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1.  Remitted major depression is characterized by reward network hyperactivation during reward anticipation and hypoactivation during reward outcomes 
Journal of Affective Disorders  2011;136(3):1126-1134.
Background
Although functional brain imaging has established that individuals with unipolar major depressive disorder (MDD) are characterized by frontostriatal dysfunction during reward processing, no research to date has examined the chronometry of neural responses to rewards in euthymic individuals with a history of MDD.
Method
A monetary incentive delay task was used during fMRI scanning to assess neural responses in frontostriatal reward regions during reward anticipation and outcomes in 19 participants with remitted major depressive disorder (rMDD) and in 19 matched control participants.
Results
During the anticipation phase of the task, the rMDD group was characterized by relatively greater activation in bilateral anterior cingulate gyrus, in right midfrontal gyrus, and in the right cerebellum. During the outcome phase of the task, the rMDD group was characterized by relatively decreased activation in bilateral orbital frontal cortex, right frontal pole, left insular cortex, and left thalamus. Exploratory analyses indicated that activation within a right frontal pole cluster that differentiated groups during reward anticipation predicted the number of lifetime depressive episodes within the rMDD group.
Limitations
Replication with larger samples is needed.
Conclusions
Results suggest a double dissociation between reward network reactivity and temporal phase of the reward response in rMDD, such that rMDD is generally characterized by reward network hyperactivation during reward anticipation and reward network hypoactivation during reward outcomes. More broadly, these data suggest that aberrant frontostriatal response to rewards may potentially represent a trait marker for MDD, though future research is needed to evaluate the prospective utility of this functional neural endophenype as a marker of MDD risk.
doi:10.1016/j.jad.2011.09.048
PMCID: PMC3272083  PMID: 22036801
Major Depressive Disorder; Remission; Reward; Anhedonia; Anticipation; Magnetic Resonance Imaging
2.  Neural responses to incongruency in a blocked-trial Stroop fMRI task in major depressive disorder 
Journal of affective disorders  2012;143(1-3):241-247.
Background
Patients with major depressive disorder (MDD) perform poorly on the Stroop task, which is a measure of the executive control of attention, with impaired interference resolution. The neural correlates of this deficit are not well described. To examine how this deficit relates to pathophysiological abnormalities in MDD, we conducted an fMRI Stroop study comparing MDD subjects to controls.
Methods
Forty-two unmedicated patients with current MDD and 17 control subjects underwent fMRI scanning with a color-word Stroop task. Subjects assessed font color during alternating color identification (ex. ‘XXXX’ in blue) and incongruent color/word blocks (ex. the word ‘red’ in blue). We examined neural activation that was greater in incongruent than color identification blocks (Z>2.3 and corrected p<0.05), controlling for trial-by-trial reaction time.
Results
Compared to controls, MDD subjects exhibited lower activation during incongruent blocks across multiple brain regions, including middle frontal gyrus, paracingulate and posterior cingulate, precuneus, occipital regions, and brain stem. No brain regions were identified in which MDD subjects were more active than controls during incongruent blocks.
Limitations
Not all MDD subjects were antidepressant-naïve.
Conclusions
Brain regions related to executive function, visual processing, and semantic processing are less active during processing of incongruent stimuli in MDD subjects as compared to controls. Deficits of attention in MDD may be the product of a failure to maintain activity across a distributed network in a sustained manner, as is required over the sequential trials in this block design. Further studies may clarify whether the abnormalities represent a trait or state deficit.
doi:10.1016/j.jad.2012.05.016
PMCID: PMC3501555  PMID: 22995943
Stroop task; functional magnetic resonance imaging; depression; executive function; incongruency; attention
3.  Neural Response to Catecholamine Depletion in Unmedicated Subjects With Major Depressive Disorder in Remission and Healthy Subjects 
Archives of general psychiatry  2008;65(5):521-531.
Context
The pathophysiologic mechanism of major depressive disorder (MDD) has been consistently associated with altered catecholaminergic function, especially with decreased dopamine neurotransmission, by various sources of largely indirect evidence. An instructive paradigm for more directly investigating the relationship between catecholaminergic function and depression has involved the mood response to experimental catecholamine depletion (CD).
Objectives
To determine whether catecholaminergic dysfunction represents a trait abnormality in MDD and to identify brain circuitry abnormalities involved in the pathophysiologic mechanism of MDD.
Design
Randomized, double-blind, placebo-controlled, crossover, single-site experimental trial.
Setting
Psychiatric outpatient clinic.
Participants
Fifteen unmedicated subjects with MDD in full remission (hereinafter referred to as RMDD subjects) and 13 healthy controls.
Intervention
Induction of CD by oral administration of α-methylparatyrosine. Sham depletion used identical capsules containing hydrous lactose.
Main Outcome Measures
Quantitative positron emission tomography of regional cerebral glucose utilization to study the neural effects of CD and sham depletion. Behavioral assessments included the Montgomery-Asberg Depression Rating Scale and the Snaith-Hamilton Pleasure Scale (anhedonia).
Results
Depressive and anhedonic symptoms increased during CD to a greater extent in RMDD subjects than in controls. In both groups, CD increased metabolism in the anteroventral striatum and decreased metabolism in the orbital gyri. In a limbic-cortical-striatal-pallidal-thalamic network previously implicated in MDD, composed of the ventromedial frontal polar cortex, midcingulate and subgenual anterior cingulate cortex, temporopolar cortex, ventral striatum, and thalamus, metabolism increased in RMDD subjects but decreased or remained unchanged in controls. Metabolic changes induced by CD in the left ventromedial frontal polar cortex correlated positively with depressive symptoms, whereas changes in the anteroventral striatum were correlated with anhedonic symptoms.
Conclusions
This study provides direct evidence for catecholaminergic dysfunction as a trait abnormality in MDD. It demonstrates that depressive and anhedonic symptoms as a result of decreased catecholaminergic neurotransmission are related to elevated activity within the limbic-cortical-striatal-pallidal-thalamic circuitry.
doi:10.1001/archpsyc.65.5.521
PMCID: PMC2676777  PMID: 18458204
4.  Unique Functional Abnormalities in Youth with Combined Marijuana Use and Depression: An fMRI Study 
Prior research has shown a relationship between early onset marijuana (MJ) use and depression; however, this relationship is complex and poorly understood. Here, we utilized passive music listening and fMRI to examine functional brain activation to a rewarding stimulus in 75 participants [healthy controls (HC), patients with major depressive disorder (MDD), frequent MJ users, and the combination of MDD and MJ (MDD + MJ)]. For each participant, a preferred and neutral piece of instrumental music was determined (utilizing ratings on a standardized scale), and each completed two 6-min fMRI scans of a passive music listening task. Data underwent pre-processing and 61 participants were carried forward for analysis (17 HC, 15 MDD, 15 MJ, 14 MDD + MJ). Two statistical analyses were performed using SPM8, an analysis of covariance with two factors (group × music type) and a whole brain, multiple regression analysis incorporating two predictors of interest [MJ use in past 28 days; and Beck Depression Inventory (BDI) score]. We identified a significant group × music type interaction. Post hoc comparisons showed that the preferred music had significantly greater activation in the MDD + MJ group in areas including the right middle and inferior frontal gyri extending into the claustrum and putamen and the anterior cingulate. No significant differences were identified in MDD, MJ, or HC groups. Multiple regression analysis showed that activation in medial frontal cortex was positively correlated with amount of MJ use, and activation in areas including the insula was negatively correlated with BDI score. Results showed modulation in brain activation during passive music listening specific to MDD, frequent MJ users. This supports the suggestion that frequent MJ use, when combined with MDD, is associated with changes in neurocircuitry involved in reward processing in ways that are absent with either frequent MJ use or MDD alone. This could help inform clinical recommendations for youth with MDD.
doi:10.3389/fpsyt.2014.00130
PMCID: PMC4176032  PMID: 25309462
reward; cannabis; major depressive disorder; adolescent; young adult; mental health
5.  Affective context interferes with cognitive control in unipolar depression: An fMRI investigation 
Journal of affective disorders  2008;114(1-3):131-142.
Background
Unipolar major depressive disorder (MDD) is characterized by aberrant amygdala responses to sad stimuli and poor cognitive control, but the interactive effects of these impairments are poorly understood.
Aim
To evaluate brain activation in MDD in response to cognitive control stimuli embedded within sad and neutral contexts.
Method
Fourteen adults with MDD and fifteen matched controls participated in a mixed block/event-related functional magnetic resonance imaging (fMRI) task that presented oddball target stimuli embedded within blocks of sad or neutral images.
Results
Target events activated similar prefrontal brain regions in both groups. However, responses to target events embedded within blocks of emotional images revealed a clear group dissociation. During neutral blocks, the control group demonstrated greater activation to targets in the midfrontal gyrus and anterior cingulate relative to the MDD group, replicating previous findings of prefrontal hypo-activation in MDD samples to cognitive control stimuli. However, during sad blocks, the MDD group demonstrated greater activation in a number of prefrontal regions, including the mid-, inferior, and orbito-frontal gyri and the anterior cingulate, suggesting that relatively more prefrontal brain activation was required to disengage from the sad images to respond to the target events.
Limitations
A larger sample size would have provided greater statistical power, and more standardized stimuli would have increased external validity.
Conclusions
This double dissociation of prefrontal responses to target events embedded within neutral and sad context suggests that MDD impacts not only responses to affective events, but extends to other cognitive processes carried out in the context of affective engagement. This implies that emotional reactivity to sad events in MDD may impact functioning more broadly than previously understood.
doi:10.1016/j.jad.2008.06.027
PMCID: PMC2656256  PMID: 18706701
Unipolar depression; Target detection; Cognitive control; Functional magnetic resonance imaging; Prefrontal cortex; Amygdala
6.  Widespread reductions in gray matter volume in depression☆ 
NeuroImage : Clinical  2013;3:332-339.
Abnormalities in functional limbic–anterior cingulate–prefrontal circuits associated with emotional reactivity, evaluation and regulation have been implicated in the pathophysiology of major depressive disorder (MDD). However, existing knowledge about structural alterations in depression is equivocal and based on cohorts of limited sample size. This study used voxel-based morphometry (VBM) and surface-based cortical thickness to investigate the structure of these circuits in a large and well-characterized patient cohort with MDD.
Non-geriatric MDD outpatients (n = 102) and age- and gender-matched healthy control participants (n = 34) provided T1-weighted magnetic resonance imaging data during their baseline visit as part of the International Study to Predict Optimized Treatment for Depression. Whole-brain VBM volumetric and surface-based cortical thickness assessments were performed voxel-wise and compared (at p < 0.05 corrected for multiple comparisons) between the MDD and control groups.
MDD participants had reduced gray matter volume in the anterior cingulate cortex, regions of the prefrontal circuits, including dorsolateral and dorsomedial prefrontal cortices, and lateral and medial orbitofrontal cortices, but not in limbic regions. Additional reductions were observed cortically in the posterior temporal and parieto-occipital cortices and, subcortically in the basal ganglia and cerebellum. Focal cortical thinning in the medial orbitofrontal cortex was also observed for the MDD group. These alterations in volume and cortical thickness were not associated with severity of depressive symptoms.
The findings demonstrate that widespread gray matter structural abnormalities are present in a well-powered study of patients with depression. The patterns of gray matter loss correspond to the same brain functional network regions that were previously established to be abnormal in MDD, which may support an underlying structural abnormality for these circuits.
Highlights
•Focal gray matter volume decrease in depression exceeded loss via aging 11–50 years.•Gray matter differences were found in regions with established roles in depression.•Structural change findings support the idea of depression as a network abnormality.•Hippocampal gray matter volume loss likely has no role in non-geriatric depression.•Amygdala gray matter volume loss likely plays no role in depression pathophysiology.
doi:10.1016/j.nicl.2013.08.016
PMCID: PMC3814952  PMID: 24273717
AAL, Automated Anatomical Labeling; ACC, Anterior Cingulate Cortex; BAs, Brodmann Areas; CVNA, Change in Volume expected in that region through Normal Aging; DLPFC, Dorsolateral Prefrontal Cortex; DTI, Diffusion Tensor Imaging; FDR, False Discovery Rate; fMRI, functional Magnetic Resonance Imaging; GM, Gray Matter; HRSD17, 17-Item Hamilton Rating Scale for Depression; iSPOT-D, International Study to Predict Optimized Treatment in Depression; MDD, Major Depressive Disorder; MPFC, Medial Prefrontal Cortex; MRI, Magnetic Resonance Imaging; OFC, Orbitofrontal Cortex; PFC, Prefrontal Cortex; VBM, Voxel-Based Morphometry; Gray matter; Major depressive disorder; VBM; Volume; Cortical thickness; iSPOT-D
7.  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
8.  Depression and Eating Disorders: Treatment and Course 
Journal of affective disorders  2010;130(3):470-477.
Background
We examined the course of major depressive disorder (MDD) and predictors of MDD recovery and relapse in a longitudinal sample of women with eating disorders (ED).
Methods
246 Boston area women with DSM-IV anorexia nervosa-restricting (ANR; n=51), AN-binge/purge (ANBP; n=85), and bulimia nervosa (BN; n=110) were recruited between 1987-1991 and interviewed using the Eating Disorders Longitudinal Interval Follow-up Evaluation (LIFE-EAT-II) every 6-12 months for up to 12 years. 100 participants had MDD at study intake and 45 developed MDD during the study. Psychological functioning and treatment were assessed.
Results
Times to MDD onset (1 week – 4.3 years), recovery (8 weeks – 8.7 years), and relapse (1 week – 5.2 years) varied. 70% recovered from MDD, but 65% subsequently relapsed. ANR patients were significantly less likely to recover from MDD than ANBP patients (p=0.029). Better psychological functioning and history of MDD were associated with higher chance of MDD recovery. Higher baseline depressive severity and full recovery from ED were associated with greater likelihood of MDD relapse; increased weight loss was somewhat protective. Adequate antidepressant treatment was given to 72% of patients with MDD and generally continued after MDD recovery. Time on antidepressants did not predict MDD recovery (p=0.27) or relapse (p=0.26).
Limitations
Small ED diagnostic subgroups; lack of non-ED control group.
Conclusions
The course of MDD in EDs is protracted; MDD recovery may depend on ED type. Antidepressants did not impact likelihood of MDD recovery, nor protect against relapse, which may impact on treatment strategies for comorbid MDD and EDs.
doi:10.1016/j.jad.2010.10.043
PMCID: PMC3085695  PMID: 21109307
Major Depressive Disorder; Eating Disorders; Anorexia Nervosa; Bulimia Nervosa; Antidepressants
9.  fMRI activation in amygdala and orbitofrontal cortex in unmedicated subjects with major depressive disorder 
Psychiatry Research  2010;183(3):209-217.
Although amygdala and frontal lobe functional abnormalities have been reported in patients with mood disorders, the literature regarding Major Depressive Disorder (MDD) is inconsistent. Likely confounds include heterogeneity of patient samples, medication status, and analytic approach. This study evaluated amygdala and frontal lobe activation in unmedicated MDD patients. Fifteen MDD patients and 15 matched healthy controls were scanned using fMRI during the performance of an emotional faces task known to robustly activate the amygdala and prefrontal cortex (PFC). Whole-brain and region of interest analyses were performed, and correlations between clinical features and activation were examined. Significant amygdala and lateral PFC activation were seen within patient and control groups. In a between-group comparison, patients showed significantly reduced activation in the insula, temporal and occipital cortices. In MDD, the presence of anxiety symptoms was associated with decreased orbitofrontal activation. We found robust activation in both the MDD and control groups in fronto-limbic regions with no significant between-group differences using either analytic approach. The current study replicates previous research on unmedicated subjects showing no significant differences in amygdala function in depressed vs. control subjects with respect to simple tasks involving emotion observation.
doi:10.1016/j.pscychresns.2010.06.001
PMCID: PMC3382985  PMID: 20708906
amygdala; DLPFC; emotion; Major Depressive Disorder
10.  Prefrontal cortical abnormalities in currently depressed versus currently remitted patients with major depressive disorder 
NeuroImage  2010;54(4):2643-2651.
Previous neuromorphometric investigations of major depressive disorder (MDD) have reported abnormalities in gray matter in several regions, although the results have been inconsistent across studies. Some discrepancies in the results across studies may reflect design limitations such as small sample sizes, whereas others may reflect biological variability that potentially manifests as differences in clinical course. For example, it remains unclear whether the abnormalities found in persistently depressed MDD subjects extend to or persist in patients who experience prolonged remission. The aim of the present study was to investigate gray matter (GM) differences in unmedicated, currently-depressed participants (dMDD) and unmedicated, currently-remitted (rMDD) participants with MDD compared to healthy controls (HC).
The GM density and volume was compared across groups using voxel-based morphometry, a quantitative neuroanatomical technique, and high-resolution MRI images from 107 HC, 58 dMDD and 27 rMDD subjects.
Relative to the HC group the dMDD group had reduced GM in the dorsal anterolateral (DALPFC), the dorsomedial (DMPFC) and the ventrolateral prefrontal cortex (VLPFC). Relative to the rMDD group the dMDD group showed reduced GM in the DALPFC, the VLPFC, the anterior cingulate cortex (ACC), the precuneus and the inferior parietal lobule. No regions were identified in which the rMDD group showed significantly lower GM compared to the HC group after p-values were corrected for the number of comparisons performed.
In unmedicated patients in the depressed phase of MDD, we found evidence of morphometric abnormalities in DALPFC and in medial prefrontal cortical regions belonging to the visceromotor network. These findings, along with the absence of GM abnormalities in the remitted sample imply a possible link between greater GM tissue and better clinical outcome. Consistent with other neuroimaging and post-mortem neuropathological studies of MDD, we also found evidence of decreased white matter in patients with dMDD and rMDD.
doi:10.1016/j.neuroimage.2010.11.011
PMCID: PMC3020249  PMID: 21073959
Voxel-based morphometry (VBM); remission; dorsolateral prefrontal cortex (DLPFC); gray matter; clinical outcome
11.  Functional Anatomy of Autobiographical Memory Recall Deficits in Depression 
Psychological medicine  2011;42(2):345-357.
Background
Major depressive disorder (MDD) is associated with deficits in recalling specific autobiographical memories (AMs). Extensive research has examined the functional anatomical correlates of AM in healthy humans, but no studies have examined the neurophysiological underpinnings of AM deficits in individuals with MDD. The goal of the present study was to examine the differences in the hemodynamic response between MDD and healthy control (HC) participants while they engage in AM recall.
Methods
Participants (12 unmedicated MDD; 14 HCs) underwent functional MRI scanning while recalling AMs in response to positive, negative, and neutral cue words. The hemodynamic response during recall of the different memory classifications versus performing subtraction problems was compared between depressed and control samples.
Results
Behavioral results showed that relative to controls, the MDDs had fewer specific(p=0.013), positive(p=0.030), highly arousing(p=0.036), and recent(p=0.020) AMs, and more categorical(p<0.001) AMs. During AM recall the BOLD responses in the anterior cingulate cortex, parahippocampal gyrus, and hippocampus was higher for memory recall versus subtraction in HCs and lower in MDDs. Additionally, activity in the anterior insula and lateral orbitofrontal cortex was lower in the AM task than the in subtraction task, with the magnitude of the decrement greater in MDDs.
Conclusions
We replicated previous findings of fewer specific and more categorical AMs in MDDs versus HCs. We found differential activity in medial temporal and prefrontal lobe structures involved in AM retrieval between MDDs and HCs as they engaged in AM recall. These neurophysiological deficits may underlie AM recall impairments seen in MDD.
doi:10.1017/S0033291711001371
PMCID: PMC3226869  PMID: 21798113
12.  Decreased frontal regulation during pain anticipation in unmedicated subjects with major depressive disorder 
Translational Psychiatry  2013;3(3):e239-.
Major depressive disorder (MDD) is characterized by impaired processing of negative information, possibly due to dysfunction in both, the bottom-up emotional network and top-down modulatory network. By acquiring functional magnetic resonance imaging (fMRI) on a pain-anticipation task, we tested the hypothesis that individuals with MDD would show increased negative biasing that may be associated with reduced frontal connectivity. Thirty-one (15 females) unmedicated young adults with current MDD and 22 (11 females) healthy subjects with no history of MDD were recruited. Groups did not differ significantly in age, race, level of education, marital status or gender distribution. fMRI data were collected during an event-related pain-anticipation paradigm, during which subjects were cued to anticipate painful heat stimuli of high or low intensity. All temperature stimuli were applied to each subject's left forearm. We found that relative to healthy comparison subjects, participants with MDD showed significantly stronger responses to high versus low pain anticipation within right ventral anterior insula (AI), but overlapping response within right dorsal AI, which correlated positively with the depression symptoms severity in the MDD group. Functional connectivity analyses showed increased functional connectivity between dorsal insula and posterior thalamus and decreased functional connectivity between dorsal insula and the right inferior frontal gyrus in the MDD compared with the non-MDD group. Our results demonstrate that unmedicated individuals with current MDD compared with healthy never-depressed subjects show both differential and overlapping response within AI during anticipation of pain. Furthermore, the overlapping insular response is less regulated by frontal brain systems and is more subservient to affective processing regions in the posterior thalamus in MDD. These results support and provide functional validation of the co-occurring enhanced ‘bottom-up' and attenuated ‘top-down' processing of salient, unpleasant emotional information in MDD.
doi:10.1038/tp.2013.15
PMCID: PMC3625914  PMID: 23481626
depression; emotion; fMRI; imaging; insula; modulation
13.  Learning from negative feedback in patients with major depressive disorder is attenuated by SSRI antidepressants 
One barrier to interpreting past studies of cognition and major depressive disorder (MDD) has been the failure in many studies to adequately dissociate the effects of MDD from the potential cognitive side effects of selective serotonin reuptake inhibitors (SSRIs) use. To better understand how remediation of depressive symptoms affects cognitive function in MDD, we evaluated three groups of subjects: medication-naïve patients with MDD, medicated patients with MDD receiving the SSRI paroxetine, and healthy control (HC) subjects. All were administered a category-learning task that allows for dissociation between learning from positive feedback (reward) vs. learning from negative feedback (punishment). Healthy subjects learned significantly better from positive feedback than medication-naïve and medicated MDD groups, whose learning accuracy did not differ significantly. In contrast, medicated patients with MDD learned significantly less from negative feedback than medication-naïve patients with MDD and healthy subjects, whose learning accuracy was comparable. A comparison of subject’s relative sensitivity to positive vs. negative feedback showed that both the medicated MDD and HC groups conform to Kahneman and Tversky’s (1979) Prospect Theory, which expects losses (negative feedback) to loom psychologically slightly larger than gains (positive feedback). However, medicated MDD and HC profiles are not similar, which indicates that the state of medicated MDD is not “normal” when compared to HC, but rather balanced with less learning from both positive and negative feedback. On the other hand, medication-naïve patients with MDD violate Prospect Theory by having significantly exaggerated learning from negative feedback. This suggests that SSRI antidepressants impair learning from negative feedback, while having negligible effect on learning from positive feedback. Overall, these findings shed light on the importance of dissociating the cognitive consequences of MDD from those of SSRI treatment, and from cognitive evaluation of MDD subjects in a medication-naïve state before the administration of antidepressants. Future research is needed to correlate the mood-elevating effects and the cognitive balance between reward- and punishment-based learning related to SSRIs.
doi:10.3389/fnint.2013.00067
PMCID: PMC3779792  PMID: 24065894
major depressive disorder; selective serotonin reuptake inhibitor; basal ganglia; reward; punishment
14.  Amplitude of Low-Frequency Oscillations in First-Episode, Treatment-Naive Patients with Major Depressive Disorder: A Resting-State Functional MRI Study 
PLoS ONE  2012;7(10):e48658.
Background
Resting-state fMRI is a novel approach to measure spontaneous brain activity in patients with major depressive disorder (MDD). Although most resting-state fMRI studies have focused on the examination of temporal correlations between low-frequency oscillations (LFOs), few studies have explored the amplitude of these LFOs in MDD. In this study, we applied the approaches of amplitude of low-frequency fluctuation (ALFF) and fractional ALFF to examine the amplitude of LFOs in MDD.
Methodology/Principal Findings
A total of 36 subjects, 18 first-episode, treatment-naive patients with MDD matched with 18 healthy controls (HCs) completed the fMRI scans. Compared with HCs, MDD patients showed increased ALFF in the right fusiform gyrus and the right anterior and posterior lobes of the cerebellum but decreased ALFF in the left inferior temporal gyrus, bilateral inferior parietal lobule, and right lingual gyrus. The fALFF in patients was significantly increased in the right precentral gyrus, right inferior temporal gyrus, bilateral fusiform gyrus, and bilateral anterior and posterior lobes of the cerebellum but was decreased in the left dorsolateral prefrontal cortex, bilateral medial orbitofrontal cortex, bilateral middle temporal gyrus, left inferior temporal gyrus, and right inferior parietal lobule. After taking gray matter (GM) volume as a covariate, the results still remained.
Conclusions/Significance
These findings indicate that MDD patients have altered LFO amplitude in a number of regions distributed over the frontal, temporal, parietal, and occipital cortices and the cerebellum. These aberrant regions may be related to the disturbances of multiple emotion- and cognition-related networks observed in MDD and the apparent heterogeneity in depressive symptom domains. Such brain functional alteration of MDD may contribute to further understanding of MDD-related network imbalances demonstrated in previous fMRI studies.
doi:10.1371/journal.pone.0048658
PMCID: PMC3485382  PMID: 23119084
15.  Remitted Major Depression is Characterized by Reduced Prefrontal Cortex Reactivity to Reward Loss 
Journal of affective disorders  2013;151(2):756-762.
Background
Major depression (MDD) is characterized by anhedonia. Although a growing body of literature has linked anhedonia in MDD to reduced frontostriatal activity during reward gains, relatively few studies have examined neural responsivity to loss, and no studies to date have examined neural responses to loss in euthymic individuals with a history of MDD.
Methods
An fMRI monetary incentive delay task was administered to 19 participants with remitted MDD (rMDD) and 19 never depressed controls. Analyses examined group activation differences in brain reward circuitry during monetary loss anticipation and outcomes. Secondary analyses examined the association between self-reported rumination and brain activation in the rMDD group.
Results
Compared to controls, the rMDD group showed less superior frontal gyrus activation during loss anticipation and less inferior and superior frontal gyri activation during loss outcomes (cluster corrected p’s<.05). Ruminative Responses Scale scores were negatively correlated with superior frontal gyrus activation (r=−.68, p=.001) during loss outcomes in the rMDD group. Limitations: Replication with a larger sample is needed.
Conclusions
Euthymic individuals with a history of MDD showed prefrontal cortex hypoactivation during loss anticipation and outcomes, and the degree of superior frontal gyrus hypoactivation was associated with rumination. Abnormal prefrontal cortex responses to loss may reflect a trait-like vulnerability to MDD, although future research is needed to evaluate the utility of this functional neural endophenotype as a prospective risk marker.
doi:10.1016/j.jad.2013.06.016
PMCID: PMC3797197  PMID: 23835103
Major depressive disorder; Remission; Reward; Rumination; Anticipation; Magnetic resonance imaging
16.  Whole-brain functional connectivity during emotional word classification in medication-free Major Depressive Disorder: Abnormal salience circuitry and relations to positive emotionality☆ 
NeuroImage : Clinical  2013;2:790-796.
Major Depressive Disorder (MDD) has been associated with biased processing and abnormal regulation of negative and positive information, which may result from compromised coordinated activity of prefrontal and subcortical brain regions involved in evaluating emotional information. We tested whether patients with MDD show distributed changes in functional connectivity with a set of independently derived brain networks that have shown high correspondence with different task demands, including stimulus salience and emotional processing. We further explored if connectivity during emotional word processing related to the tendency to engage in positive or negative emotional states. In this study, 25 medication-free MDD patients without current or past comorbidity and matched controls (n = 25) performed an emotional word-evaluation task during functional MRI. Using a dual regression approach, individual spatial connectivity maps representing each subject's connectivity with each standard network were used to evaluate between-group differences and effects of positive and negative emotionality (extraversion and neuroticism, respectively, as measured with the NEO-FFI). Results showed decreased functional connectivity of the medial prefrontal cortex, ventrolateral prefrontal cortex, and ventral striatum with the fronto-opercular salience network in MDD patients compared to controls. In patients, abnormal connectivity was related to extraversion, but not neuroticism. These results confirm the hypothesis of a relative (para)limbic–cortical decoupling that may explain dysregulated affect in MDD. As connectivity of these regions with the salience network was related to extraversion, but not to general depression severity or negative emotionality, dysfunction of this network may be responsible for the failure to sustain engagement in rewarding behavior.
Highlights
•We studied whole-brain functional connectivity in MDD during an emotional task.•We used a set of independent template networks, corresponding to various task demands.•We showed lower connectivity of reward related regions with a salience network in MDD.•Lower salience connectivity specifically related to extraversion in patients•Results may reflect vulnerability for MDD via a circuit vital for rewarding behavior.
doi:10.1016/j.nicl.2013.05.012
PMCID: PMC3777780  PMID: 24179829
Depression; Extraversion; Functional magnetic resonance imagint; Salience network; Whole-brain functional connectivity
17.  Influence of COMT val158met Genotype on the Depressed Brain during Emotional Processing and Working Memory 
PLoS ONE  2013;8(9):e73290.
Major depressive disorder (MDD) has been associated with abnormal prefrontal-limbic interactions and altered catecholaminergic neurotransmission. The val158met polymorphism on the catechol-O-methyltransferase (COMT) gene has been shown to influence prefrontal cortex (PFC) activation during both emotional processing and working memory (WM). Although COMT-genotype is not directly associated with MDD, it may affect MDD pathology by altering PFC activation, an endophenotype associated with both COMT and MDD. 125 participants, including healthy controls (HC, n=28) and MDD patients were genotyped for the COMT val158met polymorphism and underwent functional magnetic resonance imaging (fMRI-neuroimaging) during emotion processing (viewing of emotional facial expressions) and a WM task (visuospatial planning). Within HC, we observed a positive correlation between the number of met-alleles and right inferior frontal gyrus activation during emotional processing, whereas within patients the number of met-alleles was not correlated with PFC activation. During WM a negative correlation between the number of met-alleles and middle frontal gyrus activation was present in the total sample. In addition, during emotional processing there was an effect of genotype in a cluster including the amygdala and hippocampus. These results demonstrate that COMT genotype is associated with relevant endophenotypes for MDD. In addition, presence of MDD only interacts with genotype during emotional processing and not working memory.
doi:10.1371/journal.pone.0073290
PMCID: PMC3772077  PMID: 24069183
18.  Cortical thickness in youth with major depressive disorder 
BMC Psychiatry  2014;14:83.
Background
Studies in adults with major depressive disorder (MDD) have implicated dysregulation of frontal-limbic circuits in the symptomology of this disorder. We hypothesized that the middle frontal gyrus (MFG; a core portion of the dorsolateral prefrontal cortex or DLPFC) and the anterior cingulate (caudal), regions implicated in emotive and cognitive control, would display a reduced cortical thickness in youth with MDD as compared to healthy, non-depressed adolescents.
Methods
Sixteen healthy control adolescents (17.19 ± 1.87 years; 7 males, 9 females) and thirty MDD participants (16.89 ± 2.01 years; 9 males, 21 females) underwent magnetic resonance imaging (MRI). Cortical thickness analysis was carried out using FreeSurfer software.
Results
Counter to our hypothesis, we observed thicker right and left rostral MFG in MDD adolescents as compared to controls (p = 0.004 and p = 0.005, respectively). Furthermore, the left caudal anterior cingulate cortex was thicker in MDD subjects as compared to controls (p = 0.009). In MDD subjects, there was a significant inverse correlation between age and left MFG thickness (r = -0.45, p = 0.001).
Conclusions
These results have implications for the developmental trajectory of the frontal lobe in adolescent MDD. The MFG is implicated in the frontal-limbic circuits underlying executive functioning and their interaction with affective processing. Alterations in this region are likely involved with the symptoms of MDD. Limitations include a small sample size and cross sectional design.
doi:10.1186/1471-244X-14-83
PMCID: PMC3994552  PMID: 24645731
Adolescence; Cortical thickness; Depression; Magnetic resonance imaging; Prefrontal cortex
19.  Impact of Chronic Hypercortisolemia on Affective Processing 
Neuropharmacology  2011;62(1):217-225.
Cushing syndrome (CS) is the classic condition of cortisol dysregulation, and cortisol dysregulation is the prototypic finding in Major Depressive Disorder (MDD). We hypothesized that subjects with active CS would show dysfunction in frontal and limbic structures relevant to affective networks, and also manifest poorer facial affect identification accuracy, a finding reported in MDD.Twenty-one patients with confirmed CS (20 ACTH-dependent and 1 ACTH-independent) were compared to 21 healthy controlsubjects. Identification of affective facial expressions (Facial Emotion Perception Test) was conducted in a 3 Tesla GE fMRI scanner using BOLD fMRI signal. The impact of disease (illness duration, current hormone elevation and degree of disruption of circadian rhythm), performance, and comorbid conditions secondary to hypercortisolemia were evaluated.CS patients made more errors in categorizing facial expressions and had less activation in left anterior superior temporal gyrus, a region important in emotion processing. CS patients showed higher activation in frontal, medial, and subcortical regions relative to controls. Two regions of elevated activation in CS, left middle frontal and lateral posterior/pulvinar areas, were positively correlated with accuracy in emotion identification in the CS group, reflecting compensatory recruitment. In addition, within the CSgroup, greater activation in left dorsal anterior cingulatewas related to greater severity of hormone dysregulation. In conclusion, cortisol dysregulation in CS patients is associated with problems in accuracy of affective discrimination and altered activation of brain structures relevant to emotion perception, processing and regulation, similar to the performance decrements and brain regions shown to be dysfunctional in MDD.
doi:10.1016/j.neuropharm.2011.07.006
PMCID: PMC3196277  PMID: 21787793
HPA; cortisol; ACTH; emotion; affect; fMRI; Cushings
20.  Altered functional connectivity in posttraumatic stress disorder with versus without comorbid major depressive disorder: a resting state fMRI study 
F1000Research  2013;2:289.
Posttraumatic stress disorder (PTSD) is an anxiety disorder that is often diagnosed with comorbid depressive disorder. Therefore, neuroimaging studies investigating PTSD typically include both patients with and without comorbid depression. Differences in activity of the anterior cingulate cortex (ACC) and insula have been shown to differentiate PTSD patients with and without major depressive disorder (MDD). Whether or not comorbid MDD affects resting state functional connectivity of PTSD patients has not been investigated to our knowledge. Here, resting state functional connectivity of PTSD patients with (PTSD+MDD; n=27) and without (PTSD-MDD; n=23) comorbid MDD was investigated. The subgenual ACC and insula were investigated as seed regions. Connectivity between the subgenual ACC and perigenual parts of the ACC was increased in PTSD+MDD versus PTSD-MDD. Reduced functional connectivity of the subgenual ACC with the thalamus was found in the PTSD+MDD group versus the PTSD-MDD group. These results remained significant after controlling for PTSD severity. In addition, the PTSD+MDD group showed reduced functional connectivity of the insula with the hippocampus compared to the PTSD-MDD group. However, this cluster was no longer significantly different when controlling for PTSD severity. Thus, resting state functional connectivity of the subgenual ACC may distinguish PTSD+MDD from PTSD-MDD. As PTSD patients with comorbid MDD are more treatment resistant, this result may be important for treatment development.
doi:10.12688/f1000research.2-289.v1
PMCID: PMC4184309  PMID: 25309726
21.  Enhanced visual motion perception in Major Depressive Disorder 
Major Depressive Disorder (MDD) is a mood disorder that is not traditionally considered to affect the visual system. However, recent findings have reported decreased cortical levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in occipital cortex. To explore possible functional consequences of MDD on visual processing, we applied a psychophysical visual motion processing task in which healthy young adults typically exhibit impaired perceptual discrimination of large high contrast stimuli. It has been suggested that this phenomenon, spatial suppression, is mediated by GABAergic center-surround antagonism in visual pathways. Based on previous findings linking MDD to occipital GABA dysfunction, we hypothesized that MDD patients would exhibit decreased spatial suppression, leading to the counterintuitive hypothesis of better psychophysical performance. Indeed, motion perception for typically suppressed stimuli was enhanced in patients with MDD compared to age-matched controls. Furthermore, the degree of spatial suppression correlated with an individual’s illness load; patients with greater lifetime duration of depression exhibited the least spatial suppression and performed the best in the high contrast motion discrimination task. Notably, this decrease in spatial suppression persisted beyond recovery and without the confound of acute illness or treatment; all patients had been clinically recovered and unmedicated for several months at the time of testing, suggesting that depression has ubiquitous consequences that may persist long after mood symptoms have receded. This finding raises the possibility that spatial suppression may represent a sensitive endophenotypic marker of trait vulnerability in MDD.
doi:10.1523/JNEUROSCI.1003-09.2009
PMCID: PMC2772577  PMID: 19605644
visual motion; center-surround; depression; GABA; suppression; perception deficit
22.  Repetitive Transcranial Magnetic Stimulation for the Treatment of Major Depressive Disorder 
Executive Summary
Objective
This review was conducted to assess the effectiveness of repetitive transcranial magnetic stimulation (rTMS) in the treatment of major depressive disorder (MDD).
The Technology
rTMS is a noninvasive way to stimulate nerve cells in areas of the brain. During rTMS, an electrical current passes through a wire coil placed over the scalp. The current induces a magnetic field that produces an electrical field in the brain that then causes nerve cells to depolarize, resulting in the stimulation or disruption of brain activity.
Researchers have investigated rTMS as an option to treat MDD, as an add-on to drug therapy, and, in particular, as an alternative to electroconvulsive therapy (ECT) for patients with treatment-resistant depression.
The advantages of rTMS over ECT for patients with severe refractory depression are that general anesthesia is not needed, it is an outpatient procedure, it requires less energy, the simulation is specific and targeted, and convulsion is not required. The advantages of rTMS as an add-on treatment to drug therapy may include hastening of the clinical response when used with antidepressant drugs.
Review Strategy
The Medical Advisory Secretariat used its standard search strategy to locate international health technology assessments and English-language journal articles published from January 1996 to March 2004.
Summary of Findings
Some early meta-analyses suggested rTMS might be effective for the treatment of MDD (for treatment-resistant MDD and as an add-on treatment to drug therapy for patients not specifically defined as treatment resistant). There were, however, several crucial methodological limitations in the included studies that were not critically assessed. These are discussed below.
Recent meta-analyses (including 2 international health technology assessments) have done evidence-based critical analyses of studies that have assessed rTMS for MDD. The 2 most recent health technology assessments (from the Oxford Cochrane Collaboration and the Norwegian Centre for Health Technology Assessment) concluded that there is no evidence that rTMS is effective for the treatment of MDD, either as compared with a placebo for patients with treatment-resistant or nontreatment-resistant MDD, or as an alternative to ECT for patients with treatment-resistant MDD. This mainly due to the poor quality of the studies.
The major methodological limitations were identified in older meta-analyses, recent health technology assessments, and the most recently published trials (Level 2–4 evidence) on the effectiveness of rTMS for MDD are discussed below.
Small sample size was a limitation acknowledged by many of the authors. There was also a lack of a priori sample size calculation or justification.
Biased randomization may have been a problem. Generally, the published reports lacked detailed information on the method of allocation concealment used. This is important because it is impossible to determine if there was a possible influence (direct or indirect) in the allocation of the patients to different treatment groups.
The trials were single blind, evaluated by external blinded assessors, rather than double blind. Double blinding is more robust, because neither the participants nor the investigators know which participants are receiving the active treatment and which are getting a placebo. Those administering rTMS, however, cannot be blinded to whether they are administering the active treatment or a placebo.
There was patient variability among the studies. In some studies, the authors said that patients were “medication resistant,” but the definitions of resistant, if provided, were inconsistent or unclear. For example, some described “medication resistant” as failing at least one trial of drugs during the current depressive episode. Furthermore, it was unclear if the term “medication resistant” referred to antidepressants only or to combinations of antidepressants and other drug augmentation strategies (such as neuroleptics, benzodiazepine, carbamazepine, and lithium). Also variable was the type of depression (i.e., unipolar and/or bipolar), if patients were inpatients or outpatients, if they had psychotic symptoms or no psychotic symptoms, and the chronicity of depression.
Dropouts or withdrawals were a concern. Some studies reported that patients dropped out, but provided no further details. Intent-to-treat analysis was not done in any of the trials. This is important, because ignoring patients who drop out of a trial can bias the results, usually in favour of the treatment. This is because patients who withdraw from trials are less likely to have had the treatment, more likely to have missed their interim checkups, and more likely to have experienced adverse effects when taking the treatment, compared with patients who do not withdraw. (1)
Measurement of treatment outcomes using scales or inventories makes interpreting results and drawing conclusions difficult. The most common scale, the Hamilton Depression Rating Scale (HDRS) is based on a semistructured interview. Some authors (2) reported that rating scales based on semistructured interviews are more susceptible to observation bias than are self-administered questionnaires such as the Beck Depression Inventory (BDI). Martin et al. (3) argued that the lack of consistency in effect as determined by the 2 scales (a positive result after 2 weeks of treatment as measured by the HDRS and a negative result for the BDI) makes definitive conclusions about the nature of the change in mood of patients impossible. It was suggested that because of difficulties interpreting results from psychometric scales, (4) and the subjective or unstable character of MDD, other, more objective, outcome measures such as readmission to hospital, time to hospital discharge, time to adjunctive treatment, and time off work should be used to assess rTMS for the treatment of depression.
A placebo effect could have influenced the results. Many studies reported response rates for patients who received placebo treatment. For example, Klein et al. (5) reported a control group response rate as high as 25%. Patients receiving placebo rTMS may receive a small dose of magnetic energy that may alter their depression.
Short-term studies were the most common. Patients received rTMS treatment for 1 to 2 weeks. Most studies followed-up patients for 2 to 4 weeks post-treatment. Dannon et al. (6) followed-up patients who responded to a course of ECT or rTMS for up to 6 months; however, the assessment procedure was not blinded, the medication regimen during follow-up was not controlled, and initial baseline data for the patient groups were not reported. The long-term effectiveness of rTMS for the treatment of depression is unknown, as is the long-term use, if any, of maintenance therapy. The cost-effectiveness of rTMS for the treatment of depression is also unknown. A lack of long-term studies makes cost-effectiveness analysis difficult.
The complexity of possible combinations for administering rTMS makes comparing like with like difficult. Wasserman and Lisanby (7) have said that the method for precisely targeting the stimulation in this area is unreliable. It is unknown if the left dorsolateral prefrontal cortex is the optimal location for treatment. Further, differences in rTMS administration include number of trains per session, duration of each train, and motor threshold.
Clinical versus statistical significance. Several meta-analyses and studies have found that the degree of therapeutic change associated with rTMS across studies is relatively modest; that is, results may be statistically, but not necessarily clinically, significant. (8-11). Conventionally, a 50% reduction in the HDRS scores is commonly accepted as a clinically important reduction in depression. Although some studies have observed a statistically significant reduction in the depression rating, many have not shows the clinically significant reduction of 50% on the HDRS. (11-13) Therefore, few patients in these studies would meet the standard criteria for response. (9)
Clinical/methodological diversity and statistical heterogeneity. In the Norwegian health technology assessment, Aarre et al. (14) said that a formal meta-analysis was not feasible because the designs of the studies varied too much, particularly in how rTMS was administered and in the characteristics of the patients. They noted that the quality of the study designs was poor. The 12 studies that comprised the assessment had small samples, and highly variable inclusion criteria and study designs. The patients’ previous histories, diagnoses, treatment histories, and treatment settings were often insufficiently characterized. Furthermore, many studies reported that patients had treatment-resistant MDD, yet did not listclear criteria for the designation. Without this information, Aarre and colleagues suggested that the interpretation of the results is difficult and the generalizability of results is questionable. They concluded that rTMS cannot be recommended as a standard treatment for depression: “More, larger and more carefully designed studies are needed to demonstrate convincingly a clinically relevant effect of rTMS.”
In the Cochrane Collaboration systematic review, Martin et al. (3;15) said that the complexity of possible combinations for administering rTMS makes comparison of like versus like difficult. A statistical test for heterogeneity (chi-square test) examines if the observed treatment effects are more different from each other than one would expect due to random error (or chance) alone. (16) However, this statistical test must be interpreted with caution because it has low power in the (common) situation of a meta-analysis when the trials have small sample sizes or are few. This means that while a statistically significant result may indicate a problem with heterogeneity, a nonsignificant result must not be taken as evidence of no heterogeneity.
Despite not finding statistically significant heterogeneity, Martin et al. reported that the overall mean baseline depression values for the severity of depression were higher in the treatment group than in the placebo group. (3;15) Although these differences were not significant at the level of each study, they may have introduced potential bias into the meta-analysis of pooled data by accentuating the tendency for regression to the mean of the more extreme values. Individual patient data from all the studies were not available; therefore, an appropriate adjustment according to baseline severity was not possible. Martin et al. concluded that the findings from the systematic review and meta-analysis provided insufficient evidence to suggest that rTMS is effective in the treatment of depression. Moreover, there were several confounding factors (e.g., definition of treatment resistance) in the studies, thus the authors concluded, “The rTMS technique needs more high quality trials to show its effectiveness for therapeutic use.”
Conclusion
Due to several serious methodological limitations in the studies that have examined the effectiveness of rTMS in patients with MDD, it is not possible to conclude that rTMS either is or is not effective as a treatment for MDD (in treatment-resistant depression or in nontreatment-resistant depression).
PMCID: PMC3387754  PMID: 23074457
23.  Functional anatomy of autobiographical memory recall deficits in depression 
Psychological Medicine  2011;42(2):345-357.
Background
Major depressive disorder (MDD) is associated with deficits in recalling specific autobiographical memories (AMs). Extensive research has examined the functional anatomical correlates of AM in healthy humans, but no studies have examined the neurophysiological underpinnings of AM deficits in MDD. The goal of the present study was to examine the differences in the hemodynamic response between patients with MDD and controls while they engage in AM recall.
Method
Participants (12 unmedicated MDD patients; 14 controls) underwent functional magnetic resonance imaging (fMRI) scanning while recalling AMs in response to positive, negative and neutral cue words. The hemodynamic response during memory recall versus performing subtraction problems was compared between MDD patients and controls. Additionally, a parametric linear analysis examined which regions correlated with increasing arousal ratings.
Results
Behavioral results showed that relative to controls, the patients with MDD had fewer specific (p=0.013), positive (p=0.030), highly arousing (p=0.036) and recent (p=0.020) AMs, and more categorical (p<0.001) AMs. The blood oxygen level-dependent (BOLD) response in the parahippocampus and hippocampus was higher for memory recall versus subtraction in controls and lower in those with MDD. Activity in the anterior insula was lower for specific AM recall versus subtraction, with the magnitude of the decrement greater in MDD patients. Activity in the anterior cingulate cortex was positively correlated with arousal ratings in controls but not in patients with MDD.
Conclusions
We replicated previous findings of fewer specific and more categorical AMs in patients with MDD versus controls. We found differential activity in medial temporal and prefrontal lobe structures involved in AM retrieval between MDD patients and controls as they engaged in AM recall. These neurophysiological deficits may underlie AM recall impairments seen in MDD.
doi:10.1017/S0033291711001371
PMCID: PMC3226869  PMID: 21798113
Anterior insula; autobiographical memory; depression; fMRI; hippocampus
24.  Cognitive Inflexibility in Obsessive-Compulsive Disorder and Major Depression Is Associated with Distinct Neural Correlates 
PLoS ONE  2013;8(4):e59600.
Obsessive-compulsive disorder (OCD) and major depressive disorder (MDD) are frequently co-morbid, and dysfunctional frontal-striatal circuits have been implicated in both disorders. Neurobiological distinctions between OCD and MDD are insufficiently clear, and comparative neuroimaging studies are extremely scarce. OCD and MDD may be characterized by cognitive rigidity at the phenotype level, and frontal-striatal brain circuits constitute the neural substrate of intact cognitive flexibility. In the present study, 18 non-medicated MDD-free patients with OCD, 19 non-medicated OCD-free patients with MDD, and 29 matched healthy controls underwent functional magnetic resonance imaging during performance of a self-paced letter/digit task switching paradigm. Results showed that both patient groups responded slower relative to controls during repeat events, but only in OCD patients slowing was associated with decreased error rates. During switching, patients with OCD showed increased activation of the putamen, anterior cingulate and insula, whereas MDD patients recruited inferior parietal cortex and precuneus to a lesser extent. Patients with OCD and MDD commonly failed to reveal anterior prefrontal cortex activation during switching. This study shows subtle behavioral abnormalities on a measure of cognitive flexibility in MDD and OCD, associated with differential frontal-striatal brain dysfunction in both disorders. These findings may add to the development of biological markers that more precisely characterize frequently co-morbid neuropsychiatric disorders such as OCD and MDD.
doi:10.1371/journal.pone.0059600
PMCID: PMC3634812  PMID: 23637737
25.  Is There a Valence-Specific Pattern in Emotional Conflict in Major Depressive Disorder? An Exploratory Psychological Study 
PLoS ONE  2012;7(2):e31983.
Objective
Patients with major depressive disorder (MDD) clinically exhibit a deficit in positive emotional processing and are often distracted by especially negative emotional stimuli. Such emotional-cognitive interference in turn hampers the cognitive abilities of patients in their ongoing task. While the psychological correlates of such emotional conflict have been well identified in healthy subjects, possible alterations of emotional conflict in depressed patients remain to be investigated. We conducted an exploratory psychological study to investigate emotional conflict in MDD. We also distinguished depression-related stimuli from negative stimuli in order to check whether the depression-related distractors will induce enhanced conflict in MDD.
Methods
A typical word-face Stroop paradigm was adopted. In order to account for valence-specificities in MDD, we included positive and general negative as well as depression-related words in the study.
Results
MDD patients demonstrated a specific pattern of emotional conflict clearly distinguishable from the healthy control group. In MDD, the positive distractor words did not significantly interrupt the processing of the negative target faces, while they did in healthy subjects. On the other hand, the depression-related distractor words induced significant emotional conflict to the positive target faces in MDD patients but not in the healthy control group.
Conclusion
Our findings demonstrated for the first time an altered valence-specific pattern in emotional conflict in MDD patients. The study sheds a novel and specific light on the affective mechanisms underlying the abnormal emotional-cognitive interference in MDD. Such emotional conflict bears important clinical relevance since it may trigger the widespread cognitive dysfunctions frequently observed in MDD. The present findings may have important clinical implications in both prediction and psychotherapy of MDD.
doi:10.1371/journal.pone.0031983
PMCID: PMC3282781  PMID: 22363782

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