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1.  Frontal and Limbic Activation During Inhibitory Control Predicts Treatment Response in Major Depressive Disorder 
Biological psychiatry  2007;62(11):1272-1280.
Inhibitory control or regulatory difficulties have been explored in major depressive disorder (MDD) but typically in the context of affectively salient information. Inhibitory control is addressed specifically by using a task devoid of affectively-laden stimuli, to disentangle the effects of altered affect and altered inhibitory processes in MDD.
Twenty MDD and 22 control volunteer participants matched by age and gender completed a contextual inhibitory control task, the Parametric Go/No-go (PGNG) task during functional magnetic resonance imaging. The PGNG includes three levels of difficulty, a typical continuous performance task and two progressively more difficult versions including Go/No-go hit and rejection trials. After this test, 15 of 20 MDD patients completed a full 10-week treatment with s-citalopram.
There was a significant interaction among response time (control subjects better), hits (control subjects better), and rejections (patients better). The MDD participants had greater activation compared with the control group in frontal and anterior temporal areas during correct rejections (inhibition). Activation during successful inhibitory events in bilateral inferior frontal and left amygdala, insula, and nucleus accumbens and during unsuccessful inhibition (commission errors) in rostral anterior cingulate predicted post-treatment improvement in depression symptoms.
The imaging findings suggest that in MDD subjects, greater neural activation in frontal, limbic, and temporal regions during correct rejection of lures is necessary to achieve behavioral performance equivalent to control subjects. Greater activation in similar regions was further predictive of better treatment response in MDD.
PMCID: PMC2860742  PMID: 17585888
Depression; executive functioning; fMRI; imaging; inhibitory control; mood disorders; SSRIs; treatment response
2.  The role of major depression in neurocognitive functioning in patients with posttraumatic stress disorder 
European Journal of Psychotraumatology  2013;4:10.3402/ejpt.v4i0.19979.
Posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) frequently co-occur after traumatic experiences and share neurocognitive disturbances in verbal memory and executive functioning. However, few attempts have been made to systematically assess the role of a comorbid MDD diagnosis in neuropsychological studies in PTSD.
The purpose of the current study is to investigate neurocognitive deficits in PTSD patients with and without MDD. We hypothesized that PTSD patients with comorbid MDD (PTSD+MDD) would have significantly lower performance on measures of verbal memory and executive functioning than PTSD patients without MDD (PTSD–MDD).
Participants included in this study were 140 treatment-seeking outpatients who had a diagnosis of PTSD after various single traumatic events and participated in a randomized controlled trial comparing different treatment types. Baseline neuropsychological data were compared between patients with PTSD+MDD (n=84) and patients with PTSD–MDD (n=56).
The PTSD+MDD patients had more severe verbal memory deficits in learning and retrieving words than patients with PTSD alone. There were no differences between the groups in recall of a coherent paragraph, recognition, shifting of attention, and cognitive interference.
The results of this study suggest that a more impaired neurocognitive profile may be associated with the presence of comorbid MDD, with medium-sized group differences for verbal memory but not for executive functioning. From a clinical standpoint, being aware that certain verbal memory functions are more restricted in patients with comorbid PTSD and MDD may be relevant for treatment outcome of trauma-focused psychotherapy.
PMCID: PMC3644057  PMID: 23671761
neuropsychology; cognitive functioning; PTSD; major depressive disorder; comorbidity
3.  Using Standardized fMRI Protocols to Identify Patterns of Prefrontal Circuit Dysregulation that are Common and Specific to Cognitive and Emotional Tasks in Major Depressive Disorder: First Wave Results from the iSPOT-D Study 
Neuropsychopharmacology  2013;38(5):863-871.
Functional neuroimaging studies have implicated dysregulation of prefrontal circuits in major depressive disorder (MDD), and these circuits are a viable target for predicting treatment outcomes. However, because of the heterogeneity of tasks and samples used in studies to date, it is unclear whether the central dysfunction is one of prefrontal hyperreactivity or hyporeactivity. We used a standardized battery of tasks and protocols for functional magnetic resonance imaging, to identify the common vs the specific prefrontal circuits engaged by these tasks in the same 30 outpatients with MDD compared with 30 matched, healthy control participants, recruited as part of the International Study to Predict Optimized Treatment in Depression (iSPOT-D). Reflecting cognitive neuroscience theory and established evidence, the battery included cognitive tasks designed to assess functions of selective attention, sustained attention-working memory and response inhibition, and emotion tasks to assess explicit conscious and implicit nonconscious viewing of facial emotion. MDD participants were distinguished by a distinctive biosignature of: hypoactivation of the dorsolateral prefrontal cortex during working memory updating and during conscious negative emotion processing; hyperactivation of the dorsomedial prefrontal cortex during working memory and response inhibition cognitive tasks and hypoactivation of the dorsomedial prefrontal during conscious processing of positive emotion. These results show that the use of standardized tasks in the same participants provides a way to tease out prefrontal circuitry dysfunction related to cognitive and emotional functions, and not to methodological or sample variations. These findings provide the frame of reference for identifying prefrontal biomarker predictors of treatment outcomes in MDD.
PMCID: PMC3671994  PMID: 23303059
Biological Psychiatry; biomarker; clinical Pharmacology/clinical trials; depression; unipolar/bipolar; functional MRI; Imaging; clinical or Preclinical; iSPOT-D; prefrontal cortex; standardized cognitive and emotion task protocols; not open access; functional MRI; prefrontal cortex; major depressive disorder; biomarker; standardized cognitive and emotion task protocols; iSPOT-D
4.  Reward Processing After Catecholamine Depletion in Unmedicated, Remitted Subjects with Major Depressive Disorder 
Biological psychiatry  2009;66(3):201-205.
We investigated whether performance on a reward processing task differs between fully remitted patients with major depressive disorder (MDD) and healthy control subjects after catecholamine depletion.
Seventeen unmedicated subjects with remitted MDD (RMDD) and 13 healthy control subjects underwent catecholamine depletion with oral α-methyl-para-tyrosine (AMPT) in a randomized, placebo-controlled, double-blind crossover study. The main outcome measure was the reaction time on the monetary incentive delay (MID) task.
A diagnosis × drug interaction was evident (p = .001), which was attributable to an increase in reaction time across all incentive levels after AMPT in RMDD subjects (p = .001) but no significant AMPT effect on reaction time in control subjects (p = .17). There was no drug × diagnosis interaction on control tasks involving working memory or attention. In the RMDD sample the AMPT-induced depressive symptoms correlated with AMPT-induced changes in reaction time at all incentive levels of the MID task (r values = .58 –.82, p < .002).
Under catecholamine depletion the RMDD subjects were robustly differentiated from control subjects by development of performance deficits on a reward processing task. These performance deficits correlated directly with the return of depressive symptoms after AMPT administration. The sensitivity of central reward processing systems to reductions in brain catecholamine levels thus seems to represent a trait-like marker in MDD.
PMCID: PMC3073352  PMID: 19393989
Anhedonia; dopamine; major depressive disorder; monetary incentive delay task; norepinephrine; reward
5.  Relationship of Asymmetrical Dimethylarginine, Nitric Oxide, and Sustained Attention during Attack in Patients with Major Depressive Disorder 
The Scientific World Journal  2014;2014:624395.
We investigated the relationship of serum nitric oxide (NO) and asymmetrical dimethylarginine (ADMA) levels with cognitive functioning in patients with major depressive disorder (MDD). 41 MDD patients (Beck depression scale scores >16) and 44 controls were included in the study. Rey verbal learning and memory test, auditory consonant trigram test, digit span test, Wisconsin card sorting test, continuous performance task (TOVA), and Stroop test scores were found to be impaired in patients with major depressive disorder when compared to healthy controls. There was no significant difference between patient and control groups in terms of serum NO and ADMA. Serum NO levels were correlated with TOVA test error scores and Stroop test time scores, whereas serum ADMA levels were negatively correlated with TOVA test error scores. Metabolic detriments especially in relation to NO metabolism in frontal cortex and hypothalamus, psychomotor retardation, or loss of motivation may explain these deficits.
PMCID: PMC3914576  PMID: 24558318
6.  Memory mood congruency phenomenon in bipolar I disorder and major depression disorder patients 
The objective of the present study was to evaluate memory performance in tasks with and without affective content (to confirm the mood congruency phenomenon) in acutely admitted patients with bipolar I disorder (BD) and major depression disorder (MDD) and in healthy participants. Seventy-eight participants (24 BD, 29 MDD, and 25 healthy controls) were evaluated. Three word lists were used as the memory task with affective content (positive, negative and indifferent). Psychiatric symptoms were also evaluated with rating scales (Young Mania Rating Scale for mania and Hamilton Depression Rating Scale for depression). Patients were selected during the first week of hospitalization. BD patients showed higher scores in the word span with positive tone than MDD patients and healthy controls (P = 0.002). No other difference was observed for tests with affective tone. MDD patients presented significantly lower scores in the Mini-Mental State Exam, logical memory test, visual recognition span, and digit span, while BD patients presented lower scores in the visual recognition test and digit span. Mood congruency effect was found for word span with positive tone among BD patients but no similar effect was observed among MDD patients for negative items. MDD patients presented more memory impairment than BD patients, but BD patients also showed memory impairment.
PMCID: PMC3854319  PMID: 22714812
Memory; Bipolar disorder; Depression; Affect
7.  Functional Anatomy of Autobiographical Memory Recall Deficits in Depression 
Psychological medicine  2011;42(2):345-357.
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.
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.
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.
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.
PMCID: PMC3226869  PMID: 21798113
8.  Major Depressive Disorder, Cognitive Symptoms, and Neuropsychological Performance among Ethnically Diverse HIV+ Men and Women 
Major depressive disorder (MDD), cognitive symptoms, and mild cognitive deficits commonly occur in HIV-infected individuals, despite highly active antiretroviral therapies. In this study, we compared neuropsychological performance and cognitive symptoms of 191 HIV-infected participants. Results indicated that participants with a formal diagnosis of current MDD performed significantly worse than participants without MDD in all seven neuropsychological domains evaluated, with the largest effect sizes in information processing speed, learning, and memory. In addition, a brief assessment of cognitive symptoms, derived from a comprehensive neuromedical interview, correlated significantly with neurocognitive functioning. Participants with MDD reported more cognitive symptoms and showed greater neurocognitive deficits than participants without MDD. These findings indicate that HIV-infected adults with MDD have more cognitive symptoms and worse neuropsychological performance than HIV-infected individuals without MDD. The results of this study have important implications for the diagnosis of HIV-associated neurocognitive disorders (HAND).
PMCID: PMC3785228  PMID: 23290446
Depression; Cognition; Cognitive complaints; Neuropsychological tests; Acquired immunodeficiency syndrome; Mood disorders
9.  Functional anatomy of autobiographical memory recall deficits in depression 
Psychological Medicine  2011;42(2):345-357.
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.
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.
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.
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.
PMCID: PMC3226869  PMID: 21798113
Anterior insula; autobiographical memory; depression; fMRI; hippocampus
10.  Cognitive Control Functions in Unipolar Major Depression with and without Co-Morbid Anxiety Disorder 
Background: Impaired cognitive control functions have been demonstrated in both major depression (MDD) and anxiety disorder (A), but few studies have systematically examined the impact of MDD with co-morbid A (MDDA), which is the main aim of this study. Method: We compared patients with MDD with (MDDA; n = 24) and without co-morbid A (n = 37) to a group of healthy controls (HC; n = 92) on three subtests from the Cambridge Neuropsychological Test Automated Battery; intra–extra dimensional, stop signal task, and spatial working memory. These tasks correspond to a theoretical model consisting of three separable but interrelated executive control functions: Shifting, Inhibition, and Updating. A simple psychomotor speed measure was also included. Results: After controlling for age, gender, and education level, the results showed that the MDDA group displayed significantly impaired performance on the functions Shifting and Updating compared to HC. There emerged no significant differences between any of the patient groups and HC regarding Inhibition. The pure MDD group did not display dysfunctions relative to the HC group on the main executive control variables, but displayed slowed psychomotor speed. Contrary to expectation there were no significant differences between the MDDA and the MDD groups. Conclusion: Co-morbid anxiety should be taken into account when studying cognitive control functions in major depression.
PMCID: PMC3059619  PMID: 21423456
unipolar major depression; co-morbid anxiety disorder; cognitive control functions; CANTAB
11.  Effects of Task-Relevant Incentives on the Electrophysiological Correlates of Error Processing in Major Depressive Disorder 
Major depressive disorder (MDD) is associated with action monitoring dysfunction, particularly disrupted error processing. Whether such dysregulation is further modulated by task incentives is largely unknown. The goal of this study was to investigate possible dysfunctions in error processing in MDD as a function of varying task incentives and clinical profile. To this end, we recorded the error-related negativity (ERN) and error positivity (Pe) in 18 MDD subjects and 18 healthy controls during a Stroop task that intermixed no-incentive and reward trials. Relative to controls, MDD subjects showed (1) larger ERN irrespective of task incentives, and (2) reduced Pe during reward (but not no-incentive) trials. Moreover, among MDD subjects, Pe amplitudes were negatively correlated with depression severity and clinical symptoms. The present findings highlight distinct effects of task incentives on electrophysiological components of error processing and are interpreted within current theories of action monitoring and incentive processing in depression.
PMCID: PMC3036946  PMID: 20233960
ERN; Pe; Depression; Reward; Anhedonia; Action Monitoring
12.  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.
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.
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.
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.
Not all MDD subjects were antidepressant-naïve.
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.
PMCID: PMC3501555  PMID: 22995943
Stroop task; functional magnetic resonance imaging; depression; executive function; incongruency; attention
13.  Neural and behavioral effects of interference resolution in depression and rumination 
Individuals diagnosed with major depressive disorder (MDD) often ruminate about their depression and their life situations, impairing their concentration and performance on daily tasks. We examined whether rumination might be due to a deficit in the ability to expel negative information from short-term memory (STM), and fMRI was used to examine the neural structures involved in this ability. MDD and healthy control (HC) participants were tested using a directed-forgetting procedure in a short-term item recognition task. As predicted, MDD participants had more difficulty than did HCs in expelling negative, but not positive, words from STM. Overall, the neural networks involved in directed forgetting were similar for both groups, but the MDDs exhibited more spatial variability in activation in the left inferior frontal gyrus (a region critical for inhibiting irrelevant information), which may contribute to their relative inability to inhibit negative information.
PMCID: PMC4006074  PMID: 21264648
fMRI; Interference; Depression; Short-term memory; Rumination
14.  Heterogeneity of Amygdala Response in Major Depressive Disorder: The Impact of Lifetime Sub-Threshold Mania 
Psychological medicine  2012;43(2):293-302.
Patients with major depressive disorder (MDD) present with highly heterogeneous symptom profiles. We aimed to examine whether individual differences in amygdala activity to emotionally-salient stimuli were related to heterogeneity in lifetime levels of depressive and sub-threshold manic symptoms among adults with MDD.
We compared age- and gender-matched adults with MDD (N=26) with healthy controls (HC, N=28). While undergoing fMRI, participants performed an implicit emotional faces task: they labeled a color flash superimposed upon initially neutral faces that dynamically morphed into one of four emotions (angry, fearful, sad, happy). Region of interest analyses examined group differences in amygdala activity. For conditions in which adults with MDD displayed abnormal amygdala activity versus HC, within-group analyses examined amygdala activity as a function of scores on a continuous measure of lifetime depression-related and mania-related pathology.
Adults with MDD showed significantly greater right-sided amygdala activity to angry and happy conditions than HC (p<0.05, corrected). Multiple regression analyses revealed that greater right amygdala activity to the happy condition in adults with MDD was associated with higher levels of sub-threshold manic symptoms experienced across the lifespan (p=0.002).
Among depressed adults with MDD, lifetime features of sub-threshold mania were associated with abnormally elevated amygdala activity to emerging happy faces. These findings are a first step toward identifying biomarkers that reflect individual differences in neural mechanisms in MDD, and challenge conventional mood disorder diagnostic boundaries by suggesting that some adults with MDD are characterized by pathophysiologic processes that overlap with bipolar disorder.
PMCID: PMC3773940  PMID: 22571805
Psychosomatic medicine  2010;72(3):316-323.
An intact ability to mount preparatory emotional, cognitive and bodily responses to anticipated environmental change is necessary for adaptive responding. Although abnormal insula activity during aversive anticipation has been observed in Major Depressive Disorder (MDD) individuals, the extent to which shifts in homeostatic state during anticipation affect insular activity in MDD subjects has not been reported. The aim of this study was to use functional Magnetic Resonance Imaging (fMRI) to examine how shifts in homeostatic state affect anticipatory insular activity in MDD.
Cued hot and warm stimuli were delivered while subjects either passively viewed a fixation cross or performed an attentional task during fMRI. The task was designed so that anticipatory brain activation related to the following three types of shifts could be measured: (1) anticipatory shifts in stimulus intensity, (2) anticipatory shifts in cognitive demand, (3) dual anticipatory shifts (i.e., shifts in both stimulus intensity and cognitive demand). Brain activation related to each of these three contrasts was compared between 15 (12F) unmedicated subjects with current MDD and 17 (10F) age- and education-comparable healthy control (HC) subjects.
MDD versus HC subjects showed lower right anterior insula activity related to anticipatory shifts in stimulus intensity, and altered brain activation during anticipatory shifts in cognitive demand and dual anticipatory shifts.
These results indicate that MDD individuals show altered brain responses to shifts in homeostatic state during anticipation, and may suggest that MDD is associated with an impaired ability to effectively prepare for changes in the environment.
PMCID: PMC2884370  PMID: 20100882
Homeostatsis; emotion; interoception; fmri; emotional allodynia; heat; pain
16.  Functional anomalies in healthy individuals with a first degree family history of major depressive disorder 
Individuals with major depressive disorder (MDD) process information with a bias towards negative stimuli. However, little is known on the link between vulnerability to MDD and brain functional anomalies associated with stimulus bias.
A cohort of 38 subjects, of which 14 were patients with acute MDD and 24 were healthy controls (HC), were recruited and compared. The HC group included 10 healthy participants with a first degree family history of depression (FHP) and 14 volunteers with no family history of any psychiatric disease (FHN). Blood oxygen level dependence signals were acquired from functional magnetic resonance imaging (fMRI) during performance in a dot-probe task using fearful and neutral stimuli. Reaction times and the number of errors were also obtained.
Although MDD patients and HC showed no behavioral difference, the MDD group exhibited smaller activation in the left middle cingulum. The MDD group also showed smaller activation in the left insula when compared to the HC group or the FHN group. Finally, FHP participants exhibited higher activation in the right Heschl's gyrus compared to FHN participants.
The present study shows that family risk for MDD is associated with increased activation in the Heschl's gyrus. Our results also suggest that acute MDD is linked to reduced activation in the insula and anterior cingulate cortex during processing of subliminal, not recognizable, masked fearful stimuli. Further research should confirm these results in a larger cohort of participants.
PMCID: PMC3384259  PMID: 22738278
17.  A systematic experimental neuropsychological investigation of the functional integrity of working memory circuits in major depression 
Verbal and visuospatial working memory (WM) impairment is a well-documented finding in psychiatric patients suffering from major psychoses such as schizophrenia or bipolar affective disorder. However, in major depression (MDD) the literature on the presence and the extent of WM deficits is inconsistent. The use of a multitude of different WM tasks most of which lack process-specificity may have contributed to these inconsistencies. Eighteen MDD patients and 18 healthy controls matched with regard to age, gender and education were tested using process- and circuit-specific WM tasks for which clear brain-behaviour relationships had been established in prior functional neuroimaging studies. Patients suffering from acute MDD showed a selective impairment in articulatory rehearsal of verbal information in working memory. By contrast, visuospatial WM was unimpaired in this sample. There were no significant correlations between symptom severity and WM performance. These data indicate a dysfunction of a specific verbal WM system in acutely ill patients with MDD. As the observed functional deficit did not correlate with different symptom scores, further, longitudinal studies are required to clarify whether and how this deficit is related to illness acuity and clinical state of MDD patients.
PMCID: PMC3071944  PMID: 21063718
Major depression; Neurocognition; Cognitive endophenotype; Psychosis; Brain imaging
18.  The Costs of Depression 
Brief summary
Data are reviewed on the societal costs of major depressive disorder (MDD). Early-onset MDD is found to predict difficulties in subsequent role transitions, including low educational attainment, high risk of teen child-bearing, marital disruption, and unstable employment. Among people with specific social and productive roles, MDD is found to predict significant decrements in role functioning (e.g., low marital quality, low work performance, low earnings). MDD is also associated with elevated risk of onset, persistence, and severity of a wide range of chronic physical disorders as well as with increased early mortality due to an even wider range of physical disorders and to suicide. Although effectiveness trials show that expanded MDD treatment can reverse many of these adverse effects, only a minority of people with MDD receives treatment and the quality of treatment is unacceptably low among the majority of those in treatment.
PMCID: PMC3292769  PMID: 22370487
Absenteeism; costs of illness; disability; illness burden; impairment; major depressive disorder
19.  Major Depressive Disorder is Associated with Broad Impairments on Neuropsychological Measures of Executive Function: A Meta-Analysis and Review 
Psychological bulletin  2012;139(1):81-132.
Cognitive impairments are now widely acknowledged as an important aspect of major depressive disorder (MDD), and it has been proposed that executive function (EF) may be particularly impaired in patients with MDD. However, the existence and nature of EF impairments associated with depression remain strongly debated. While many studies have found significant deficits associated with MDD on neuropsychological measures of EF, others have not, potentially due to low statistical power, task impurity, and diverse patient samples, and there have been no recent, comprehensive, meta-analyses investigating EF in patients with MDD. The current meta-analysis uses random effects models to synthesize 113 previous research studies that compared participants with MDD to healthy control participants on at least one neuropsychological measure of EF. Results of the meta-analysis demonstrate that MDD is reliably associated with impaired performance on neuropsychological measures of EF, with effect sizes ranging from d = 0.32–0.97. While patients with MDD also have slower processing speed, motor slowing alone cannot account for these results. In addition, some evidence suggests that deficits on neuropsychological measures of EF are greater in patients with more severe current depression symptoms, and those taking psychotropic medications, while evidence for effects of age was weaker. The results are consistent with the theory that MDD is associated with broad impairment in multiple aspects of EF. Implications for treatment of MDD and theories of EF are discussed. Future research is needed to establish the specificity and causal link between MDD and EF impairments.
PMCID: PMC3436964  PMID: 22642228
executive function; major depressive disorder; meta-analysis
20.  Effort-Based Decision-Making in Major Depressive Disorder: A Translational Model of Motivational Anhedonia 
Journal of abnormal psychology  2012;121(3):553-558.
Anhedonia is a core feature of major depressive disorder (MDD), but the precise nature of anhedonic symptoms is unknown. While anhedonia has traditionally been viewed as a deficit in the experience of pleasure, more recent evidence suggests that reduced anticipation and motivation may also be a core feature of this symptom. Here, we provide data from a study in MDD patients and healthy controls using a translational measure of reward motivation, the Effort Expenditure for Rewards Task (EEfRT or “effort”). This task offers subjects a series of trials where they may choose to expend more or less effort for the opportunity to win varying amounts of monetary rewards. We found that MDD patients were less willing to expend effort for rewards than controls. Additionally, we observed that patients were less able to effectively use reward information about magnitude and probability of rewards to guide their choice behavior. Finally, within the MDD patient group, duration of the current episode was a significant negative predictor of EEfRT task performance. These findings offer novel support for theoretical models proposing that anhedonia in MDD may reflect specific impairments in motivation and reward-based decision-making.
PMCID: PMC3730492  PMID: 22775583
21.  The effects of tryptophan depletion on neural responses to emotional words in remitted depression 
Biological psychiatry  2009;66(5):441-450.
Major depressive disorder (MDD) has been associated with both dysfunction of the central serotonergic system and abnormal responses to emotional stimuli. We used acute tryptophan depletion (ATD) to investigate the effect of temporarily reducing brain serotonin synthesis on neural and behavioural responses to emotional stimuli in remitted MDD subjects (rMDD) and healthy controls.
Twenty controls and 23 rMDD subjects who had been unmedicated and in remission for ≥3 months completed the study. Following tryptophan or sham depletion, participants performed an emotional-processing task during functional magnetic resonance imaging. In addition, resting-state regional blood-flow was measured using arterial spin labelling.
Neither group exhibited significant mood-change following ATD. However, tryptophan depletion differentially affected the groups in terms of hemodynamic responses to emotional words in a number of structures implicated in the pathophysiology of MDD, including medial thalamus and caudate. These interactions were driven by increased responses to emotional words in the controls, with little effect in the patients under the ATD condition. Following ATD, habenula blood-flow increased significantly in the rMDD subjects relative to the controls, and increasing amygdala blood-flow was associated with more negative emotional bias score across both groups.
These data provide evidence for elevated habenula blood-flow and alterations in the neural processing of emotional stimuli following ATD in rMDD subjects, even in the absence of overt mood-change. However, further studies are required to determine whether these findings represent mechanisms of resilience or vulnerability to MDD.
PMCID: PMC2745906  PMID: 19539268
Depression; Serotonin; Acute Tryptophan Depletion; Functional Magnetic Resonance Imaging (fMRI); Emotional Processing; Affective Go/No-go (AGNG)
22.  Major Depression and Risky Sexual Behavior among Substance Dependent Patients: The Moderating Roles of Distress Tolerance and Gender 
Cognitive therapy and research  2013;37(3):483-497.
The goal of the present study was to examine the main and interactive effects of major depressive disorder (MDD), distress tolerance (DT), and gender on multiple indices of risky sexual behavior (RSB) within a sample of 185 substance dependent patients in residential substance abuse treatment. Participants were interviewed to establish current MDD (as well as other Axis I and II diagnoses) and completed a behavioral measure of DT, the Paced Auditory Serial Addition Task – Computerized Version. Results provided evidence of a MDD × DT interaction for number of different past year commercial and casual sexual partners with which penetrative sex occurred. Post-hoc analyses demonstrated that participants with current MDD and low DT reported the greatest number of commercial and casual sexual partners. Results highlight one psychological vulnerability (DT) that may improve our understanding of the complex relationship between depression and RSB. Treatment implications of findings are discussed.
PMCID: PMC3953030  PMID: 24634552
Emotion Dysregulation; Mood Disorders; Risk-Taking; Sexual Risk-Taking; Substance Use Disorders
23.  Major Depressive Disorder is Associated with Attenuated Cardiovascular Reactivity and Impaired Recovery among Those Free of Cardiovascular Disease 
To examine cardiovascular reactivity and recovery to laboratory stress among a naturalistic sample of individuals diagnosed with major depressive disorder (MDD) and healthy control participants. Prospective evidence suggests that MDD confers risk for cardiovascular disease equal to or greater than the risk associated with depressed mood. Enhanced cardiovascular reactivity has been proposed as a mechanism explaining increased risk, but data are inconsistent as to whether depressed individuals exhibit enhanced or attenuated reactivity. Further, few studies have examined appraisal and recovery differences.
Participants diagnosed with MDD (N = 25) and healthy control participants (N = 25) engaged in a cardiovascular reactivity protocol including two tasks, each followed by a brief recovery period.
Main outcome measures
Blood pressure, heart rate, pre-ejection period, cardiac output and total peripheral resistance were assessed. Appraisals of tasks were assessed prior to each task.
Depressed participants exhibited significantly less systolic blood pressure, heart rate and cardiac output reactivity during speech, less heart rate reactivity during mirror tracing and less heart rate recovery after speech and mirror tracing than controls. Depressed participants appraised the tasks as more demanding, threatening, and stressful and reported being less able to cope than controls. Appraisals were related to heart rate reactivity, but appraisals did not mediate the relationship between depression group and reactivity.
Impaired recovery rather than exaggerated cardiovascular reactivity may partially explain the increased prospective cardiovascular disease risk in depressed individuals.
PMCID: PMC2657932  PMID: 19290707
Depression; cardiovascular reactivity; recovery; cognitive appraisals
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.
PMCID: PMC3634812  PMID: 23637737
25.  Response conflict and frontocingulate dysfunction in unmedicated participants with Major Depression 
Neuropsychologia  2008;46(12):2904-2913.
Individuals with major depressive disorder (MDD) often exhibit impaired executive function, particularly in experimental tasks that involve response conflict and require adaptive behavioral adjustments. Prior research suggests that these deficits might be due to dysfunction within frontocingulate pathways implicated in response conflict monitoring and the recruitment of cognitive control. However, the temporal unfolding of conflict monitoring impairments in MDD remains poorly understood. To address this issue, we recorded 128-channel event-related potentials while 20 unmedicated participants with MDD and 20 demographically matched, healthy controls performed a Stroop task. Compared to healthy controls, MDD subjects showed larger Stroop interference effects and reduced N2 and N450 amplitudes. Source localization analyses at the time of maximal N450 activity revealed that MDD subjects had significantly reduced dorsal anterior cingulate cortex (dACC; Brodmann area 24/32) and left dorsolateral prefrontal cortex (Brodmann area 10/46) activation to incongruent relative to congruent trials. Consistent with the heterogeneous nature of depression, follow-up analyses revealed that depressed participants with the lowest level of conflict-related dACC activation 620 ms post-stimulus were characterized by the largest Stroop interference effects (relatively increased slowing and reduced accuracy for incongruent trials). Conversely, MDD participants with relatively stronger dACC recruitment did not differ from controls in terms of interference effects. These findings suggest that for some, but not all individuals, MDD is associated with impaired performance in trials involving competition among different response options, and reduced recruitment of frontocingulate pathways implicated in conflict monitoring and cognitive control.
PMCID: PMC2538441  PMID: 18577391
Depression; Action Monitoring; Anterior Cingulate Cortex; Dorsolateral Prefrontal Cortex; Cognitive Control; Executive Function

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