specific trait abnormality in social emotional processing associated with vulnerability to depression, which may have implications for understanding social cognition mechanisms and for developing effective psychological therapies.

Figures in this Article

A range of deficits in emotional processing, both behavioral and neuronal, have been reported in major depressive disorder (MDD). Patients with depression show impaired processing of face emotion stimuli,14 as well as biases in memory for1,5,6 and attention to3,7,8 emotionally valenced stimuli. In general, these studies report a bias toward negative information or a bias away from positive information compared with responses of healthy control subjects. Evidence for continuing emotional processing biases following remission of symptoms is more mixed,9 although the balance of evidence suggests ongoing biases.3,4,10,11

Neuroimaging has identified neuronal substrates for a range of emotional processing abnormalities in MDD. For example, Wagner et al12 reported enhanced hippocampal response to positive images and enhanced amygdala and prefrontal responses to negative images in patients with MDD. By contrast, Lee et al13 reported reduced activity in right hippocampus and right insula in response to negative images and reduced activity in anterior cingulate cortex and left insula in response to positive images. A different pattern of responses again was reported by Anand et al,14 showing increased activation of anterior cingulate cortex, insula, and parahippocampal areas for negative images. One explanation of the discrepancy is differences in task demands. Phillips et al15 argued that limbic overactivity during initial evaluation of emotional stimuli, combined with failure of cortical control, causes a bias toward processing of negative information in MDD. Under this account, the exact neural correlates of any task will depend on the relative emotional evaluative and cognitive demands.

Bhagwagar and Cowen16 argued that studying remitted MDD (rMDD) may provide insights into trait abnormalities; however, the extent to which abnormal neuroimaging responses to emotional stimuli persist following remission is unclear.9,17 Some researchers suggest that increased responses to negative emotional stimuli (typically faces) are observed in remitted patients.1820 Others have reported normal responses to emotional faces in rMDD2123 or elevated responses to negative stimuli only if transient sad mood is induced.2426 There are several potential reasons for these discrepancies; for example, we have suggested that the degree to which abnormality persists in remission depends on personality traits associated with vulnerability to relapse.23 Traits like intraversion and neuroticism are associated with vulnerability to depression and may be related to increased functional magnetic resonance (fMR) imaging responses to negative emotional stimuli in never-depressed individuals27 and in patients with rMDD.23 In an explicit test of the association between abnormal emotional responses and vulnerability to relapse in rMDD, Farb et al28 recently showed that abnormal prefrontal responses to sad films predict relapse.

Another important issue is whether different contexts of emotional processing influence abnormalities observed in rMDD. Recent theories of emotional processing suggest an important distinction between social and nonsocial emotions.29,30 Although basic emotions like fear also have social connotations, a range of emotions necessarily depend on determining the self-relevance of other individuals' emotions. Positive social encounters tend to elicit positive social emotions (eg, love and pride), while negative social encounters tend to elicit negative social emotions (eg, jealousy and shame). Social emotional processing may be mediated by distinct neural substrates3032 that involve brain regions previously identified as important in social information processing.3337 For example, studies32,38,39 of guilt and shame have consistently shown frontopolar activation. Some of these investigations have involved a social condition requiring mentalizing or empathy compared with a condition without this requirement (eg, studies37,40 taking perspective of self compared with other). A previous study30 explicitly comparing social and nonsocial emotional processing using script-driven imagery reported increased frontopolar response to social stimuli, as well as responses in other regions of a putative social cognition network. Meanwhile, a study41 of social exclusion compared with social inclusion reported a focal increase in right inferior frontal activation. Negative social emotions like social exclusion may be particularly relevant in depression and relate to trait vulnerability and current mood,42 but to date no imaging studies have been explicitly designed to probe socially related emotional processing in people vulnerable to MDD.

The present study investigated neuronal correlates of emotional processing in a sample of unmedicated individuals with rMDD using stimuli designed to differentially probe social emotions, specifically images of social group interactions compared with single individuals. Unlike some previous investigations, we asked participants to imagine themselves in another's situation in all conditions. Rather than varying the nature of the instruction, we varied the degree of social context of the imagined situation. We hypothesized (1) that in healthy controls increased social emotional processing would be associated with increased neuronal responses in regions that include frontopolar cortex, inferofrontal gyrus (IFG), temporoparietal junction, and temporal poles30,33,3537,43,44 and (2) that participants with rMDD would show increased response to negative social emotions within these regions.

PARTICIPANTS

Participants were recruited using a Web site, local advertisement, general practice, and word of mouth. Potential suitability was established via a postal or an online screening survey (as part of a much larger study [http://www.medicine.manchester.ac.uk/mentalhealth/]), and positively screened participants were invited for interview. After complete description of the study to the participants, written informed consent was obtained. The study was approved by the Central Manchester Local Research Ethics Committee (reference 06/Q1410/72), Manchester, England. All the participants were right-handed and reported normal vision or vision corrected to normal. Their IQ was estimated using the Quick Test. All the participants completed the 240-item NEO Personality Inventory–Revised. Scores on the neuroticism and extraversion subscales are summarized in the Table.

Table Graphic Jump LocationTable. Demographic Data and Valence Ratings
PARTICIPANTS FULLY rMDD

Twenty-five participants (9 males and 16 females; mean [SE] age, 33.8 [10.1] years) with rMDD were included in the study. Participants were required to have had no lifetime history of bipolar disorder, psychosis, obsessive-compulsive disorder, or drug or alcohol misuse, as well as no neurological disorder, unstable medical condition, history of significant head trauma, or contraindication to MR imaging. Thirty-two participants were invited for interview, at which diagnosis was established using the 1994 Structured Clinical Interview for DSM-IV by the American Psychiatric Association, administered by a trained researcher (G.J., E.J.T., and D.D.) under supervision of a consultant psychiatrist (I.M.A.). Participants were required to meet DSM-IV criteria for at least 1 past major depressive episode but not for a current major depressive episode or any other psychiatric disorder. Participants were required to have a Montgomery-Asberg Depression Rating Scale45 score of less than 10, which has been proposed as an acceptable definition of clinical remission.46,47 Two participants were excluded on the basis of Montgomery-Asberg Depression Rating Scale scores above this cutoff point. All the participants with rMDD were required to be unmedicated, and 5 were excluded on the basis of current medication. Of the included participants, 18 of 25 had previously taken antidepressants but had discontinued medication at least 6 months previously, and 24 of 25 had not experienced any depression in the preceding year. The mean (SE) number of past depressed episodes was 3.5 (2.4). Participants with a history of anxiety disorder were not excluded. Depression is frequently comorbid with anxiety,48 and commonalities of symptoms and treatment response indicate a strong case for considering the disorders together in a neurobiological context.49 To exclude current anxiety, all participants were required to have a score of less than 8 on the Clinical Anxiety Scale.50 No one was excluded on this basis, and only 6 of 25 participants had a history of clinical anxiety disorder on clinical interview.

CONTROLS

Twenty-nine controls (10 males and 19 females; mean [SE] age, 32.4 [9.7] years) were included in the study. The same general exclusion criteria applied as for the patients with rMDD. In addition, controls were required to have no reported personal or immediate family history of psychiatric problems on diagnostic interview. Of 32 participants interviewed, 3 were excluded on the basis of current medication.

The rMDD and control groups did not differ in terms of age, IQ, or sex ratio (Table). Participants with rMDD scored within the normal range on the Montgomery-Asberg Depression Rating Scale and Clinical Anxiety Scale but differed significantly from controls. They were also significantly more neurotic and less extraverted than controls.

COGNITIVE ACTIVATION TASK

Participants were shown 64 images, each including 1 person highlighted by a red circle. The images were selected on the basis of a pilot study (Appendix,“Methods” section) to differentially probe social emotion. We included images of social group inclusion and exclusion designed to evoke highly social emotions and images of individual success and failure designed to evoke less pronounced social emotions. In the active conditions, each image depicted 1 of the following 4 emotive conditions: individual positive, individual negative, group positive, and group negative (Figure 1). We also included 2 control conditions showing nonemotive situations and controlling for the presence of 1 vs several persons in the individual and group conditions (eg, a person sitting reading a newspaper or a person standing in a queue at a supermarket). Red-circled individuals were young adults in all images, with equal numbers of male and female protagonists across the task. In positive images, the individuals had happy expressions; in negative images they had sad or upset expressions, and in neutral conditions they had neutral expressions. None of the negative scenarios showed explicit emotions of fear, anger, or disgust. Participants were instructed to think about how they would feel in a situation similar to that of the person highlighted. Neutral images were divided into 2 groups so that a specific set of control images existed for each emotive condition. For each emotive condition, there were 8 images (divided into 2 blocks of 4), and for each neutral condition (single person and multiple person), there were 16 images (divided into 4 blocks, 2 with single-person images and 2 with multiple-person images). Emotive conditions were presented in a counterbalanced order, with neutral control blocks interspersed between emotive blocks. The order of presentation was varied among participants. Images were presented at a rate of 1 every 11.25 seconds, with the image on screen for 8.00 seconds, followed by a fixation cross for 3.25 seconds. Therefore, each block lasted 45.00 seconds; there were 8 emotive blocks (2 for each condition) and 8 neutral blocks, rendering a total task time of 12 minutes. No explicit responses were required. After imaging, participants were asked to rate how positive or negative they had found the images seen during imaging using a 10-point Likert-type scale. The groups did not differ in their affective ratings of the images shown (Table). There were also no significant differences for either group in valence ratings between group and individual images (positive, negative, or neutral).

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Figure 1. Examples of stimuli in the following tasks: individual negative (A), individual positive (B), group negative (C), group positive (D), group neutral (E), and individual neutral (F).

fMR IMAGING PROTOCOL

Participants underwent fMR imaging using a 1.5-T imaging system (Intera; Philips Healthcare, Best, the Netherlands). Three hundred forty volumes were acquired with T2-weighted gradient-echo echoplanar imaging. Repetition time was 2.1 seconds, and echo time was 40 milliseconds. Each volume comprised 40 axial sections, at a section thickness of 4.5 mm with a 0.5-mm section gap and in-plane resolution of 3.5 × 3.5 mm. A T1-weighted structural image was acquired for use in spatial preprocessing and was examined to exclude participants with any structural abnormalities (no abnormalities were observed).

STATISTICAL ANALYSIS

Data were analyzed using statistical parametric mapping (SPM5; Wellcome Trust Centre for Neuroimaging, London, England). Images were realigned to correct for motion using the first image as a reference image. Coregistration of the structural (T1-weighted) and functional (T2-weighted) images was performed. Images were spatially normalized into a standard stereotactic space using a nonlinear transformation and were smoothed using a gaussian kernel filter of full width at half maximum of 3 times the voxel size (ie, 10.5, 10.5, and 13.5 mm). First-level analysis (fixed effects) was performed on each participant to generate a mean image for each of the following contrasts: (1) individual positive vs individual neutral, (2) individual negative vs individual neutral, (3) group positive vs group neutral, and (4) group negative vs group neutral.

At second-level analysis (random effects), we first identified differential responses to individual and group images in healthy controls. A factorial model was then used to determine how differential responses to individual and group images were modulated by diagnosis (rMDD vs controls). We assessed effects within regions of interest (ROIs) predefined using anatomical masks from the automated anatomical labels of the Wake Forest University (Winston Salem, North Carolina) Pick Atlas toolbox.51,52 Defined ROIs were frontopolar cortex, temporal poles, IFG, and temporoparietal junction, all bilateral. We created a single a priori mask comprising these regions, and within this single composite ROI we report blood oxygenation level–dependent responses surviving statistical thresholds of P < .05 (false discovery rate [FDR] corrected), although those that do not also survive at P < .05 (familywise error [FWE] corrected) must be viewed with caution. Voxels outside of these regions are reported if they reach statistical significance at P < .05 (FWE corrected) for whole brain. Montreal Neurological Institute coordinates are reported.

Correlations with neuroticism and extraversion scores were also evaluated within ROIs. In the rMDD group, correlations with the number of past depressed episodes and residual depressive and anxiety symptoms were also assessed.

In all reported contrasts, the corresponding neutral condition was subtracted from each emotive condition in first-level analysis. This was done to control for any effect of differential responses to images of single and multiple persons. For example, if it was more difficult to process images of several persons, the use of matched–neutral images would control for this.

MAIN EFFECTS IN CONTROL SUBJECTS
Response to Positive vs Neutral Images

For group-positive images compared with group-neutral images, significant response was observed in frontal pole (Montreal Neurological Institute coordinates 4, 49, 35; z = 4.09,κ = 22), surviving correction at P < .05 (FWE corrected) in ROI analysis. For individual -positive images compared with individual-neutral images, no significant response was observed in ROI analysis.

Response to Group-Positive vs Individual-Positive Images

Significantly greater response to group-positive compared with individual-positive images was observed in frontal pole (coordinates 4, 49, 35; z = 4.09; coordinates 4, 63, 20; z = 4.07,κ = 36), surviving correction at P < .05 (FWE corrected) in ROI analysis. There were no regions that showed greater response to individual-positive images than to group-positive images.

Response to Negative vs Neutral Images

For group-negative images compared with group-neutral images, significant response was observed in frontal pole (coordinates 4, 56, 10; z = 4.54,κ = 24), surviving correction at P < .05 (FWE corrected) in ROI analysis, and in right IFG (coordinates 38, 45,−10; z = 3.27), surviving correction at P < .05 (FDR corrected) in ROI analysis. For individual-negative images compared with individual-neutral images, no significant response was observed in ROI analysis.

Response to Group-Negative vs Individual-Negative Images

Significantly greater response to group-negative compared with individual-negative images was observed in frontal pole (coordinates 4, 53, 35; z = 4.19,κ = 36), surviving correction at P < .05 (FWE corrected) in ROI analysis, and in right IFG (coordinates 49, 25,−15; z = 3.62,κ = 21), surviving correction at P < .05 (FDR corrected) in ROI analysis. There were no regions that showed greater response to individual-negative images than to group-negative images.

COMPARISONS BETWEEN rMDD AND CONTROL PARTICIPANTS
Response to Positive vs Neutral Images

For group-positive images compared with group-neutral images, controls showed significantly greater response than participants with rMDD in frontal pole (coordinates−14, 60, 20; z = 3.86,κ = 19), surviving correction at P < .05 (FWE corrected) in ROI analysis. There were no regions where responses to group-positive images were greater in participants with rMDD than in controls. For individual-positive images compared with individual-neutral images, participants with rMDD showed greater response than controls in frontal pole (coordinates−4, 60, 10; z = 3.76,κ = 18), surviving correction at P < .05 (FWE corrected) in ROI analysis. There were no regions that showed responses to individual-positive images were greater in controls than in participants with rMDD.

Response to Group-Positive vs Individual-Positive Images

Controls showed significantly greater response than participants with rMDD to group-positive images compared with individual-positive images in frontal pole (coordinates−14, 60, 20; z = 4.09,κ = 12), surviving correction at P < .05 (FWE corrected) in ROI analysis (Figure 2). This interaction was driven by enhanced frontopolar signal to group images compared with individual images in controls and by the opposite pattern in participants with rMDD. There were no regions that showed greater responses to individual-positive images in controls than in participants with rMDD.

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Figure 2. Attenuated frontopolar response to group-positive vs individual-positive images in participants with remitted major depressive disorder (rMDD) compared with control subjects. A, Frontopolar response thresholded at P < .001 (uncorrected) and superimposed on a standard structural image. B, Peak voxel signal change associated with group-positive and individual-positive images in control subjects and participants with rMDD.

Response to Negative vs Neutral Images

For group-negative images compared with group-neutral images, controls showed significantly greater response than participants with rMDD in right IFG (coordinates 38, 45,−10; z = 3.27,κ = 14), surviving correction at P < .05 (FDR corrected) in ROI analysis. There were no regions that showed responses to group-negative images were greater in participants with rMDD than in controls. For individual-negative images compared with individual-neutral images, participants with rMDD showed greater response than controls in frontal pole (coordinates 7, 56, 35; z = 3.85,κ = 13), surviving correction at P < .05 (FWE corrected) in ROI analysis. There were no regions that showed greater responses to group-negative images in participants with rMDD than in controls.

Response to Group-Negative vs Individual-Negative Images

Controls showed significantly greater response than participants with rMDD to group-negative images compared with individual-negative images in frontal pole (coordinates 7, 60, 35; z = 3.64,κ = 19) and in right IFG (coordinates 49, 25,−15; z = 3.57,κ = 15), surviving correction at P < .05 (FDR corrected) in ROI analysis (Figure 3). There were no regions that showed greater responses to individual-negative images in controls than in participants with rMDD.

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Figure 3. Attenuated lateral orbitofrontal response to group-negative vs individual-negative images in participants with remitted major depressive disorder (rMDD) compared with control subjects. A, Latero-orbitofrontal response thresholded at P < .01 (uncorrected) and superimposed on a standard structural image. B, Peak voxel signal change associated with group-negative and individual-negative images in control subjects and participants with rMDD.

CORRELATIONS

No significant correlations were noted between the fMR imaging responses reported herein and the number of past depressed episodes, residual depressive symptoms (Montgomery-Asberg Depression Rating Scale score), or anxiety symptoms (Clinical Anxiety Scale score) among participants with rMDD. Furthermore, inclusion of residual depressive and anxiety symptoms as covariates of interest in the between-group analysis did not affect the results reported herein. None of the reported fMR imaging responses correlated significantly with neuroticism or extraversion in controls. For participants with rMDD, there were no significant correlations with fMR imaging signal in the regions reported herein. However, the fMR imaging response to group-negative images compared with group-neutral images was significantly negatively correlated with extraversion in hippocampus (coordinates 25,−25,−10; z = 4.66,κ = 12), a region that was not seen in any of the main effects or interactions discussed herein. This correlation survived whole-brain correction at P < .05 (FWE corrected). Therefore, less extraverted participants with rMDD showed greater blood oxygenation level–dependent response in posterior hippocampus when viewing group-negative images.

In controls, both positive and negative group images compared with neutral images were associated with responses in frontal pole. Neither positive nor negative individual images compared with neutral images were associated with differential responses in ROIs. When comparing images depicting explicit social group context with images depicting single individuals, differential responses were observed in frontopolar cortices for images of both positive and negative valence. Negative social group compared with individual images were also associated with enhanced right IFG responses. Participants with rMDD showed decreased frontopolar response to positive images and decreased IFG response to negative images compared with neutral images of group interaction and showed increased frontopolar response to both positive and negative images of individuals. When images with different social content were directly contrasted, participants with rMDD showed significantly attenuated frontopolar response to group images compared with individual images. Contrary to our hypothesis, this attenuation was observed for both positive and negative images. Negative social group compared with individual images were also associated with attenuated response in right IFG. Neither frontopolar nor IFG responses correlated with the number of previous depressive episodes, residual depressive symptoms, neuroticism, or extraversion. However, less extraverted participants with rMDD showed significantly enhanced posterior hippocampal response to negative images depicting group exclusion.

In controls, our key finding was enhanced frontopolar response to emotional images of group interactions. Frontopolar responses have been observed in many investigations of self-referential and introspective processing and have been associated with mentalizing and empathy.3335,40,43 We explicitly asked participants to imagine themselves in someone else's situation in all conditions (including neutral controls); therefore, all conditions involved mentalizing and empathy. Hence, our results indicate that frontopolar involvement in such processes is enhanced when stimuli have a more overtly social context, consistent with several theoretical accounts that suggest a specific role for frontopolar regions in processing of social interactions.34,37,53,54

Our main objective in this study was to evaluate social emotional processing in rMDD, and we demonstrate for the first time to date selective alteration in processing of emotional images depicting overt social interaction. Participants with rMDD showed reduced frontopolar response to both positive and negative images of explicit social interaction compared with images of individuals matched for subjective valence. Previous findings have suggested that rMDD may be associated with ongoing neural abnormalities in processing of positive or negative emotional stimuli, particularly faces.55 In our study, the positive images (both individual and group) showed happy persons, while the negative images showed sad persons; therefore, responses to happy and sad faces could be a factor in our task. However, opposite effects in frontopolar regions were observed for group and individual images of the same valence. This pattern is incompatible with a hypothesis of general hyperresponse or hyporesponse to stimuli showing emotional faces. Furthermore, postimaging valence judgments did not differ for group compared with individual images or for participants with rMDD compared with controls; therefore, differences in perceived valence of images are unlikely to be a significant factor affecting the results. Reduced responses to positive and negative group images seem to represent a genuine impairment in response specifically to stimuli depicting social interaction.

Schaefer et al56 showed that patients with MDD were hyporesponsive to images depicting positive social interaction in regions that included frontopolar cortex. However, in their study, this hyporesponse normalized after successful antidepressant therapy, which is somewhat at odds with our finding of hyporesponse in participants with rMDD. This may reflect lack of power in their study (n = 9) or the possibility that antidepressants may directly enhance processing of emotional and social information57 and“mask” underlying hyporesponse. The discrepancy may also reflect differences between paradigms. The paradigm by Schaefer et al required passive viewing of images. By contrast, we asked participants to imagine themselves in the situations depicted; therefore, our instructions directed participants toward a self-referential mode of processing. Self-referential processing in MDD has been associated with increased medial prefrontal response in studies58,59 of patients with current depression. Furthermore, this elevation was shown not to normalize in response to effective treatment60 and has been suggested as a vulnerability marker relating to self-focus in depression.61

Findings of abnormalities in rMDD may be associated with a“scarring” effect of prior depressive episodes. However, we observed no correlation between frontopolar abnormalities and the number of previous depressive episodes. Therefore, it is also plausible that reduced frontopolar responses to social images represent a trait vulnerability factor. Notably, Krämer et al44 reported that frontopolar responses to images of emotionally charged social situations were negatively correlated with participants' tendency to feel distress and anxiety, which has been associated with lack of self-regulation in emotional situations.62 An association between vulnerability to depression and frontopolar-mediated failure to self-regulate that leads to distress and anxiety in social emotional situations would be a plausible hypothesis.

Another explanation for decreased frontopolar responses in participants with rMDD to images of social interaction may be reduced ability to relate to the social situations depicted. This would be consistent with a history of social anxiety and withdrawal associated with MDD. The extraversion scale of the NEO Personality Inventory–Revised provides a crude measure of tendency to engage in and be motivated by social interaction, and participants with rMDD scored significantly lower on this measure than controls. However, extraversion scores did not correlate with frontopolar responses or other responses within hypothesized ROIs. Notably, among participants with rMDD, there was a significant negative correlation between extraversion and posterior hippocampal response to negative social images. Posterior hippocampal response may reflect greater engagement of autobiographical memory for images evoking feelings of exclusion or rejection. Eisenberger et al41 showed that in healthy individuals enhanced hippocampal response to social rejection was associated with a stronger link between momentary feelings of rejection and end-of-the-day social disconnection, suggesting that hippocampal responses may reflect a tendency to greater rumination on rejection. It is plausible that this tendency is increased in less extraverted persons vulnerable to depression.

Participants with rMDD also showed no increased right IFG response to negative social group images, although this result must be interpreted with caution because it did not survive stringent statistical thresholding. Enhanced right IFG response to social exclusion in healthy controls supports the finding by Eisenberger et al41 of social rejection that implicated right Brodmann area 47. Eisenberger et al also reported that functional response in this region correlated negatively with reported emotional distress, suggesting that it may fulfill a regulatory function mitigating the effect of social distress. Our study findings suggest that individuals vulnerable to depression may fail to recruit this regulatory mechanism, compatible with helplessness theories and with recent theories of emotional processing15 that emphasize a role for lateral prefrontal regions in voluntary suppression of emotions.

There are several limitations to our study. First, although none of the participants with rMDD were showing current clinically significant anxiety, we did not exclude history of anxiety disorder; therefore, it is possible that previous social anxiety symptoms may have contributed to observed effects. However, only 6 of 25 participants had a history of clinical anxiety disorder, and exclusion of these participants did not affect the significance of the results. Further study is required to relate the observed abnormalities to specific traits and to overt social behavior. Second, our design does not allow us to distinguish between potential trait abnormalities and a scarring effect of previous depressive episodes. A future study among never-depressed individuals with risk factors for depression would help address this point. Similarly, an important future direction would be a longitudinal study to determine whether abnormalities in social emotional processing are predictive of relapse in rMDD.

There are also important limitations regarding the task used. We did not require any explicit response during imaging and, therefore, have no overt measure of attention; however, differential effects of different stimuli would argue against a general attention effect. Also, we did not attempt to elicit information about subjective experiences during image viewing and therefore have no measure of the extent to which social emotions were experienced. Results of our pilot study suggest that the images successfully probe different emotions in an independent sample. Our stimuli were selected (described in eMethods) to differentially engage social feelings (inclusion and exclusion) compared with feelings of individual success and failure. Images of single individuals experiencing success and failure can certainly elicit social emotions, but critically we suggest that they do so to a lesser extent than overt images of social group interactions. Future research with more sophisticated paradigms is required to test hypotheses generated by the present study more explicitly.

Despite the limitations, our study reveals potentially important abnormalities in response to social emotion in rMDD. Although affective ratings for the images were not significantly different from those by controls, participants with rMDD showed decreased responses to images of social interaction, which we interpret in terms of a potential trait abnormality in social emotional processing. Previous studies have explored generalized emotional processing correlates, with somewhat equivocal results. In this study of unmedicated participants with rMDD, we suggest that specific social emotional processing abnormalities may represent a trait vulnerability for MDD. Improved understanding of what the neurobiological mechanisms of vulnerability and relapse are and how they relate to psychological models has important implications for developing cognitive and pharmacological approaches to primary and secondary prevention of depression.

Correspondence: Rebecca Elliott, PhD, Neuroscience and Psychiatry Unit, University of Manchester, Room G907, Stopford Bldg, Oxford Road, Manchester M13 9PT, England (Rebecca.elliott@manchester.ac.uk).

Submitted for Publication: April 14, 2011; final revision received June 1, 2011; accepted July 15, 2011.

Author Contributions: Dr Elliott had full access to all the data in the study, performed the statistical analysis, and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Financial Disclosure: In the past 12 months, Dr Elliott received consultancy fees from Cambridge Cognition and P1vital. Dr Deakin variously performed consultancy, speaking engagements, and research for Bristol-Myers Squibb, AstraZeneca, Eli Lilly, Schering Plough, Janssen-Cilag, and Servier (all fees are paid to the University of Manchester to reimburse them for the time taken); he has share options in P1vital. Dr Anderson received an honorarium for speaking from Lundbeck and grant support from Servier and AstraZeneca.

Funding/Support: This study was supported by grant LSHM-CT-2004-503474 from the NewMood European Union Integrated Research Programme. Dr Thomas was supported by a Medical Research Council Studentship.

Role of the Sponsor: The sponsor provided peer review of the study design and funded the work but had no further role in the design or conduct of the study or in the preparation, review, or approval of the manuscript.

Additional Contributions: Diana Chase, PhD; Kathryn Lloyd-Williams, BSc; Ivan Koychev, PhD; and Christine Bowen, BSc (Hons), assisted with recruitment and data acquisition. Roland Zahn, MD, provided helpful comments on a draft of the manuscript. For all their assistance, we thank the staff of the Wellcome Trust Clinical Research Facility, Manchester, where this research was performed.

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Gotlib IH, Krasnoperova E, Yue DN, Joormann J. Attentional biases for negative interpersonal stimuli in clinical depression.  J Abnorm Psychol. 2004;113(1):121-135
PubMed   |  Link to Article
Erickson K, Drevets WC, Clark L, Cannon DM, Bain EE, Zarate CA Jr, Charney DS, Sahakian BJ. Mood-congruent bias in affective go/no-go performance of unmedicated patients with major depressive disorder.  Am J Psychiatry. 2005;162(11):2171-2173
PubMed   |  Link to Article
Leppänen JM. Emotional information processing in mood disorders: a review of behavioral and neuroimaging findings.  Curr Opin Psychiatry. 2006;19(1):34-39
PubMed   |  Link to Article
Atchley RA, Ilardi SS, Enloe A. Hemispheric asymmetry in the processing of emotional content in word meanings: the effect of current and past depression.  Brain Lang. 2003;84(1):105-119
PubMed   |  Link to Article
Bhagwagar Z, Cowen PJ, Goodwin GM, Harmer CJ. Normalization of enhanced fear recognition by acute SSRI treatment in subjects with a previous history of depression.  Am J Psychiatry. 2004;161(1):166-168
PubMed   |  Link to Article
Wagner V, Müller JL, Sommer M, Klein HE, Hajak G. Changes in the emotional processing in depressive patients: a study with functional magnetoresonance tomography under the employment of pictures with affective contents.  Psychiatr Prax. 2004;31:(suppl 1)  S70-S72
PubMed   |  Link to Article
Lee BT, Seok JH, Lee BC, Cho SW, Yoon BJ, Lee KU, Chae JH, Choi IG, Ham BJ. Neural correlates of affective processing in response to sad and angry facial stimuli in patients with major depressive disorder.  Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(3):778-785
PubMed   |  Link to Article
Anand A, Li Y, Wang Y, Wu J, Gao S, Bukhari L, Mathews VP, Kalnin A, Lowe MJ.  Activity and connectivity of brain mood regulating circuit in depression: a functional magnetic resonance study.  Biol Psychiatry. 2005;57(10):1079-1088
PubMed   |  Link to Article
Phillips ML, Drevets WC, Rauch SL, Lane R. Neurobiology of emotion perception II: implications for major psychiatric disorders.  Biol Psychiatry. 2003;54(5):515-528
PubMed   |  Link to Article
Bhagwagar Z, Cowen PJ. “It's not over when it's over”: persistent neurobiological abnormalities in recovered depressed patients.  Psychol Med. 2008;38(3):307-313
PubMed   |  Link to Article
Elliott R, Zahn R, Deakin JF, Anderson IM. Affective cognition and its disruption in mood disorders.  Neuropsychopharmacology. 2011;36(1):153-182
PubMed   |  Link to Article
Neumeister A, Drevets WC, Belfer I, Luckenbaugh DA, Henry S, Bonne O, Herscovitch P, Goldman D, Charney DS. Effects ofα C-adrenoreceptor gene polymorphism on neural responses to facial expressions in depression.  Neuropsycho pharmacology. 2006;31(8):1750-1756
PubMed   |  Link to Article
Norbury R, Taylor MJ, Selvaraj S, Murphy SE, Harmer CJ, Cowen PJ. Short-term antidepressant treatment modulates amygdala response to happy faces.  Psychopharmacology (Berl). 2009;206(2):197-204
PubMed   |  Link to Article
Victor TA, Furey ML, Fromm SJ, Ohman A, Drevets WC. Relationship between amygdala responses to masked faces and mood state and treatment in major depressive disorder.  Arch Gen Psychiatry. 2010;67(11):1128-1138
PubMed   |  Link to Article
Sheline YI, Barch DM, Donnelly JM, Ollinger JM, Snyder AZ, Mintun MA. Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment: an fMRI study.  Biol Psychiatry. 2001;50(9):651-658
PubMed   |  Link to Article
Fu CH, Williams SC, Cleare AJ, Brammer MJ, Walsh ND, Kim J, Andrew CM, Pich EM, Williams PM, Reed LJ, Mitterschiffthaler MT, Suckling J, Bullmore ET. Attenuation of the neural response to sad faces in major depression by antidepressant treatment: a prospective, event-related functional magnetic resonance imaging study.  Arch Gen Psychiatry. 2004;61(9):877-889
PubMed   |  Link to Article
Thomas EJ, Elliott R, McKie S, Arnone D, Downey D, Juhasz G, Deakin JF, Anderson IM. Interaction between a history of depression and rumination on neural response to emotional faces.  Psychol Med. 2011;41(9):1845-1855
PubMed   |  Link to Article
Gemar MC, Segal ZV, Mayberg HS, Goldapple K, Carney C. Changes in regional cerebral blood flow following mood challenge in drug-free, remitted patients with unipolar depression.  Depress Anxiety. 2007;24(8):597-601
PubMed   |  Link to Article
Liotti M, Mayberg HS, Brannan SK, McGinnis S, Jerabek P, Fox PT. Differential limbic—cortical correlates of sadness and anxiety in healthy subjects: implications for affective disorders.  Biol Psychiatry. 2000;48(1):30-42
PubMed   |  Link to Article
Ramel W, Goldin PR, Eyler LT, Brown GG, Gotlib IH, McQuaid JR. Amygdala reactivity and mood-congruent memory in individuals at risk for depressive relapse.  Biol Psychiatry. 2007;61(2):231-239
PubMed   |  Link to Article
Chan SW, Norbury R, Goodwin GM, Harmer CJ. Risk for depression and neural responses to fearful facial expressions of emotion.  Br J Psychiatry. 2009;194(2):139-145
PubMed   |  Link to Article
Farb NA, Anderson AK, Bloch RT, Segal ZV. Mood-linked responses in medial prefrontal cortex predict relapse in patients with recurrent unipolar depression.  Biol Psychiatry. 2011;70(4):366-372
PubMed   |  Link to Article
Hareli S, Parkinson B. What's social about emotions?  J Theory Soc Behav. 2008;38:131-156
Link to Article
Frewen PA, Dozois DJ, Neufeld RW, Densmore M, Stevens TK, Lanius RA. Neuroimaging social emotional processing in women: fMRI study of script-driven imagery.  Soc Cogn Affect Neurosci. 2011;6(3):375-392
PubMed   |  Link to Article
Takahashi H, Matsuura M, Koeda M, Yahata N, Suhara T, Kato M, Okubo Y. Brain activations during judgments of positive self-conscious emotion and positive basic emotion: pride and joy.  Cereb Cortex. 2008;18(4):898-903
PubMed   |  Link to Article
Takahashi H, Yahata N, Koeda M, Matsuda T, Asai K, Okubo Y. Brain activation associated with evaluative processes of guilt and embarrassment: an fMRI study.  Neuroimage. 2004;23(3):967-974
PubMed   |  Link to Article
Frith CD, Frith U. The neural basis of mentalizing.  Neuron. 2006;50(4):531-534
PubMed   |  Link to Article
Amodio DM, Frith CD. Meeting of minds: the medial frontal cortex and social cognition.  Nat Rev Neurosci. 2006;7(4):268-277
PubMed   |  Link to Article
Legrand D, Ruby P. What is self-specific? theoretical investigation and critical review of neuroimaging results.  Psychol Rev. 2009;116(1):252-282
PubMed   |  Link to Article
Saxe R, Moran JM, Scholz J, Gabrieli J. Overlapping and non-overlapping brain regions for theory of mind and self reflection in individual subjects.  Soc Cogn Affect Neurosci. 2006;1(3):229-234
PubMed   |  Link to Article
Van Overwalle F. Social cognition and the brain: a meta-analysis.  Hum Brain Mapp. 2009;30(3):829-858
PubMed   |  Link to Article
Zahn R, Moll J, Paiva M, Garrido G, Krueger F, Huey ED, Grafman J. The neural basis of human social values: evidence from functional MRI.  Cereb Cortex. 2009;19(2):276-283
PubMed   |  Link to Article
Moll J, de Oliveira-Souza R, Garrido GJ, Bramati IE, Caparelli-Daquer EMA, Paiva ML, Zahn R, Grafman J. The self as a moral agent: linking the neural bases of social agency and moral sensitivity.  Soc Neurosci. 2007;2(3-4):336-352
PubMed   |  Link to Article
Ochsner KN, Knierim K, Ludlow DH, Hanelin J, Ramachandran T, Glover G, Mackey SC. Reflecting upon feelings: an fMRI study of neural systems supporting the attribution of emotion to self and other.  J Cogn Neurosci. 2004;16(10):1746-1772
PubMed   |  Link to Article
Eisenberger NI, Lieberman MD, Williams KD. Does rejection hurt? an FMRI study of social exclusion.  Science. 2003;302(5643):290-292
PubMed   |  Link to Article
Zuroff DC, Mongrain M, Santor DA. Conceptualizing and measuring personality vulnerability to depression: comment on Coyne and Whiffen (1995).  Psychol Bull. 2004;130(3):489-522
PubMed   |  Link to Article
Northoff G, Heinzel A, de Greck M, Bermpohl F, Dobrowolny H, Panksepp J. Self-referential processing in our brain—a meta-analysis of imaging studies on the self.  Neuroimage. 2006;31(1):440-457
PubMed   |  Link to Article
Krämer UM, Mohammadi B, Doñamayor N, Samii A, Münte TF. Emotional and cognitive aspects of empathy and their relation to social cognition—an fMRI-study.  Brain Res. 2010;1311:110-120
PubMed   |  Link to Article
Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change.  Br J Psychiatry. 1979;134:382-389
PubMed   |  Link to Article
Hawley CJ, Gale TM, Sivakumaran T.Hertfordshire Neuroscience Research group.  Defining remission by cut off score on the MADRS: selecting the optimal value.  J Affect Disord. 2002;72(2):177-184
PubMed   |  Link to Article
Thase ME. Evaluating antidepressant therapies: remission as the optimal outcome.  J Clin Psychiatry. 2003;64:(suppl 13)  18-25
PubMed   |  Link to Article
Gorman JM. Comorbid depression and anxiety spectrum disorders.  Depress Anxiety. 1996/1997;4(4):160-168
PubMed   |  Link to Article
Ressler KJ, Mayberg HS. Targeting abnormal neural circuits in mood and anxiety disorders: from the laboratory to the clinic.  Nat Neurosci. 2007;10(9):1116-1124
PubMed   |  Link to Article
Snaith RP, Baugh SJ, Clayden AD, Husain A, Sipple MA. The Clinical Anxiety Scale: an instrument derived from the Hamilton Anxiety Scale.  Br J Psychiatry. 1982;141:518-523
PubMed   |  Link to Article
Maldjian JA, Laurienti PJ, Kraft RA, Burdette JH. An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets.  Neuroimage. 2003;19(3):1233-1239
PubMed   |  Link to Article
Tzourio-Mazoyer N, Landeau B, Papathanassiou D, Crivello F, Etard O, Delcroix N, Mazoyer B, Joliot M. Automated anatomical labeling of activations in SPM using a macroscopic anatomical parcellation of the MNI MRI single-subject brain.  Neuroimage. 2002;15(1):273-289
PubMed   |  Link to Article
Schilbach L, Wohlschlaeger AM, Kraemer NC, Newen A, Shah NJ, Fink GR, Vogeley K. Being with virtual others: neural correlates of social interaction.  Neuropsychologia. 2006;44(5):718-730
PubMed   |  Link to Article
Gilbert SJ, Williamson ID, Dumontheil I, Simons JS, Frith CD, Burgess PW. Distinct regions of medial rostral prefrontal cortex supporting social and nonsocial functions.  Soc Cogn Affect Neurosci. 2007;2(3):217-226
PubMed   |  Link to Article
Anderson IM, Juhasz G, Thomas E, Downey D, McKie S, Deakin JF, Elliott R. The effect of acute citalopram on face emotion processing in remitted depression: a pharmacoMRI study.  Eur Neuropsychopharmacol. 2011;21(1):140-148
PubMed   |  Link to Article
Schaefer HS, Putnam KM, Benca RM, Davidson RJ. Event-related functional magnetic resonance imaging measures of neural activity to positive social stimuli in pre- and post-treatment depression.  Biol Psychiatry. 2006;60(9):974-986
PubMed   |  Link to Article
Brühl ABKT, Kaffenberger T, Herwig U. Serotonergic and noradrenergic modulation of emotion processing by single dose antidepressants.  Neuropsychopharmacology. 2010;35(2):521-533
PubMed   |  Link to Article
Lemogne C, le Bastard G, Mayberg H, Volle E, Bergouignan L, Lehéricy S, Allilaire JF, Fossati P. In search of the depressive self: extended medial prefrontal network during self-referential processing in major depression.  Soc Cogn Affect Neurosci. 2009;4(3):305-312
PubMed   |  Link to Article
Yoshimura S, Okamoto Y, Onoda K, Matsunaga M, Ueda K, Suzuki S, Shigetoyamawaki S. Rostral anterior cingulate cortex activity mediates the relationship between the depressive symptoms and the medial prefrontal cortex activity.  J Affect Disord. 2010;122(1-2):76-85
PubMed   |  Link to Article
Lemogne C, Mayberg H, Bergouignan L, Volle E, Delaveau P, Lehéricy S, Allilaire JF, Fossati P. Self-referential processing and the prefrontal cortex over the course of depression: a pilot study.  J Affect Disord. 2010;124(1-2):196-201
PubMed   |  Link to Article
Lemogne C, Delaveau P, Freton M, Guionnet S, Fossati P. Medial prefrontal cortex and the self in major depression [published online ahead of print December 22, 2010].  J Affect DisordLink to Article
Decety J, Jackson PL. The functional architecture of human empathy.  Behav Cogn Neurosci Rev. 2004;3(2):71-100
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Graphic Jump Location

Figure 1. Examples of stimuli in the following tasks: individual negative (A), individual positive (B), group negative (C), group positive (D), group neutral (E), and individual neutral (F).

Place holder to copy figure label and caption
Graphic Jump Location

Figure 2. Attenuated frontopolar response to group-positive vs individual-positive images in participants with remitted major depressive disorder (rMDD) compared with control subjects. A, Frontopolar response thresholded at P < .001 (uncorrected) and superimposed on a standard structural image. B, Peak voxel signal change associated with group-positive and individual-positive images in control subjects and participants with rMDD.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 3. Attenuated lateral orbitofrontal response to group-negative vs individual-negative images in participants with remitted major depressive disorder (rMDD) compared with control subjects. A, Latero-orbitofrontal response thresholded at P < .01 (uncorrected) and superimposed on a standard structural image. B, Peak voxel signal change associated with group-negative and individual-negative images in control subjects and participants with rMDD.

Tables

Table Graphic Jump LocationTable. Demographic Data and Valence Ratings

References

Harmer CJ, O’Sullivan U, Favaron E, Massey-Chase R, Ayres R, Reinecke A, Goodwin GM, Cowen PJ. Effect of acute antidepressant administration on negative affective bias in depressed patients.  Am J Psychiatry. 2009;166(10):1178-1184
PubMed   |  Link to Article
Gilboa-Schechtman E, Erhard-Weiss D, Jeczemien P. Interpersonal deficits meet cognitive biases: memory for facial expressions in depressed and anxious men and women.  Psychiatry Res. 2002;113(3):279-293
PubMed   |  Link to Article
Joormann J, Gotlib IH. Selective attention to emotional faces following recovery from depression.  J Abnorm Psychol. 2007;116(1):80-85
PubMed   |  Link to Article
Anderson IM, Shippen C, Juhasz G, Chase D, Thomas E, Downey D, Toth ZG, Lloyd-Williams K, Elliott R, Deakin JF. State-dependent alteration in face emotion recognition in depression [published online ahead of print January 24, 2011].  Br J PsychiatryLink to Article
Rinck M, Becker ES. A comparison of attentional biases and memory biases in women with social phobia and major depression.  J Abnorm Psychol. 2005;114(1):62-74
PubMed   |  Link to Article
Direnfeld DM, Roberts JE. Mood congruent memory in dysphoria: the roles of state affect and cognitive style.  Behav Res Ther. 2006;44(9):1275-1285
PubMed   |  Link to Article
Gotlib IH, Krasnoperova E, Yue DN, Joormann J. Attentional biases for negative interpersonal stimuli in clinical depression.  J Abnorm Psychol. 2004;113(1):121-135
PubMed   |  Link to Article
Erickson K, Drevets WC, Clark L, Cannon DM, Bain EE, Zarate CA Jr, Charney DS, Sahakian BJ. Mood-congruent bias in affective go/no-go performance of unmedicated patients with major depressive disorder.  Am J Psychiatry. 2005;162(11):2171-2173
PubMed   |  Link to Article
Leppänen JM. Emotional information processing in mood disorders: a review of behavioral and neuroimaging findings.  Curr Opin Psychiatry. 2006;19(1):34-39
PubMed   |  Link to Article
Atchley RA, Ilardi SS, Enloe A. Hemispheric asymmetry in the processing of emotional content in word meanings: the effect of current and past depression.  Brain Lang. 2003;84(1):105-119
PubMed   |  Link to Article
Bhagwagar Z, Cowen PJ, Goodwin GM, Harmer CJ. Normalization of enhanced fear recognition by acute SSRI treatment in subjects with a previous history of depression.  Am J Psychiatry. 2004;161(1):166-168
PubMed   |  Link to Article
Wagner V, Müller JL, Sommer M, Klein HE, Hajak G. Changes in the emotional processing in depressive patients: a study with functional magnetoresonance tomography under the employment of pictures with affective contents.  Psychiatr Prax. 2004;31:(suppl 1)  S70-S72
PubMed   |  Link to Article
Lee BT, Seok JH, Lee BC, Cho SW, Yoon BJ, Lee KU, Chae JH, Choi IG, Ham BJ. Neural correlates of affective processing in response to sad and angry facial stimuli in patients with major depressive disorder.  Prog Neuropsychopharmacol Biol Psychiatry. 2008;32(3):778-785
PubMed   |  Link to Article
Anand A, Li Y, Wang Y, Wu J, Gao S, Bukhari L, Mathews VP, Kalnin A, Lowe MJ.  Activity and connectivity of brain mood regulating circuit in depression: a functional magnetic resonance study.  Biol Psychiatry. 2005;57(10):1079-1088
PubMed   |  Link to Article
Phillips ML, Drevets WC, Rauch SL, Lane R. Neurobiology of emotion perception II: implications for major psychiatric disorders.  Biol Psychiatry. 2003;54(5):515-528
PubMed   |  Link to Article
Bhagwagar Z, Cowen PJ. “It's not over when it's over”: persistent neurobiological abnormalities in recovered depressed patients.  Psychol Med. 2008;38(3):307-313
PubMed   |  Link to Article
Elliott R, Zahn R, Deakin JF, Anderson IM. Affective cognition and its disruption in mood disorders.  Neuropsychopharmacology. 2011;36(1):153-182
PubMed   |  Link to Article
Neumeister A, Drevets WC, Belfer I, Luckenbaugh DA, Henry S, Bonne O, Herscovitch P, Goldman D, Charney DS. Effects ofα C-adrenoreceptor gene polymorphism on neural responses to facial expressions in depression.  Neuropsycho pharmacology. 2006;31(8):1750-1756
PubMed   |  Link to Article
Norbury R, Taylor MJ, Selvaraj S, Murphy SE, Harmer CJ, Cowen PJ. Short-term antidepressant treatment modulates amygdala response to happy faces.  Psychopharmacology (Berl). 2009;206(2):197-204
PubMed   |  Link to Article
Victor TA, Furey ML, Fromm SJ, Ohman A, Drevets WC. Relationship between amygdala responses to masked faces and mood state and treatment in major depressive disorder.  Arch Gen Psychiatry. 2010;67(11):1128-1138
PubMed   |  Link to Article
Sheline YI, Barch DM, Donnelly JM, Ollinger JM, Snyder AZ, Mintun MA. Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment: an fMRI study.  Biol Psychiatry. 2001;50(9):651-658
PubMed   |  Link to Article
Fu CH, Williams SC, Cleare AJ, Brammer MJ, Walsh ND, Kim J, Andrew CM, Pich EM, Williams PM, Reed LJ, Mitterschiffthaler MT, Suckling J, Bullmore ET. Attenuation of the neural response to sad faces in major depression by antidepressant treatment: a prospective, event-related functional magnetic resonance imaging study.  Arch Gen Psychiatry. 2004;61(9):877-889
PubMed   |  Link to Article
Thomas EJ, Elliott R, McKie S, Arnone D, Downey D, Juhasz G, Deakin JF, Anderson IM. Interaction between a history of depression and rumination on neural response to emotional faces.  Psychol Med. 2011;41(9):1845-1855
PubMed   |  Link to Article
Gemar MC, Segal ZV, Mayberg HS, Goldapple K, Carney C. Changes in regional cerebral blood flow following mood challenge in drug-free, remitted patients with unipolar depression.  Depress Anxiety. 2007;24(8):597-601
PubMed   |  Link to Article
Liotti M, Mayberg HS, Brannan SK, McGinnis S, Jerabek P, Fox PT. Differential limbic—cortical correlates of sadness and anxiety in healthy subjects: implications for affective disorders.  Biol Psychiatry. 2000;48(1):30-42
PubMed   |  Link to Article
Ramel W, Goldin PR, Eyler LT, Brown GG, Gotlib IH, McQuaid JR. Amygdala reactivity and mood-congruent memory in individuals at risk for depressive relapse.  Biol Psychiatry. 2007;61(2):231-239
PubMed   |  Link to Article
Chan SW, Norbury R, Goodwin GM, Harmer CJ. Risk for depression and neural responses to fearful facial expressions of emotion.  Br J Psychiatry. 2009;194(2):139-145
PubMed   |  Link to Article
Farb NA, Anderson AK, Bloch RT, Segal ZV. Mood-linked responses in medial prefrontal cortex predict relapse in patients with recurrent unipolar depression.  Biol Psychiatry. 2011;70(4):366-372
PubMed   |  Link to Article
Hareli S, Parkinson B. What's social about emotions?  J Theory Soc Behav. 2008;38:131-156
Link to Article
Frewen PA, Dozois DJ, Neufeld RW, Densmore M, Stevens TK, Lanius RA. Neuroimaging social emotional processing in women: fMRI study of script-driven imagery.  Soc Cogn Affect Neurosci. 2011;6(3):375-392
PubMed   |  Link to Article
Takahashi H, Matsuura M, Koeda M, Yahata N, Suhara T, Kato M, Okubo Y. Brain activations during judgments of positive self-conscious emotion and positive basic emotion: pride and joy.  Cereb Cortex. 2008;18(4):898-903
PubMed   |  Link to Article
Takahashi H, Yahata N, Koeda M, Matsuda T, Asai K, Okubo Y. Brain activation associated with evaluative processes of guilt and embarrassment: an fMRI study.  Neuroimage. 2004;23(3):967-974
PubMed   |  Link to Article
Frith CD, Frith U. The neural basis of mentalizing.  Neuron. 2006;50(4):531-534
PubMed   |  Link to Article
Amodio DM, Frith CD. Meeting of minds: the medial frontal cortex and social cognition.  Nat Rev Neurosci. 2006;7(4):268-277
PubMed   |  Link to Article
Legrand D, Ruby P. What is self-specific? theoretical investigation and critical review of neuroimaging results.  Psychol Rev. 2009;116(1):252-282
PubMed   |  Link to Article
Saxe R, Moran JM, Scholz J, Gabrieli J. Overlapping and non-overlapping brain regions for theory of mind and self reflection in individual subjects.  Soc Cogn Affect Neurosci. 2006;1(3):229-234
PubMed   |  Link to Article
Van Overwalle F. Social cognition and the brain: a meta-analysis.  Hum Brain Mapp. 2009;30(3):829-858
PubMed   |  Link to Article
Zahn R, Moll J, Paiva M, Garrido G, Krueger F, Huey ED, Grafman J. The neural basis of human social values: evidence from functional MRI.  Cereb Cortex. 2009;19(2):276-283
PubMed   |  Link to Article
Moll J, de Oliveira-Souza R, Garrido GJ, Bramati IE, Caparelli-Daquer EMA, Paiva ML, Zahn R, Grafman J. The self as a moral agent: linking the neural bases of social agency and moral sensitivity.  Soc Neurosci. 2007;2(3-4):336-352
PubMed   |  Link to Article
Ochsner KN, Knierim K, Ludlow DH, Hanelin J, Ramachandran T, Glover G, Mackey SC. Reflecting upon feelings: an fMRI study of neural systems supporting the attribution of emotion to self and other.  J Cogn Neurosci. 2004;16(10):1746-1772
PubMed   |  Link to Article
Eisenberger NI, Lieberman MD, Williams KD. Does rejection hurt? an FMRI study of social exclusion.  Science. 2003;302(5643):290-292
PubMed   |  Link to Article
Zuroff DC, Mongrain M, Santor DA. Conceptualizing and measuring personality vulnerability to depression: comment on Coyne and Whiffen (1995).  Psychol Bull. 2004;130(3):489-522
PubMed   |  Link to Article
Northoff G, Heinzel A, de Greck M, Bermpohl F, Dobrowolny H, Panksepp J. Self-referential processing in our brain—a meta-analysis of imaging studies on the self.  Neuroimage. 2006;31(1):440-457
PubMed   |  Link to Article
Krämer UM, Mohammadi B, Doñamayor N, Samii A, Münte TF. Emotional and cognitive aspects of empathy and their relation to social cognition—an fMRI-study.  Brain Res. 2010;1311:110-120
PubMed   |  Link to Article
Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change.  Br J Psychiatry. 1979;134:382-389
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