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1.  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
2.  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
3.  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
4.  Abnormal hippocampal activation in patients with extensive history of major depression: an fMRI study 
Background
Impairment of recollection memory is consistently reported in patients with major depressive disorder (MDD) and may reflect underlying functional hippocampal changes, particularly in those with extensive histories of illness. We hypothesized that relative to controls, patients with a protracted course of illness would show diminished hippocampal activation on functional magnetic resonance imaging (fMRI) during a recollection memory task.
Methods
Patients who experienced 3 or more previously treated depressive episodes were compared with age- and sex-matched controls. We acquired fMRI data while participants performed a recollection memory process dissociation task.
Results
Using bilateral regions of interest (ROIs) prescribed for the right and left hippocampal/ parahippocampal complex, we observed increased activation of the right hippocampal and left parahippocampal gyrus in controls compared with patients with MDD during recollection memory trials. Within-group comparisons revealed heightened engagement of the hippocampal head (R/L) for controls during recollection trials, and greater activation of the hippocampal body/tail (R/L) during the learn-list encoding period in both the MDD and control groups. Recollection memory performance was significantly correlated with changes in blood oxygen level–dependent signal during recollection trials in the ROIs of the right hippocampus and right hippocampal head.
Limitations
This study was limited by the inclusion of patients taking antidepressant medication, raising the possibility that the reported findings were treatment effects.
Conclusion
The findings of decreased recruitment of the right hippocampal and left parahippocampal gyrus in patients with MDD suggest that these regions may be sensitive to the impact of disease burden and repeated episodes of MDD. This attenuated activation may represent stable changes in hippocampal function that occur over the course of illness in patients with MDD. The findings from within-group comparisons show that the group differences in the activation of the right hippocampal head were driven by greater engagement of this region among controls during recollection memory performance. These results also associate recollection performance impairments in patients with MDD with diminished hippocampal engagement.
doi:10.1503/jpn.110004
PMCID: PMC3244496  PMID: 21745440
5.  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
6.  Heterogeneity of Amygdala Response in Major Depressive Disorder: The Impact of Lifetime Sub-Threshold Mania 
Psychological medicine  2012;43(2):293-302.
Background
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1017/S0033291712000918
PMCID: PMC3773940  PMID: 22571805
7.  Single versus Recurrent Depression History: Differentiating risk-factors among current U.S. Smokers 
Drug and alcohol dependence  2010;109(1-3):90-95.
Introduction
The strong relationship between persistent tobacco use and Major Depressive Disorder (MDD) has motivated clinical trials of specialized treatments targeting smokers with a history of MDD. Meta-analyses suggest positive responses to specialized treatments have been observed consistently among smokers with history of recurrent rather than a single episode of MDD. Approximately 15% of current US smokers have a history of recurrent MDD. Little is known about the risk factors that contribute to persistent smoking and differentiate these at-risk smokers. US.
Methods
The National Comorbidity Survey – Replication (NCS-R) included a survey of 1560 smokers participants aged 18 and older in the United States. Lifetime history of MDD was categorized according to chronicity: No History (No MDD), single episode (MDD-S) and recurrent depression (MDD-R). The relationship between the chronicity of MDD, smoking characteristics, cessation history, nicotine dependence, comorbidity with psychiatric disorders, and current functional impairments were examined.
Results
MDD-R smokers reported fewer lifetime cessation efforts, smoked more cigarettes, had higher levels of nicotine dependence, had higher rates of co-morbid psychiatric disorders and greater functional impairment than smokers with No MDD. MDD-S smokers were not consistently distinguished from No MDD smokers on cessation attempts, level of daily smoking, nicotine dependence or functional impairment indices.
Conclusions
The study highlights the importance of chronicity when characterizing depression related risk of persistent smoking behavior. Although, clinical trials suggest MDD-R smokers specifically benefit from specialized behavioral treatments, these services are not widely available and more efforts are needed to engage MDD-R smokers in efficacious treatments. Abstract Word Count: 249
doi:10.1016/j.drugalcdep.2009.12.020
PMCID: PMC2890270  PMID: 20074868
Smoking; Depression; Recurrent Depression; Nicotine Dependence; Item
8.  Burden of Depressive Disorders by Country, Sex, Age, and Year: Findings from the Global Burden of Disease Study 2010 
PLoS Medicine  2013;10(11):e1001547.
In this paper, Ferrari and colleagues analyzed the burden of depressive disorders in GBD 2010 and identified depressive disorders as a leading cause of burden. The authors present severity proportions; burden by country, region, age, sex, and year; as well as burden of depressive disorders as a risk factor for suicide and ischemic heart disease.
Please see later in the article for the Editors' Summary
Background
Depressive disorders were a leading cause of burden in the Global Burden of Disease (GBD) 1990 and 2000 studies. Here, we analyze the burden of depressive disorders in GBD 2010 and present severity proportions, burden by country, region, age, sex, and year, as well as burden of depressive disorders as a risk factor for suicide and ischemic heart disease.
Methods and Findings
Burden was calculated for major depressive disorder (MDD) and dysthymia. A systematic review of epidemiological data was conducted. The data were pooled using a Bayesian meta-regression. Disability weights from population survey data quantified the severity of health loss from depressive disorders. These weights were used to calculate years lived with disability (YLDs) and disability adjusted life years (DALYs). Separate DALYs were estimated for suicide and ischemic heart disease attributable to depressive disorders.
Depressive disorders were the second leading cause of YLDs in 2010. MDD accounted for 8.2% (5.9%–10.8%) of global YLDs and dysthymia for 1.4% (0.9%–2.0%). Depressive disorders were a leading cause of DALYs even though no mortality was attributed to them as the underlying cause. MDD accounted for 2.5% (1.9%–3.2%) of global DALYs and dysthymia for 0.5% (0.3%–0.6%). There was more regional variation in burden for MDD than for dysthymia; with higher estimates in females, and adults of working age. Whilst burden increased by 37.5% between 1990 and 2010, this was due to population growth and ageing. MDD explained 16 million suicide DALYs and almost 4 million ischemic heart disease DALYs. This attributable burden would increase the overall burden of depressive disorders from 3.0% (2.2%–3.8%) to 3.8% (3.0%–4.7%) of global DALYs.
Conclusions
GBD 2010 identified depressive disorders as a leading cause of burden. MDD was also a contributor of burden allocated to suicide and ischemic heart disease. These findings emphasize the importance of including depressive disorders as a public-health priority and implementing cost-effective interventions to reduce its burden.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Depressive disorders are common mental disorders that occur in people of all ages across all world regions. Depression—an overwhelming feeling of sadness and hopelessness that can last for months or years—can make people feel that life is no longer worth living. People affected by depression lose interest in the activities they used to enjoy and can also be affected by physical symptoms such as disturbed sleep. Major depressive disorder (MDD, also known as clinical depression) is an episodic disorder with a chronic (long-term) outcome and increased risk of death. It involves at least one major depressive episode in which the affected individual experiences a depressed mood almost all day, every day for at least 2 weeks. Dysthymia is a milder, chronic form of depression that lasts for at least 2 years. People with dysthymia are often described as constantly unhappy. Both these subtypes of depression (and others such as that experienced in bipolar disorder) can be treated with antidepressant drugs and with talking therapies.
Why Was This Study Done?
Depressive disorders were a leading cause of disease burden in the 1990 and 2000 Global Burden of Disease (GBD) studies, collaborative scientific efforts that quantify the health loss attributable to diseases and injuries in terms of disability adjusted life years (DALYs; one DALY represents the loss of a healthy year of life). DALYs are calculated by adding together the years of life lived with a disability (YLD, a measure that includes a disability weight factor reflecting disease severity) and the years of life lost because of disorder-specific premature death. The GBD initiative aims to provide data that can be used to improve public-health policy. Thus, knowing that depressive disorders are a leading cause of disease burden worldwide has helped to prioritize depressive disorders in global public-health agendas. Here, the researchers analyze the burden of MDD and dysthymia in GBD 2010 by country, region, age, and sex, and calculate the burden of suicide and ischemic heart disease attributable to depressive disorders (depression is a risk factor for suicide and ischemic heart disease). GBD 2010 is broader in scope than previous GBD studies and quantifies the direct burden of 291 diseases and injuries and the burden attributable to 67 risk factors across 187 countries.
What Did the Researchers Do and Find?
The researchers collected data on the prevalence, incidence, remission rates, and duration of MDD and dysthymia and on the excess deaths caused by these disorders from published articles. They pooled these data using a statistical method called Bayesian meta-regression and calculated YLDs for MDD and dysthymia using disability weights collected in population surveys. MDD accounted for 8.2% of global YLDs in 2010, making it the second leading cause of YLDs. Dysthymia accounted for 1.4% of global YLDs. MDD and dysthymia were also leading causes of DALYs, accounting for 2.5% and 0.5% of global DALYs, respectively. The regional variation in the burden was greater for MDD than for dysthymia, the burden of depressive disorders was higher in women than men, the largest proportion of YLDs from depressive disorders occurred among adults of working age, and the global burden of depressive disorders increased by 37.5% between 1990 and 2010 because of population growth and ageing. Finally, MDD explained an additional 16 million DALYs and 4 million DALYs when it was considered as a risk factor for suicide and ischemic heart disease, respectively. This “attributable” burden increased the overall burden of depressive disorders to 3.8% of global DALYs.
What Do These Findings Mean?
These findings update and extend the information available from GBD 1990 and 2000 on the global burden of depressive disorders. They confirm that depressive disorders are a leading direct cause of the global disease burden and show that MDD also contributes to the burden allocated to suicide and ischemic heart disease. The estimates of the global burden of depressive disorders reported in GBD 2010 are likely to be more accurate than those in previous GBD studies but are limited by factors such as the sparseness of data on depressive disorders from developing countries and the validity of the disability weights used to calculate YLDs. Even so, these findings reinforce the importance of treating depressive disorders as a public-health priority and of implementing cost-effective interventions to reduce their ubiquitous burden.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001547.
The US National Institute of Mental Health provides information on all aspects of depression
The UK National Health Service Choices website also provides detailed information about depression and includes personal stories about depression
More personal stories about depression are available from healthtalkonline.org
MedlinePlus provides links to other resources about depression (in English and Spanish)
The World Health Organization provides information on depression and on the global burden of disease (in several languages)
Information about the Global Burden of Disease initiative is available
beyondblue provides many resources on depression
The Queensland Centre for Mental Health Research provides information on epidemiology and the global burden of disease specifically for mental disorders
doi:10.1371/journal.pmed.1001547
PMCID: PMC3818162  PMID: 24223526
9.  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
10.  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.
doi:10.1038/npp.2012.252
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
11.  Frontal and Limbic Activation During Inhibitory Control Predicts Treatment Response in Major Depressive Disorder 
Biological psychiatry  2007;62(11):1272-1280.
Background
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.
Methods:
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.
Results:
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.
Conclusions:
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.
doi:10.1016/j.biopsych.2007.02.019
PMCID: PMC2860742  PMID: 17585888
Depression; executive functioning; fMRI; imaging; inhibitory control; mood disorders; SSRIs; treatment response
12.  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.
Background
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.
Objective
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).
Method
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).
Results
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.
Conclusions
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.
doi:10.3402/ejpt.v4i0.19979
PMCID: PMC3644057  PMID: 23671761
neuropsychology; cognitive functioning; PTSD; major depressive disorder; comorbidity
13.  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
14.  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.
doi:10.1590/S0100-879X2012007500098
PMCID: PMC3854319  PMID: 22714812
Memory; Bipolar disorder; Depression; Affect
15.  Potential of Pretreatment Neural Activity in the Visual Cortex During Emotional Processing to Predict Treatment Response to Scopolamine in Major Depressive Disorder 
JAMA psychiatry (Chicago, Ill.)  2013;70(3):280-290.
Context
The need for improved treatment options for patients with major depressive disorder (MDD) is critical. Faster-acting antidepressants and biomarkers that predict clinical response will facilitate treatment. Scopolamine produces rapid antidepressant effects and thus offers the opportunity to characterize potential biomarkers of treatment response within short periods.
Objective
To determine if baseline brain activity when processing emotional information can predict treatment response to scopolamine in MDD.
Design
A double-blind, placebo-controlled, crossover study together with repeated functional magnetic resonance imaging, acquired as participants performed face-identity and face-emotion working memory tasks.
Setting
National Institute of Mental Health Division of Intramural Research Programs.
Participants
Fifteen currently depressed outpatients meeting DSM-IV criteria for recurrent MDD and 21 healthy participants, between 18 and 55 years of age.
Main Outcome Measure
The magnitude of treatment response to scopolamine (percentage of change in the Montgomery-Asberg Depression Rating Scale score between study end and baseline) was correlated with blood oxygen level–dependent (BOLD) signal associated with each working memory component (encode, maintenance, and test) for both identity and emotion tasks. Treatment response also was correlated with change in BOLD response (scopolamine vs baseline). Baseline activity was compared between healthy and MDD groups.
Results
Baseline BOLD response in the bilateral middle occipital cortex, selectively during the stimulus-processing components of the emotion working memory task (no correlation during the identity task), correlated with treatment response magnitude. Change in BOLD response following scopolamine administration in overlapping areas in the middle occipital cortex while performing the same task conditions also correlated with clinical response. Healthy controls showed higher activity in the same visual regions than patients with MDD during baseline.
Conclusion
These results implicate cholinergic and visual processing dysfunction in the pathophysiology of MDD and suggest that neural response in the visual cortex, selectively to emotional stimuli, may provide a useful biomarker for identifying patients who will respond favorably to scopolamine.
Trial Registration
clinicaltrials.gov Identifier: NCT00055575
doi:10.1001/2013.jamapsychiatry.60
PMCID: PMC3717361  PMID: 23364679
16.  Characteristics of subjects with comorbidity of symptoms of generalized anxiety and major depressive disorders and the corresponding threshold and subthreshold conditions in an Arab general population sample 
Summary
Background
There is controversy about differential meaningfulness between comorbid generalized anxiety disorder (GAD)/ major depressive disorder (MDD), the corresponding “pure” disorders and subthreshold conditions. We compared subjects who met DSM-IVTR criteria of symptoms and functional impairment for comorbid GAD/MDD, versus those with GAD, MDD, subthreshold conditions, and without significant symptoms. The comparison measures were socio-demographics, clinical severity, and quality of life (QOL).
Material/Methods
Participants (N=3155: 55.1% female, aged 16–87 yrs) were a general population sample of Kuwaitis who self-completed DSM-IVTR criteria-based questionnaires and the WHOQOL-BREF in 2006/7. We scrutinized the questionnaires and classified them into categories.
Results
Of the 273 GAD and 210 MDD cases, the prevalence of comorbidity among cases with GAD was 30.8%, and 40% among MDD. Of the 398 subthreshold GAD and 194 subthreshold MDD cases, 58 had subthreshold anxiety/depression comorbidity. Comorbid threshold GAD/MDD cases were significantly older, and more likely to be women, divorced and unemployed, compared with GAD and MDD. In all measures, the threshold GAD/MDD comorbidity was the severest condition. There was a monotonic decrease in QOL with increasing anxiety-depression symptoms. For the predictors of subjective QOL, the GAD/MDD comorbidity group differed markedly from the others.
Conclusions
The high prevalence of comorbidity and subthreshold conditions supports the recommendation to assess them routinely, regardless of the primary reason for consultation. Our findings support a dimensional model with comorbid GAD/MDD at the higher end of a continuum, and differing from the “pure” conditions by a later onset and predictors of subjective wellbeing.
doi:10.12659/MSM.882521
PMCID: PMC3560754  PMID: 22367127
comorbidity; anxiety; depression; subthreshold
17.  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.
doi:10.1016/j.neuropsychologia.2008.05.028
PMCID: PMC2538441  PMID: 18577391
Depression; Action Monitoring; Anterior Cingulate Cortex; Dorsolateral Prefrontal Cortex; Cognitive Control; Executive Function
18.  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.
doi:10.1007/s00406-010-0165-3
PMCID: PMC3071944  PMID: 21063718
Major depression; Neurocognition; Cognitive endophenotype; Psychosis; Brain imaging
19.  Neurocognitive impairment in adolescent major depressive disorder: State vs. trait illness markers 
Journal of affective disorders  2011;133(3):625-632.
Background
Current treatment outcomes of Major Depressive Disorder (MDD) in adolescents remain suboptimal. Discriminating between state and trait markers of MDD in adolescents would help identify markers that may guide choice of appropriate interventions and help improve longer-term outcome for individuals with the illness.
Methods
We compared neurocognitive performance in executive function, sustained attention and short-term memory in 20 adolescents with MDD in acute episode (MDDa), 20 previously depressed adolescents in remission (MDDr) and 17 healthy control participants (HC).
Results
There was a group difference that emerged for executive function with increasing task difficulty (p = 0.033). MDDa showed impaired executive function, as measured by using more moves to solve 4-move problems on a forward planning task, relative to MDDr and HC (p = 0.01, d = 0.94 and p = 0.015, d = 0.77 respectively). MDDa showed more impulsivity as measured by lower response bias (B″) on a sustained attention task than both MDDr and HC (p = 0.01, d = 0.85 and p = 0.008, d = 0.49 respectively). Higher impulsivity was associated with more severe depression (r = −0.365, p = 0.022) and earlier age of onset of depression (r = 0.402, p = 0.012) and there was a trend for a correlation between more executive dysfunction and more severe depression (r = 0.301 p = 0.059) in MDDa and MDDr combined. The three groups did not differ significantly on short-term memory or target detection on the sustained attention task.
Limitation
These results need to be replicated in the future with a larger sample size.
Conclusion
Executive dysfunction and impulsivity appear to be state-specific markers of MDD in adolescents that are related to depression severity and not present in remission.
doi:10.1016/j.jad.2011.04.041
PMCID: PMC4119611  PMID: 21620477
Depression; Adolescent; Neurocognition; Executive function; Impulsivity
20.  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
21.  RIGHT ANTERIOR INSULA HYPOACTIVITY DURING ANTICIPATION OF HOMEOSTATIC SHIFTS IN MAJOR DEPRESSIVE DISORDER 
Psychosomatic medicine  2010;72(3):316-323.
Objective
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1097/PSY.0b013e3181d07873
PMCID: PMC2884370  PMID: 20100882
Homeostatsis; emotion; interoception; fmri; emotional allodynia; heat; pain
22.  Reduced Caudate and Nucleus Accumbens Response to Rewards in Unmedicated Subjects with Major Depressive Disorder 
The American journal of psychiatry  2009;166(6):702-710.
Objective
Major depressive disorder (MDD) is characterized by impaired reward processing, possibly due to dysfunction in the basal ganglia. However, few neuroimaging studies of depression have distinguished between anticipatory and consummatory phases of reward processing. Using functional magnetic resonance imaging (fMRI) and a task that dissociates anticipatory and consummatory phases of reward processing, the authors tested the hypothesis that MDD participants would show reduced reward-related responses in basal ganglia structures.
Method
A monetary incentive delay task was presented to 30 unmedicated MDD subjects and 31 healthy comparison subjects during fMRI scanning. Whole-brain analyses focused on neural responses to reward-predicting cues and rewarding outcomes (i.e., monetary gains). Secondary analyses focused on the relationship between anhedonic symptoms and basal ganglia volumes.
Results
Relative to comparison subjects, MDD participants showed significantly weaker responses to gains in the left nucleus accumbens and bilateral caudate. Group differences in these regions were specific to rewarding outcomes and did not generalize to neutral or negative outcomes, although relatively reduced responses to monetary penalties in MDD emerged in other caudate regions. By contrast, evidence for group differences during reward anticipation was weaker, although MDD subjects showed reduced activation to reward cues in a small sector of the left posterior putamen. Among MDD subjects, anhedonic symptoms and depression severity were associated with reduced bilateral caudate volume.
Conclusions
These results indicate that basal ganglia dysfunction in MDD may affect the consummatory phase of reward processing. Additionally, morphometric results suggest that anhedonia in MDD is related to caudate volume.
doi:10.1176/appi.ajp.2008.08081201
PMCID: PMC2735451  PMID: 19411368
23.  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
24.  Recruitment of the left hemispheric emotional attention neural network in risk for and protection from depression 
Background
Family history of major depressive disorder (MDD) increases individuals’ vulnerability to depression and alters the way depression manifests itself. Emotion processing and attention shifting are functions altered by MDD and family history of the disease; therefore, it is important to recognize the neural correlates of these functions in association with both factors.
Methods
Our study determines neural correlates of emotion processing and attention shifting for healthy individuals and patients with MDD with and without family history of depression. We compared the performance and neural activity in a functional magnetic resonance imaging experiment examining emotion processing and attention shifting in all participants.
Results
Our sample included 4 study groups: healthy controls without family history of depression (n = 25), patients with MDD without family history of the disease (n = 20), unaffected healthy first-degree relatives of patients with MDD (n = 21) and patients with MDD with family history of MDD (n = 30). Compared with healthy controls, unaffected first-degree relatives overactivate the somatosensory cortex and the attention controlling areas during both emotion processing and attention shifting. Patients with family history of MDD have stronger neural activation in subcortical areas during shifting attention from negative stimuli. Patients without family history of MDD have less activation in the paralimbic regions and more activation in core limbic areas, especially during emotion processing.
Limitations
The conclusions about the intergroup differences in activation can be drawn only about neural areas engaged in the task.
Conclusion
Unaffected first-degree relatives of patients with MDD overreact to external emotional cues and compensate for the vulnerability with increased involvement of executive control. Patients with a family history of MDD have less executive control over their attentional shifts in the face of negative stimuli. Patients without a family history of MDD process emotional stimuli in a more visceral way than controls.
doi:10.1503/jpn.110188
PMCID: PMC3581592  PMID: 23010257
25.  Neurocognitive Effects of Repetitive Transcranial Magnetic Stimulation in Adolescents with Major Depressive Disorder 
Objectives: It is estimated that 30–40% of adolescents with major depressive disorder (MDD) do not receive full benefit from current antidepressant therapies. Repetitive transcranial magnetic stimulation (rTMS) is a novel therapy approved by the US Food and Drug Administration to treat adults with MDD. Research suggests rTMS is not associated with adverse neurocognitive effects in adult populations; however, there is no documentation of its neurocognitive effects in adolescents. This is a secondary post hoc analysis of neurocognitive outcome in adolescents who were treated with open-label rTMS in two separate studies.
Methods: Eighteen patients (mean age, 16.2 ± 1.1 years; 11 females, 7 males) with MDD who failed to adequately respond to at least one antidepressant agent were enrolled in the study. Fourteen patients completed all 30 rTMS treatments (5 days/week, 120% of motor threshold, 10 Hz, 3,000 stimulations per session) applied to the left dorsolateral prefrontal cortex. Depression was rated using the Children’s Depression Rating Scale-Revised. Neurocognitive evaluation was performed at baseline and after completion of 30 rTMS treatments with the Children’s Auditory Verbal Learning Test (CAVLT) and Delis–Kaplan Executive Function System Trail Making Test.
Results: Over the course of 30 rTMS treatments, adolescents showed a substantial decrease in depression severity. Commensurate with improvement in depressive symptoms was a statistically significant improvement in memory and delayed verbal recall. Other learning and memory indices and executive function remained intact. Neither participants nor their family members reported clinically meaningful changes in neurocognitive function.
Conclusion: These preliminary findings suggest rTMS does not adversely impact neurocognitive functioning in adolescents and may provide subtle enhancement of verbal memory as measured by the CAVLT. Further controlled investigations with larger sample sizes and rigorous trial designs are warranted to confirm and extend these findings.
doi:10.3389/fpsyt.2013.00165
PMCID: PMC3859914  PMID: 24376426
adolescents; depression; neurocognition; memory; learning; TMS

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