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1.  Abnormal Left-Sided Orbitomedial Prefrontal Cortical–Amygdala Connectivity during Happy and Fear Face Processing: A Potential Neural Mechanism of Female MDD 
Background: Pathophysiologic processes supporting abnormal emotion regulation in major depressive disorder (MDD) are poorly understood. We previously found abnormal inverse left-sided ventromedial prefrontal cortical–amygdala effective connectivity to happy faces in females with MDD. We aimed to replicate and expand this previous finding in an independent participant sample, using a more inclusive neural model, and a novel emotion processing paradigm. Methods: Nineteen individuals with MDD in depressed episode (12 females), and 19 healthy individuals, age, and gender matched, performed an implicit emotion processing and automatic attentional control paradigm to examine abnormalities in prefrontal cortical–amygdala neural circuitry during happy, angry, fearful, and sad face processing measured with functional magnetic resonance imaging in a 3-T scanner. Effective connectivity was estimated with dynamic causal modeling in a trinodal neural model including two anatomically defined prefrontal cortical regions, ventromedial prefrontal cortex, and subgenual cingulate cortex (sgACC), and the amygdala. Results: We replicated our previous finding of abnormal inverse left-sided top-down ventromedial prefrontal cortical–amygdala connectivity to happy faces in females with MDD (p = 0.04), and also showed a similar pattern of abnormal inverse left-sided sgACC–amygdala connectivity to these stimuli (p = 0.03). These findings were paralleled by abnormally reduced positive left-sided ventromedial prefrontal cortical–sgACC connectivity to happy faces in females with MDD (p = 0.008), and abnormally increased positive left-sided sgACC–amygdala connectivity to fearful faces in females, and all individuals, with MDD (p = 0.008; p = 0.003). Conclusion: Different patterns of abnormal prefrontal cortical–amygdala connectivity to happy and fearful stimuli might represent neural mechanisms for the excessive self-reproach and comorbid anxiety that characterize female MDD.
doi:10.3389/fpsyt.2011.00069
PMCID: PMC3233901  PMID: 22163223
major depressive disorder; effective connectivity; emotion regulation; dynamic causal modeling; amygdala; prefrontal cortex
2.  Perception of Facial Emotion in Adults with Bipolar or Unipolar Depression and Controls 
Journal of psychiatric research  2010;44(16):1229-1235.
Previous research indicates that patients with depression display deficits in their ability to perceive emotions. However, few studies have used animated facial stimuli or explored sensitivity to facial expressions in depressed individuals. Moreover, limited research is available on facial processing in unipolar versus bipolar depression. In this study, 34 patients with DSM-IV major depressive disorder (MDD), 21 patients with DSM-IV bipolar disorder (BPD) in the depressed phase, and 24 never-depressed controls completed the Emotional Expression Multimorph Task, which presents facial emotions in gradations from neutral to 100% emotional expression (happy, sad, surprised, fearful, angry, and disgusted). Groups were compared in terms of sensitivity and accuracy in identifying emotions. Our preliminary findings suggest that subjects with bipolar depression may have emotional processing abnormalities relative to controls.
doi:10.1016/j.jpsychires.2010.04.024
PMCID: PMC2932776  PMID: 20510425
Bipolar disorder (BPD); cognition; facial expression; emotion perception; unipolar depression
3.  BDNF Gene Polymorphism (Val66Met) Predicts Amygdala and Anterior Hippocampus Responses to Emotional Faces in Anxious and Depressed Adolescents 
NeuroImage  2009;53(3):952-961.
A polymorphism of the human Brain Derived Neurotrophic Factor (BDNF) gene that produces a valine-to-methionine substitution at codon 66 (Val66Met), is linked to adult anxiety and mood disorders, possibly through effects on brain circuitry function. Associations between BDNF gene variants and brain activity have not been explored in anxious and depressed adolescents. The current study investigated the association between BDNF genotype and amygdala-hippocampal responses to emotional stimuli in adolescents with anxiety disorders and/or major depressive disorder (MDD) and in healthy adolescents. Twenty-seven unmedicated patients with acutely-impairing current anxiety disorders and/or MDD and 31 healthy adolescents, matched on age, gender and IQ, rated their fear of fearful, angry, neutral and happy facial expressions during collection of fMRI data on the amygdala and hippocampus. Left and right amygdala and hippocampal responses were analyzed using Repeated-measures Analyses of Variance models, with Diagnosis (patients, healthy) and Genotype (Met-carriers, Val/Val homozygotes) as between-group factors and facial expression (fearful, angry, neutral, happy) as a within-subject factor. Significant effects of Diagnosis and Diagnosis-by-Genotype interactions (F’s>4, p’s<.05) characterized activations in amygdala and anterior hippocampal regions. Greater activations in patients than healthy adolescents were found. Critically, these hyperactivations were modulated by BDNF genotype: Met-carriers showed greater neural responses of emotional faces than Val/Val homozygotes in patients only. These data are first to demonstrate the contribution of BDNF gene variants to the neural correlates of adolescent anxiety and depression. Early “gene-brain” linkages may lay the foundation for longer-term patterns of neural dysfunction in affective disorders.
doi:10.1016/j.neuroimage.2009.11.026
PMCID: PMC2888869  PMID: 19931400
Brain Derived Neurotrophic Factor Gene; adolescence; anxiety; depression; medial temporal lobe; fMRI; development
4.  Affective priming in major depressive disorder 
Research on cognitive biases in depression has provided considerable evidence for the impact of emotion on cognition. Individuals with depression tend to preferentially process mood-congruent material and to show deficits in the processing of positive material leading to biases in attention, memory, and judgments. More research is needed, however, to fully understand which cognitive processes are affected. The current study further examines the impact of emotion on cognition using a priming design with facial expressions of emotion. Specifically, this study tested whether the presentation of facial expressions of emotion affects subsequent processing of affective material in participants with major depressive disorder (MDD) and healthy controls (CTL). Facial expressions displaying happy, sad, angry, disgusted, or neutral expressions were presented as primes for 500 ms, and participants' speed to identify a subsequent target's emotional expression was assessed. All participants displayed greater interference from emotional vs. neutral primes, marked by slower response times to judge the emotion of the target face when it was preceded by an emotional prime. Importantly, the CTL group showed the strongest interference when happy emotional expressions served as primes whereas the MDD group failed to show this bias. These results add to a growing literature that shows that depression is associated with difficulties in the processing of positive material.
doi:10.3389/fnint.2012.00076
PMCID: PMC3464437  PMID: 23060758
affective priming; cognitive biases; depression
5.  Frontal EEG Asymmetry During Emotional Challenge Differentiates Individuals with and without Lifetime Major Depressive Disorder 
Journal of affective disorders  2010;129(1-3):167-174.
Background
Although it has been argued that frontal electroencephalographic (EEG) asymmetry at rest may be a risk marker for major depressive disorder (MDD), it is unclear whether a pattern of relatively less left than right activity characterizes depressed individuals during emotional challenges. Examination of frontal asymmetry during emotion task manipulations could provide an assessment of the function of systems relevant for MDD, and test the limits of frontal EEG asymmetry as a marker of risk for depression.
Methods
EEG data were assessed during a facial emotion task, wherein 306 individuals age 18–34 (31% male) with (n =143) and without (n = 163) DSM-IV defined lifetime MDD made directed facial actions of approach (angry and happy) and withdrawal (afraid and sad) expressions.
Results
Lifetime depressed individuals displayed less relative left frontal activity than never-depressed individuals during all facial expressions across four EEG reference montages, findings that were not due to emotional experience, facial expression quality, electromyographic (EMG) activity, or current depression status.
Limitations
Although this was a sizable sample, only one emotion task was utilized.
Conclusions
Results provide further support for frontal EEG asymmetry as a risk marker for MDD.
doi:10.1016/j.jad.2010.08.029
PMCID: PMC3021630  PMID: 20870293
EEG asymmetry; depression; biological marker; emotion
6.  Attention and Memory Biases in Social Anxiety Disorder: The Role of Comorbid Depression 
Cognitive therapy and research  2010;36(1):47-57.
Cognitive biases play an important role in the onset and maintenance of Social Anxiety Disorder (SAD). Few studies, however, have examined the role of comorbid Major Depressive Disorder (MDD) in the processing of emotional material. In addition, little is known about the relation among different cognitive biases. In the current study, 73 participants (54.79% female) completed an emotion face dot-probe task followed by a recognition memory test. Compared to participants with SAD, participants with comorbid SAD and MDD oriented away from supraliminally presented angry faces. Subsequently, SAD participants with and without comorbidity recognized fewer angry faces than non-disordered controls. Furthermore, attention biases for subliminally presented stimuli predicted recognition accuracy only for comorbid participants. These results suggest that the presence of comorbid MDD affects attentional orienting in SAD participants. In addition, it highlights the interconnectedness of attention and memory biases for comorbid participants.
doi:10.1007/s10608-010-9322-2
PMCID: PMC3475322  PMID: 23087492
7.  Altered Negative Unconscious Processing in Major Depressive Disorder: An Exploratory Neuropsychological Study 
PLoS ONE  2011;6(7):e21881.
Objective
Major depressive disorder (MDD) has been characterized by abnormalities in emotional processing. However, what remains unclear is whether MDD also shows deficits in the unconscious processing of either positive or negative emotions. We conducted a psychological study in healthy and MDD subjects to investigate unconscious emotion processing and its valence-specific alterations in MDD patients.
Methods
We combined a well established paradigm for unconscious visual processing, the continuous flash suppression, with positive and negative emotional valences to detect the attentional preference evoked by the invisible emotional facial expressions.
Results
Healthy subjects showed an attentional bias for negative emotions in the unconscious condition while this valence bias remained absent in MDD patients. In contrast, this attentional bias diminished in the conscious condition for both healthy subjects and MDD.
Conclusion
Our findings demonstrate for the first time valence-specific deficits specifically in the unconscious processing of emotions in MDD; this may have major implications for subsequent neurobiological investigations as well as for clinical diagnosis and therapy.
doi:10.1371/journal.pone.0021881
PMCID: PMC3130746  PMID: 21755006
8.  The Temporal Electrocortical Profile of Emotive Facial Processing in Depressed Males and Females and Healthy Controls 
Journal of Affective Disorders  2011;136(3):1072-1081.
Background
Previous work indicates that emotive processing, such as of facial expressions, may be altered in major depressive disorder (MDD). Individuals with MDD tend to exhibit a mood-congruent processing bias, though MDD may also be characterized by blunted emotive processing in general. Females tend to exhibit enhanced facial emotive processing than males. Few groups have examined temporal electrophysiological event-related potential (ERP)-indexed profiles, spanning preconscious to sustained, conscious processing of facial expressions in MDD; systematic comparisons of ERPs to emotive stimuli between depressed males and females are also lacking.
Methods
This study examined the temporal ERP profile to a simple expression recognition task in adult depressed males and females (N=52; 29 females) and controls (N=43; 23 females).
Results
The MDD group rated facial expressions as sadder overall than controls. Females exhibited enhanced and speeded pre- and conscious face processing than males. Subtle group differences emerged to specific expressions at mid-latency ERPs (N2, P2) indicating both blunted late pre-conscious perceptual processing of expressions and prolonged processing of intensely sad faces.
Limitations
A more involved emotive processing task, employing threatening faces, may have revealed more robust group ERP differences. Menstrual cycle should be controlled for in future work.
Conclusions
This is the first study to systematically assess the temporal ERP profile, including of ERPs preceding the face-sensitive N170/VPP, to expressions in MDD. Overall, early perceptual and late conscious expression processing did not differ fundamentally between groups. Altered emotive processing may be a candidate index for monitoring and predicting antidepressant treatment outcome.
doi:10.1016/j.jad.2011.10.047
PMCID: PMC3288478  PMID: 22127390
Depression; event-related potentials (ERP); emotion; faces; sex
9.  Piccolo genotype modulates neural correlates of emotion processing but not executive functioning 
Translational Psychiatry  2012;2(4):e99-.
Major depressive disorder (MDD) is characterized by affective symptoms and cognitive impairments, which have been associated with changes in limbic and prefrontal activity as well as with monoaminergic neurotransmission. A genome-wide association study implicated the polymorphism rs2522833 in the piccolo (PCLO) gene—involved in monoaminergic neurotransmission—as a risk factor for MDD. However, the role of the PCLO risk allele in emotion processing and executive function or its effect on their neural substrate has never been studied. We used functional magnetic resonance imaging (fMRI) to investigate PCLO risk allele carriers vs noncarriers during an emotional face processing task and a visuospatial planning task in 159 current MDD patients and healthy controls. In PCLO risk allele carriers, we found increased activity in the left amygdala during processing of angry and sad faces compared with noncarriers, independent of psychopathological status. During processing of fearful faces, the PCLO risk allele was associated with increased amygdala activation in MDD patients only. During the visuospatial planning task, we found no genotype effect on performance or on BOLD signal in our predefined areas as a function of increasing task load. The PCLO risk allele was found to be specifically associated with altered emotion processing, but not with executive dysfunction. Moreover, the PCLO risk allele appears to modulate amygdala function during fearful facial processing in MDD and may constitute a possible link between genotype and susceptibility for depression via altered processing of fearful stimuli. The current results may therefore aid in better understanding underlying neurobiological mechanisms in MDD.
doi:10.1038/tp.2012.29
PMCID: PMC3337071  PMID: 22832909
emotion processing; executive function; genome-wide association; major depressive disorder; neuroimaging genetics; PCLO
10.  Sad benefit in face working memory: An emotional bias of melancholic depression 
Journal of Affective Disorders  2011;135(1-3):251-257.
Emotion biases feature prominently in cognitive theories of depression and are a focus of psychological interventions. However, there is presently no stable neurocognitive marker of altered emotion–cognition interactions in depression. One reason may be the heterogeneity of major depressive disorder. Our aim in the present study was to find an emotional bias that differentiates patients with melancholic depression from controls, and patients with melancholic from those with non-melancholic depression. We used a working memory paradigm for emotional faces, where two faces with angry, happy, neutral, sad or fearful expression had to be retained over one second. Twenty patients with melancholic depression, 20 age-, education- and gender-matched control participants and 20 patients with non-melancholic depression participated in the study. We analysed performance on the working memory task using signal detection measures. We found an interaction between group and emotion on working memory performance that was driven by the higher performance for sad faces compared to other categories in the melancholic group. We computed a measure of “sad benefit”, which distinguished melancholic and non-melancholic patients with good sensitivity and specificity. However, replication studies and formal discriminant analysis will be needed in order to assess whether emotion bias in working memory may become a useful diagnostic tool to distinguish these two syndromes.
doi:10.1016/j.jad.2011.08.002
PMCID: PMC3245890  PMID: 21872338
Depression; Melancholia; Working memory; Facial expression; Emotion
11.  Abnormal amygdala-prefrontal effective connectivity to happy faces differentiates bipolar from major depression 
Biological psychiatry  2009;66(5):451-459.
Background
Bipolar disorder is frequently misdiagnosed as major depressive disorder delaying appropriate treatment and worsening outcome for many bipolar individuals. Emotion dysregulation is a core feature of bipolar disorder. Measures of dysfunction in neural systems supporting emotion regulation may therefore help discriminate bipolar from major depressive disorder.
Methods
Thirty-one depressed individuals, 15 bipolar depressed (BD) and 16 major depressed (MDD), DSM-IV diagnostic criteria, aged 18–55 years, matched for age, age of illness onset, illness duration, depression severity, and 16 age- and gender-matched healthy controls (HC) performed two event-related paradigms: labeling the emotional intensity of happy and sad faces, respectively. We employed dynamic causal modeling to examine significant among-group alterations in effective connectivity (EC) between right-and left-sided neural regions supporting emotion regulation: amygdala and orbitomedial prefrontal cortex (OMPFC).
Results
During classification of happy faces, we found profound and asymmetrical differences in effective connectivity between the OMPFC and amygdala. Left-sided differences involved top-down connections and discriminated between depressed and control subjects. Furthermore, greater medication load was associated with an amelioration of this abnormal top-down EC. Conversely, on the right side the abnormality was in bottom-up EC that was specific to bipolar disorder. These effects replicated when we considered only female subjects.
Conclusions
Abnormal left-sided top-down OMPFC-amygdala and right-sided bottom-up amygdala-OMPFC EC during happy labeling distinguish BD and MDD, suggesting different pathophysiological mechanisms associated with the two types of depression.
doi:10.1016/j.biopsych.2009.03.024
PMCID: PMC2740996  PMID: 19450794
Fmri; bipolar; disorder; major depression disorder; amygdala; orbitomedial prefrontal cortex; dynamic causal modeling
12.  Elevated Amygdala Activity to Sad Facial Expressions: A State Marker of Bipolar but Not Unipolar Depression 
Biological psychiatry  2009;67(5):414-421.
Background
Difficulties in emotion processing and poor social function are common to bipolar disorder (BD) and major depressive disorder (MDD) depression, resulting in many BD depressed individuals being misdiagnosed with MDD. The amygdala is a key region implicated in processing emotionally salient stimuli, including emotional facial expressions. It is unclear, however, whether abnormal amygdala activity during positive and negative emotion processing represents a persistent marker of BD regardless of illness phase or a state marker of depression common or specific to BD and MDD depression.
Methods
Sixty adults were recruited: 15 depressed with BD type 1 (BDd), 15 depressed with recurrent MDD, 15 with BD in remission (BDr), diagnosed with DSM-IV and Structured Clinical Interview for DSM-IV Research Version criteria; and 15 healthy control subjects (HC). Groups were age- and gender ratio-matched; patient groups were matched for age of illness onset and illness duration; depressed groups were matched for depression severity. The BDd were taking more psychotropic medication than other patient groups. All individuals participated in three separate 3T neuroimaging event-related experiments, where they viewed mild and intense emotional and neutral faces of fear, happiness, or sadness from a standardized series.
Results
The BDd—relative to HC, BDr, and MDD—showed elevated left amygdala activity to mild and neutral facial expressions in the sad (p < .009) but not other emotion experiments that was not associated with medication. There were no other significant between-group differences in amygdala activity.
Conclusions
Abnormally elevated left amygdala activity to mild sad and neutral faces might be a depression-specific marker in BD but not MDD, suggesting different pathophysiologic processes for BD versus MDD depression.
doi:10.1016/j.biopsych.2009.09.027
PMCID: PMC2854029  PMID: 19931855
Amygdala; bipolar disorder; emotional processing; fMRI; major depressive disorder; mood disorders
13.  Antidepressant treatment normalizes hypoactivity in dorsolateral prefrontal cortex during emotional interference processing in major depression 
Journal of affective disorders  2008;112(1-3):206-211.
Background
Major depression (MDD) is characterized by altered emotion processing and deficits in cognitive control. In cognitive interference tasks, patients with MDD have shown excessive amygdala activity and under-recruitment of dorsolateral prefrontal cortex (DLPFC). The purpose of this study was to examine the effects of antidepressant treatment on anomalous neural activity in cognitive-control and emotion-processing circuitry.
Methods
Functional magnetic resonance imaging was conducted on depressed patients (n=23) (both before and after antidepressant treatment) compared with matched controls (n= 18) while they performed a cognitive task involving attended and unattended fear-related stimuli.
Results
After eight weeks of SSRI antidepressant treatment, patients with depression showed significantly increased DLPFC activity to unattended fear-related stimuli and no longer differed from controls in either DLPFC or amygdala activity.
Conclusions
These results suggest that antidepressant treatment increases DLPFC under-activity during cognitive tasks that include emotional interference.
Limitations
The sample was fairly homogeneous and this may limit generalizability.
doi:10.1016/j.jad.2008.04.027
PMCID: PMC2825146  PMID: 18559283
14.  Increased Affective Bias Revealed Using Experimental Graded Heat Stimuli in Young Depressed Adults: Evidence of “Emotional Allodynia” 
Psychosomatic medicine  2008;70(3):338-344.
Objective
Pain and depression often occur together. Pain is both a sensation and an affective experience. Similarly, depression is associated frequently with somatic symptoms as well as emotional dysphoria. Existing evidence indicates that major depressive disorder (MDD) may be associated with altered pain processing. However, the extent to which alterations in experimentally controlled heat pain sensations are related to increased affective bias in MDD is unknown. This psychophysical study examined the hypothesis that young adults with MDD would show increased affective bias to painful and non-painful experimental heat stimuli, as evidenced by an increased responsiveness to warm and hot temperatures.
Method
Graded non-noxious and noxious heat stimuli were delivered randomly with a thermode applied to the volar surface of the left arm of 15 unmedicated subjects with current MDD and 15 age- and gender-matched healthy comparison subjects. MDD and non-MDD subjects rated the intensity and unpleasantness of all stimuli.
Results
Two main results were observed. Firstly, MDD relative to non-MDD subjects showed decreased heat pain thresholds. Secondly, a significantly increased affective bias (= unpleasantness/intensity) was observed in MDD subjects, particularly over the range of non-noxious heat stimuli. This bias was independent of the change in sensory pain thresholds.
Conclusion
These findings represent corroborative evidence of abnormal affective heat pain processing in young adults with MDD, and suggest that MDD is associated with “emotional allodynia”, a qualitatively altered negative emotional response to normally non-aversive thermal stimuli.
doi:10.1097/PSY.0b013e3181656a48
PMCID: PMC2742693  PMID: 18378870
psychophysics; allodynia; MDD; thermode; heat; nociception
15.  Relationship of Emotional Processing to Masked Faces in the Amygdala to Mood State and Treatment in Major Depressive Disorder 
Archives of General Psychiatry  2010;67(11):1128-1138.
Context
Major depressive disorder (MDD) is associated with behavioral and neurophysiological evidence for mood-congruent processing biases toward explicitly presented, emotionally-valenced stimuli. However, few studies have investigated such biases toward implicitly presented stimuli.
Objective
To investigate differential amygdala responses to sad, happy and neutral faces presented below the level of explicit conscious awareness using a backward masking task in unmedicated subjects with MDD and healthy controls.
Design
Initial cross-sectional design followed by a longitudinal treatment trial using functional magnetic resonance imaging.
Setting
Psychiatric outpatient clinic at the National Institute of Mental Health.
Participants
Twenty-two unmedicated, currently-depressed subjects with MDD (dMDD), 16 unmedicated subjects with MDD in full remission (rMDD), and 25 healthy controls (HC).
Interventions
Ten dMDD subjects underwent 8 weeks of antidepressant treatment with the selective serotonin reuptake inhibitor, sertraline.
Main Outcome Measures
Amygdala region-of-interest and whole brain analyses evaluated the hemodynamic response during exposure to masked-sad versus masked-happy faces, to masked-sad versus neutral faces, and to masked-happy versus neutral faces.
Results
dMDD subjects showed greater amygdala responses than HC to masked-sad faces, while HC subjects showed greater amygdala responses to masked-happy faces. The bias toward sad faces also was evident in the rMDD relative to HC subjects and did not differ between the dMDD and rMDD subjects. This processing bias reversed toward the normative pattern in the dMDD subjects following sertraline treatment.
Conclusions
Emotional processing biases occur in the amygdala to sad faces presented below conscious awareness in currently-depressed or remitted-MDD subjects and to happy faces in controls. By influencing the salience of social stimuli, mood-congruent processing biases in the amygdala may contribute to dysfunction in conscious perceptions and social interactions in MDD. Our data suggest, however, that the negative bias resolves and a positive bias develops in MDD subjects during selective serotonin reuptake inhibitor treatment.
doi:10.1001/archgenpsychiatry.2010.144
PMCID: PMC3253452  PMID: 21041614
16.  "I won, but I’m not getting my hopes up": Depression Moderates the Relationship Outcomes and Reward Anticipation 
Psychiatry research  2011;194(3):393-395.
Major Depressive Disorder (MDD) in adolescents is characterized by alterations in positive emotions and reward processing. Recent investigations using functional magnetic resonance imaging (fMRI) find depression-related differences in reward anticipation. However, it is unknown whether feedback influences subsequent reward anticipation, which may highlight the context of reward processing. Ten youth with MDD and sixteen youth with no history of MDD completed an fMRI assessment using a reward task. Reward anticipation was indexed by blood oxygen level dependent signal change in the striatum following winning; losing; non-winning; and non-losing outcomes. A significant interaction between diagnostic status and outcome condition predicted reward anticipation in the caudate. Decomposition of the interaction indicated that following winning outcomes, depressed youth demonstrated reduced reward anticipation relative to healthy youth. However, no significant differences between depressed and healthy youth were found after other outcomes. Reward anticipation is altered following winning outcomes. This finding has implications for understanding the developmental pathophysiology of MDD and suggests specific contexts where altered motivational system functioning may play a role in maintaining depression.
doi:10.1016/j.pscychresns.2011.04.009
PMCID: PMC3225637  PMID: 22079656
major depression; reward; fMRI; adolescence; striatum; context
17.  Emotion identification in girls at high risk for depression 
Background
Children of depressed mothers are themselves at elevated risk for developing a depressive disorder. We have little understanding, however, of the specific factors that contribute to this increased risk. This study investigated whether never-disordered daughters whose mothers have experienced recurrent episodes of depression during their daughters’ lifetime differ from never-disordered daughters of never-disordered mothers in their processing of facial expressions of emotion.
Method
Following a negative mood induction, daughters completed an emotion identification task in which they watched faces slowly change from a neutral to a full-intensity happy, sad, or angry expression. We assessed both the intensity that was required to accurately identify the emotion being expressed and errors in emotion identification.
Results
Daughters of depressed mothers required greater intensity than did daughters of control mothers to accurately identify sad facial expressions; they also made significantly more errors identifying angry expressions.
Conclusion
Cognitive biases may increase vulnerability for the onset of disorders and should be considered in early intervention and prevention efforts.
doi:10.1111/j.1469-7610.2009.02175.x
PMCID: PMC2862827  PMID: 19788553
Affective disorders; cognition; depression; emotion; facial expression; risk factors
18.  Functional atlas of emotional faces processing: a voxel-based meta-analysis of 105 functional magnetic resonance imaging studies 
Background
Most of our social interactions involve perception of emotional information from the faces of other people. Furthermore, such emotional processes are thought to be aberrant in a range of clinical disorders, including psychosis and depression. However, the exact neurofunctional maps underlying emotional facial processing are not well defined.
Methods
Two independent researchers conducted separate comprehensive PubMed (1990 to May 2008) searches to find all functional magnetic resonance imaging (fMRI) studies using a variant of the emotional faces paradigm in healthy participants. The search terms were: “fMRI AND happy faces,” “fMRI AND sad faces,” “fMRI AND fearful faces,” “fMRI AND angry faces,” “fMRI AND disgusted faces” and “fMRI AND neutral faces.” We extracted spatial coordinates and inserted them in an electronic database. We performed activation likelihood estimation analysis for voxel-based meta-analyses.
Results
Of the originally identified studies, 105 met our inclusion criteria. The overall database consisted of 1785 brain coordinates that yielded an overall sample of 1600 healthy participants. Quantitative voxel-based meta-analysis of brain activation provided neurofunctional maps for 1) main effect of human faces; 2) main effect of emotional valence; and 3) modulatory effect of age, sex, explicit versus implicit processing and magnetic field strength. Processing of emotional faces was associated with increased activation in a number of visual, limbic, temporoparietal and prefrontal areas; the putamen; and the cerebellum. Happy, fearful and sad faces specifically activated the amygdala, whereas angry or disgusted faces had no effect on this brain region. Furthermore, amygdala sensitivity was greater for fearful than for happy or sad faces. Insular activation was selectively reported during processing of disgusted and angry faces. However, insular sensitivity was greater for disgusted than for angry faces. Conversely, neural response in the visual cortex and cerebellum was observable across all emotional conditions.
Limitations
Although the activation likelihood estimation approach is currently one of the most powerful and reliable meta-analytical methods in neuroimaging research, it is insensitive to effect sizes.
Conclusion
Our study has detailed neurofunctional maps to use as normative references in future fMRI studies of emotional facial processing in psychiatric populations. We found selective differences between neural networks underlying the basic emotions in limbic and insular brain regions.
PMCID: PMC2783433  PMID: 19949718
19.  Common and Distinct Amygdala-Function Perturbations in Depressed vs Anxious Adolescents 
Archives of general psychiatry  2009;66(3):275-285.
Context
Few studies directly compare amygdala function in depressive and anxiety disorders. Data from longitudinal research emphasize the need for such studies in adolescents.
Objective
To compare amygdala response to varying attention and emotion conditions among adolescents with major depressive disorder (MDD) or anxiety disorders, relative to adolescents with no psychopathology.
Design
Case-control study.
Setting
Government clinical research institute.
Participants
Eighty-seven adolescents matched on age, sex, intelligence, and social class: 26 with MDD (14 with and 12 without anxiety disorders), 16 with anxiety disorders but no depression, and 45 without psychopathology.
Main Outcome Measures
Blood oxygen level–dependent signal in the amygdala, measured by means of event-related functional magnetic resonance imaging. During imaging, participants viewed facial expressions (neutral, fearful, angry, and happy) while attention was constrained (afraid, hostility, and nose-width ratings) or unconstrained (passive viewing).
Results
Left and right amygdala activation differed as a function of diagnosis, facial expression, and attention condition both when patients with comorbid MDD and anxiety were included and when they were excluded (group × emotion × attention interactions, P≤.03). Focusing on fearful face–viewing events, patients with anxiety and those with MDD both differed in amygdala responses from healthy participants and from each other during passive viewing. However, both MDD and anxiety groups, relative to healthy participants, exhibited similar signs of amygdala hyperactivation to fearful faces when subjectively experienced fear was rated.
Conclusions
Adolescent MDD and anxiety disorders exhibit common and distinct functional neural correlates during face processing. Attention modulates the degree to which common or distinct amygdala perturbations manifest in these patient groups, relative to healthy peers.
doi:10.1001/archgenpsychiatry.2008.545
PMCID: PMC2891508  PMID: 19255377
20.  Two-Year Prospective Naturalistic Study of Remission From Major Depressive Disorder as a Function of Personality Disorder Comorbidity 
In this study, the authors examined prospectively the 24-month natural course of remission from major depressive disorder (MDD) as a function of personality disorder (PD) comorbidity. In 302 participants (196 women, 106 men), psychiatric and PDs were assessed at baseline with diagnostic interviews, and the course of MDD was assessed with the Longitudinal Interval Follow-Up Evaluation at 6-, 12-, and 24-month follow-ups. Survival analyses revealed an overall 24-month remission rate of 73.5% for MDD that differed little by gender. Participants with MDD who had certain forms of coexisting PD psychopathology (schizotypal, borderline, or avoidant) as their primary PD diagnoses had a significantly longer time to remission from MDD than did patients with MDD without any PD. These PDs emerged as robust predictors of slowed remission from MDD even when controlling for other negative prognostic predictors.
doi:10.1037/0022-006X.73.1.78
PMCID: PMC3289285  PMID: 15709834
21.  Exploring men's and women's experiences of depression and engagement with health professionals: more similarities than differences? A qualitative interview study 
BMC Family Practice  2007;8:43.
Background
It is argued that the ways in which women express emotional distress mean that they are more likely to be diagnosed with depression, while men's relative lack of articulacy means their depression is hidden. This may have consequences for communicating with health professionals. The purpose of this analysis was to explore how men and women with depression articulate their emotional distress, and examine whether there are gender differences or similarities in the strategies that respondents found useful when engaging with health professionals.
Methods
In-depth qualitative interviews with 22 women and 16 men in the UK who identified themselves as having had depression, recruited through general practitioners, psychiatrists and support groups.
Results
We found gender similarities and gender differences in our sample. Both men and women found it difficult to recognise and articulate mental health problems and this had consequences for their ability to communicate with health professionals. Key gender differences noted were that men tended to value skills which helped them to talk while women valued listening skills in health professionals, and that men emphasised the importance of getting practical results from talking therapies in their narratives, as opposed to other forms of therapy which they conceptualised as 'just talking'. We also found diversity among women and among men; some respondents valued a close personal relationship with health professionals, while others felt that this personal relationship was a barrier to communication and preferred 'talking to a stranger'.
Conclusion
Our findings suggest that there is not a straightforward relationship between gender and engagement with health professionals for people with depression. Health professionals need to be sensitive to patients who have difficulties in expressing emotional distress and critical of gender stereotypes which suggest that women invariably find it easy to express emotional distress and men invariably find it difficult. In addition it is important to recognise that, for a minority of patients, a personal relationship with health professionals can act as a barrier to the disclosure of emotional distress.
doi:10.1186/1471-2296-8-43
PMCID: PMC1941733  PMID: 17650340
22.  Mood Induction in Depressive Patients: A Comparative Multidimensional Approach 
PLoS ONE  2012;7(1):e30016.
Anhedonia, reduced positive affect and enhanced negative affect are integral characteristics of major depressive disorder (MDD). Emotion dysregulation, e.g. in terms of different emotion processing deficits, has consistently been reported. The aim of the present study was to investigate mood changes in depressive patients using a multidimensional approach for the measurement of emotional reactivity to mood induction procedures. Experimentally, mood states can be altered using various mood induction procedures. The present study aimed at validating two different positive mood induction procedures in patients with MDD and investigating which procedure is more effective and applicable in detecting dysfunctions in MDD. The first procedure relied on the presentation of happy vs. neutral faces, while the second used funny vs. neutral cartoons. Emotional reactivity was assessed in 16 depressed and 16 healthy subjects using self-report measures, measurements of electrodermal activity and standardized analyses of facial responses. Positive mood induction was successful in both procedures according to subjective ratings in patients and controls. In the cartoon condition, however, a discrepancy between reduced facial activity and concurrently enhanced autonomous reactivity was found in patients. Relying on a multidimensional assessment technique, a more comprehensive estimate of dysfunctions in emotional reactivity in MDD was available than by self-report measures alone and this was unsheathed especially by the mood induction procedure relying on cartoons. The divergent facial and autonomic responses in the presence of unaffected subjective reactivity suggest an underlying deficit in the patients' ability to express the felt arousal to funny cartoons. Our results encourage the application of both procedures in functional imaging studies for investigating the neural substrates of emotion dysregulation in MDD patients. Mood induction via cartoons appears to be superior to mood induction via faces and autobiographical material in uncovering specific emotional dysfunctions in MDD.
doi:10.1371/journal.pone.0030016
PMCID: PMC3253810  PMID: 22253861
23.  Racial/Ethnic Differences in the Association Between Obesity and Major Depressive Disorder: Findings from the Comprehensive Psychiatric Epidemiology Surveys 
Public Health Reports  2010;125(5):698-708.
SYNOPSIS
Objectives
This study examined whether the association between obesity and 12-month prevalence of major depressive disorder (MDD) varied according to racial/ethnic status and nativity in representative national samples of black, Latino, Asian, and non-Hispanic white people.
Methods
We used data from the Comprehensive Psychiatric Epidemiology Surveys.
Results
In analyses by gender, obesity was associated with an elevated risk of MDD among non-Hispanic white women (adjusted odds ratio [AOR] =1.73; 95% confidence interval [CI] 1.27, 2.35; p=0.001). Formal test for interaction revealed significant variation by race present between non-Hispanic white women and black, Latin, and Asian women. No significant differences were evident among men. In analyses by nativity, the association between obesity and MDD was significant among U.S.-born non-Hispanic white women (AOR=1.62; 95% CI 1.16, 2.27; p=0.001) and U.S.-born black women (AOR=1.29; 95% CI 1.01, 1.66; p=0.041). Significant interactions were present among U.S.-born white and black women, Latin women, and Asian women. No significant interactions were evident among foreign-born women. Similarly, no significant differences were present among native-born or foreign-born men.
Conclusions
The findings suggest that the association between obesity and MDD varies according to racial/ethnic status and nativity. Understanding the link between obesity and depression may be imperative to designing interventions to address body weight maintenance and reduction strategies among women.
PMCID: PMC2925006  PMID: 20873286
24.  A case study of a mother's intertwining experiences with incest and postpartum depression 
The association between childhood sexual abuse (CSA) and major depression disorder (MDD) gives reason to suspect that many mothers with postpartum depression (PPD) have a history of CSA. However, few studies have investigated how CSA and PPD are related. In this case study we explore how the experience of incest intertwines with the experience of postpartum depression. We focus on participant subject “Nina,” who has experienced both. We interviewed her three times and we analysed the interviews with Giorgi's phenomenological descriptive method to arrive at a contextualised meaning structure. Nina's intruding fantasies of men who abuse her children merge with her recollections of her own incest experiences. She may succeed in forcing these fantasies out of her consciousness, but they still alter her perceptions, thoughts, and emotions. She feels overwhelmed and succumbs to sadness, while she also is drawn towards information about CSA, which in turn feeds her fantasies. The psychodynamic concepts of repetition compulsion, transference, and projection may provide some explanation of Nina's actions, thoughts, and emotions through her past experiences. With our phenomenological stance, we aim to acknowledge Nina's descriptions of her everyday life here and now. With reference to Husserl, Heidegger, Merleau-Ponty, and Minkowski, we show that Nina's past is not a dated memory; rather it determines the structure of her consciousness that constitutes her past as her true present and future. Incest dominates Nina's world, and her possibilities for action are restricted by this perceived world. Any suspension of action implies anguish, and she resolves this by incest-structured action that in turn feeds and colours her expectations. Thus anxiety and depression are intertwined in the structure of this experience.
doi:10.3402/qhw.v6i3.7244
PMCID: PMC3136228  PMID: 21760836
Child sexual abuse; incest; postpartum depression; descriptive phenomenology; case study
25.  Neural mechanisms of subclinical depressive symptoms in women: a pilot functional brain imaging study 
BMC Psychiatry  2012;12:152.
Background
Studies of individuals who do not meet criteria for major depressive disorder (MDD) but with subclinical levels of depressive symptoms may aid in the identification of neurofunctional abnormalities that possibly precede and predict the development of MDD. The purpose of this study was to evaluate relations between subclinical levels of depressive symptoms and neural activation patterns during tasks previously shown to differentiate individuals with and without MDD.
Methods
Functional magnetic resonance imaging (fMRI) was used to assess neural activations during active emotion regulation, a resting state scan, and reward processing. Participants were twelve females with a range of depressive symptoms who did not meet criteria for MDD.
Results
Increased depressive symptom severity predicted (1) decreased left midfrontal gyrus activation during reappraisal of sad stimuli; (2) increased right midfrontal gyrus activation during distraction from sad stimuli; (3) increased functional connectivity between a precuneus seed region and left orbitofrontal cortex during a resting state scan; and (4) increased paracingulate activation during non-win outcomes during a reward-processing task.
Conclusions
These pilot data shed light on relations between subclinical levels of depressive symptoms in the absence of a formal MDD diagnosis and neural activation patterns. Future studies will be needed to test the utility of these activation patterns for predicting MDD onset in at-risk samples.
doi:10.1186/1471-244X-12-152
PMCID: PMC3500241  PMID: 22998631
FMRI; Depression symptoms; Emotion regulation; Resting state; Reward

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