Function In Major Depression Research Articles

Incidental and intentional memory performance in depression and amnestic mild cognitive impairment

Incidental and intentional memory performance in depression and amnestic mild cognitive impairment

How treatment affects the brain: meta-analysis evidence of neural substrates underpinning drug therapy and psychotherapy in major depression.

The idea that modifications of affect, behavior and cognition produced by psychotherapy are mediated by biological underpinnings predates the advent of the modern neurosciences. Recently, several studies demonstrated that psychotherapy outcomes are linked to modifications in specific brain regions. This opened the debate over the similarities and dissimilarities between psychotherapy and pharmacotherapy. In this study, we used activation likelihood estimation meta-analysis to investigate the effects of psychotherapy (PsyTh) and pharmacotherapy (DrugTh) on brain functioning in Major Depression (MD). Our results demonstrate that the two therapies modify different neural circuits. Specifically, PsyTh induces selective modifications in the left inferior and superior frontal gyri, middle temporal gyrus, lingual gyrus and middle cingulate cortex, as well as in the right middle frontal gyrus and precentral gyrus. Otherwise, DrugTh selectively affected brain activation in the right insula in MD patients. These results are in line with previous evidence of the synergy between psychotherapy and pharmacotherapy but they also demonstrate that the two therapies have different neural underpinnings.

Signaling Pathways Involved in Antidepressant-Induced Cell Proliferation and Synaptic Plasticity

In the last years it has been proposed that the antidepressant action is mediated not only by changes in monoamine levels but also in association with modifications involving cell proliferation and plasticity in some brain limbic areas as hippocampus, and also frontal cortex and amygdala. This leads to the merging of the classic "monoaminergic hypothesis of depression", with the newer "neurotrophic hypothesis of depression". Here we review two important signaling pathways: the Wnt/β-catenin pathway -implicated in cellular proliferation and synaptic plasticity- that is downregulated in major depression and upregulated after antidepressant treatment; and the mTOR pathway -controling synaptic plasticity- recently related to present disrupted functioning in major depression, and as the target of some drugs with fast-acting potential antidepressant action. These pieces of evidences are confirmed in a variety of animal models of depression and are predictive of antidepressant actions. We also review the role of another two important neurotrophic factors: brain derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) that mediate the antidepressant effects. All of the above intracellular pathways interact by a crosstalk mediated by Akt, a key regulator molecule that may underlie the fine tuning between proliferative and neuroplasticity changes induced by antidepressant drugs.

EPA-0743 – Stress-gene interactions on brain structure and function in major depression

Major depressive disorder (MDD) is a complex disorder and recent research suggests that muliple genetic and environmental factors seem to underly MDD criteria as well as seem to influence brain structure and function. Aim of the study was to investigate whether epigenetic regulation and mRNA expression of glucocorticoid inducible genes (SGK-1, GILZ) are associated with structural alterations in hippocampal subfields and functional brain changes. Moreover, we investigated whether there are interactive effects between the genetic variant of the BICC1 gene and ELA. Patients with MDD and healthy controls were investigated using structural magnetic resonance imaging (MRI) and functional MRI with an emotion inhibition task. Analysis of a single nucleotide polymorphism in the BICC1-1 (rs999845) gene as well as mRNA expression and methylation of DNA was performed. Hippocampal subfield volumes of dendate gyrus and CA2 were reduced in patients with MDD. These were associated with reduced mRNA expression of glucocorticoid inducible genes and with DNA methylation. Moreover, MDD patients with a history of ELA, who carry the protective T-allele, had smaller hippocampal head volumes compared to MDD patients without ELA. FMRI showed that patients and controls carrying the protective T-allele of BICC1 activate the emotion regulation system significantly more compared to those participants homozygous for the major C-allele (p<0.05, family wise error corrected). These results are suggestive for environment x gene interactions in MDD and for the impact of epigenetic regulation on brain structure and function.

EPA-0983 – Revisiting default mode network function in major depression: evidence for disrupted subsystem connectivity

Major depressive disorder (MDD) is characterized by alterations of brain function that are identifiable also during the brain's’resting state’. One functional network that is disrupted in this disorder is the default mode network (DMN), a set of large-scale connected brain regions that oscillate with low-frequency fluctuations and are more active during rest relative to during a goal-directed task. Recent studies support the idea that the DMN is not a unitary system, but rather is composed of smaller and distinct functional subsystems that interact with each other. The functional relevance of these subsystems in depression, however, is unclear. Here, we investigate the functional connectivity of distinct DMN subsystems and their interplay in depression using resting state functional magnetic resonance imaging (rs-fMRI). We show that patients with MDD exhibit increased within-network connectivity in posterior, ventral and core DMN subsystems along with reduced interplay from the anterior to the ventral DMN subsystems. These data suggest that MDD is characterized by alterations of subsystems within the DMN as well as their interactions. Our findings highlight the critical role of DMN circuitry in the pathophysiology of MDD, thus suggesting these subsystems as potential therapeutic targets.

Electrical brain imaging reveals the expression and timing of altered error monitoring functions in major depression.

Major depressive disorder (MDD) is characterized by disturbances in affect, motivation, and cognitive control processes, including error detection. However, the expression and timing of the impairments during error monitoring remain unclear in MDD. The behavior and event-related brain responses (ERPs) of 20 patients with MDD were compared with those of 20 healthy controls (HCs), while they performed a Go/noGo task. Errors during this task were associated with 2 ERP components, the error-related negativity (ERN/Ne) and the error positivity (Pe). Results show that the ERN/Ne-correct-related negativity (CRN) amplitude difference was significantly larger in MDD patients (after controlling for speed), compared with HCs, although MDD patients exhibited overactive medial frontal cortex (MFC) activation. By comparison, the subsequent Pe component was smaller in MDD patients compared with HCs and this effect was accompanied by a reduced activation of ventral anterior cingulate cortex (ACC) regions. These results suggest that MDD has multiple cascade effects on early error monitoring brain mechanisms.

Revisiting default mode network function in major depression: evidence for disrupted subsystem connectivity

Major depressive disorder (MDD) is characterized by alterations in brain function that are identifiable also during the brain's 'resting state'. One functional network that is disrupted in this disorder is the default mode network (DMN), a set of large-scale connected brain regions that oscillate with low-frequency fluctuations and are more active during rest relative to a goal-directed task. Recent studies support the idea that the DMN is not a unitary system, but rather is composed of smaller and distinct functional subsystems that interact with each other. The functional relevance of these subsystems in depression, however, is unclear. Here, we investigated the functional connectivity of distinct DMN subsystems and their interplay in depression using resting-state functional magnetic resonance imaging. We show that patients with MDD exhibit increased within-network connectivity in posterior, ventral and core DMN subsystems along with reduced interplay from the anterior to the ventral DMN subsystems. These data suggest that MDD is characterized by alterations of subsystems within the DMN as well as of their interactions. Our findings highlight a critical role of DMN circuitry in the pathophysiology of MDD, thus suggesting these subsystems as potential therapeutic targets.

Reduced Specificity of Personal Goals and Explanations for Goal Attainment in Major Depression

ObjectivesOvergeneralization has been investigated across many domains of cognitive functioning in major depression, including the imagination of future events. However, it is unknown whether this phenomenon extends to representations of personal goals, which are important in structuring long-term behaviour and providing meaning in life. Furthermore, it is not clear whether depressed individuals provide less specific explanations for and against goal attainment.MethodClinically depressed individuals and controls generated personally important approach and avoidance goals, and then generated explanations why they would and would not achieve these goals. Goals and causal explanations were subsequently coded as either specific or general.ResultsCompared to controls, depressed individuals did not generate significantly fewer goals or causal explanations for or against goal attainment. However, compared to controls, depressed individuals generated less specific goals, less specific explanations for approach (but not avoidance) goal attainment, and less specific explanations for goal nonattainment.SignificanceOur results suggest that motivational deficits in depression may stem partly from a reduction in the specificity of personal goal representations and related cognitions that support goal-directed behaviour. Importantly, the findings have the potential to inform the ongoing development of psychotherapeutic approaches in the treatment of depression.

Association between cortisol awakening response and memory function in major depression

While impaired memory and altered cortisol secretion are characteristic features of major depression, much less is known regarding the impact of antidepressant medication. We examined whether the cortisol awakening response (CAR) is increased in depressed patients with and without medication compared with healthy controls (HC) and whether CAR is associated with memory function in each group. We examined 21 patients with major depression without medication, 20 depressed patients on antidepressant treatment, and 41 age-, sex- and education-matched healthy subjects. We tested verbal (Auditory Verbal Learning Task) and visuospatial (Rey figure) memory and measured CAR on two consecutive days. Patient groups did not differ in severity of depression. We found a significant effect of group (p = 0.03) for CAR. Unmedicated patients exhibited a greater CAR compared with medicated patients (p = 0.04) with no differences between patient groups and HC. We found a significant effect of group for verbal (p = 0.03) and non-verbal memory (p = 0.04). Unmedicated patients performed worse compared with medicated patients and HC in both memory domains. Medicated patients and HC did not differ. Regression analyses revealed a negative association between CAR and memory function in depressed patients, but not in HC. While in unmedicated depressed patients the magnitude of CAR is associated with impaired memory, medicated patients showed a smaller CAR and unimpaired cognitive function compared with HC. Our findings are compatible with the idea that antidepressants reduce CAR and partially restore memory function even if depressive psychopathology is still present.

Application of image-derived and venous input functions in major depression using [carbonyl-11C]WAY-100635

Image-derived input functions (IDIFs) represent a promising non-invasive alternative to arterial blood sampling for quantification in positron emission tomography (PET) studies. However, routine applications in patients and longitudinal designs are largely missing despite widespread attempts in healthy subjects. The aim of this study was to apply a previously validated approach to a clinical sample of patients with major depressive disorder (MDD) before and after electroconvulsive therapy (ECT). Eleven scans from 5 patients with venous blood sampling were obtained with the radioligand [carbonyl-(11)C]WAY-100635 at baseline, before and after 11.0±1.2 ECT sessions. IDIFs were defined by two different image reconstruction algorithms 1) OSEM with subsequent partial volume correction (OSEM+PVC) and 2) reconstruction based modelling of the point spread function (TrueX). Serotonin-1A receptor (5-HT1A) binding potentials (BPP, BPND) were quantified with a two-tissue compartment (2TCM) and reference region model (MRTM2). Compared to MRTM2, good agreement in 5-HT1A BPND was found when using input functions from OSEM+PVC (R(2)=0.82) but not TrueX (R(2)=0.57, p<0.001), which is further reflected by lower IDIF peaks for TrueX (p<0.001). Following ECT, decreased 5-HT1A BPND and BPP were found with the 2TCM using OSEM+PVC (23%-35%), except for one patient showing only subtle changes. In contrast, MRTM2 and IDIFs from TrueX gave unstable results for this patient, most probably due to a 2.4-fold underestimation of non-specific binding. Using image-derived and venous input functions defined by OSEM with subsequent PVC we confirm previously reported decreases in 5-HT1A binding in MDD patients after ECT. In contrast to reference region modeling, quantification with image-derived input functions showed consistent results in a clinical setting due to accurate modeling of non-specific binding with OSEM+PVC.

Inflammatory bowel disease: perspectives from cingulate cortex in the first brain

The article by Agostini etal. (2013) in this issue of Neurogastroenterology and Motility evaluated patients with Crohn's disease (CD) for volumetric changes throughout the brain. They observed decreased gray matter volumes in dorsolateral prefrontal cortex and anterior midcingulate cortex (aMCC) and disease duration was negatively correlated with volumes in subgenual anterior cingulate (sACC), posterior MCC (pMCC), ventral posterior cingulate (vPCC), and parahippocampal cortices. As all patients were in remission and suffered from ongoing abdominal pain, this study provides a critical link between forebrain changes and abdominal pain experience independent of active disease and drug treatment. The aMCC has a role in feedback-mediated decision making and there are specific cognitive tasks that differentiate aMCC and pMCC that can be used to evaluate defects in CD. The sACC is an important area as it has impaired functions in major depression. As depressive symptoms are a feature in a subset of patients with active inflammatory diseases including IBD, treatment targeting this subregion should prove efficacious. Finally, vPCC has a role in ongoing self-monitoring of the personal relevance of sensory stimuli including visceral signals via sACC. This pathway may be interrupted by vPCC atrophy in CD. Cingulate atrophy in CD leads to targeting chronic pain and psychiatric symptoms via cingulate-mediated therapies. These include psychotherapy, guided imagery and relaxation training, analgesic dosages of morphine or antidepressants, and hypnosis. Thus, a new generation of novel treatments may emerge from drug and non-traditional therapies for CD in this formative area of research.

Comparison of neuropsychological functioning and emotional processing in major depression and social anxiety disorder subjects, and matched healthy controls

Few studies of neuropsychological function in major depression have examined emotional processing or the impact of gender. Patients have also been compared with highly selected control participants and rarely with other patient groups. The objective of this study was to compare neuropsychological function in a major depressive episode (MDE) with a group of patients with an anxiety disorder, social anxiety disorder (SAD), and healthy controls, to include measures of emotional processing and to analyse the effects of gender on neuropsychological function and emotional processing in these groups. One hundred and one medication-free patients with MDE, 30 patients with SAD and 76 healthy control participants were recruited. The groups were matched for age and estimated premorbid intelligence and education. Subjects performed a battery of neuropsychological tests assessing; verbal learning and memory, visuospatial learning and memory, attention, executive function and psychomotor performance. They also performed a task measuring the accuracy of recognition of facial emotional expressions. Compared with healthy participants and those with SAD, patients with MDE were significantly impaired in verbal learning and spatial working memory. The SAD group misclassified significantly more neutral expressions as angry and fewer as sad, compared with the MDE group and healthy controls, but there were no significant differences between the MDE group and healthy controls. The profile of performance was the same regardless of gender. The study confirms a significant impairment in neuropsychological function in a clinical sample of outpatients with MDE, which is likely to have important implications for day-to-day functioning and treatment.

Changes in Prefrontal-Limbic Function in Major Depression after 15 Months of Long-Term Psychotherapy

Neuroimaging studies of depression have demonstrated treatment-specific changes involving the limbic system and regulatory regions in the prefrontal cortex. While these studies have examined the effect of short-term, interpersonal or cognitive-behavioural psychotherapy, the effect of long-term, psychodynamic intervention has never been assessed. Here, we investigated recurrently depressed (DSM-IV) unmedicated outpatients (N = 16) and control participants matched for sex, age, and education (N = 17) before and after 15 months of psychodynamic psychotherapy. Participants were scanned at two time points, during which presentations of attachment-related scenes with neutral descriptions alternated with descriptions containing personal core sentences previously extracted from an attachment interview. Outcome measure was the interaction of the signal difference between personal and neutral presentations with group and time, and its association with symptom improvement during therapy. Signal associated with processing personalized attachment material varied in patients from baseline to endpoint, but not in healthy controls. Patients showed a higher activation in the left anterior hippocampus/amygdala, subgenual cingulate, and medial prefrontal cortex before treatment and a reduction in these areas after 15 months. This reduction was associated with improvement in depressiveness specifically, and in the medial prefrontal cortex with symptom improvement more generally. This is the first study documenting neurobiological changes in circuits implicated in emotional reactivity and control after long-term psychodynamic psychotherapy.

Administration of memantine and imipramine alters mitochondrial respiratory chain and creatine kinase activities in rat brain

Several studies have appointed for a role of glutamatergic system and/or mitochondrial function in major depression. In the present study, we evaluated the creatine kinase and mitochondrial respiratory chain activities after acute and chronic treatments with memantine (N-methyl-D: -aspartate receptor antagonist) and imipramine (tricyclic antidepressant) in rats. To this aim, rats were acutely or chronically treated for 14 days once a day with saline, memantine (5, 10 and 20 mg/kg) and imipramine (10, 20 and 30 mg/kg). After acute or chronic treatments, we evaluated mitochondrial respiratory chain complexes (I, II, II-III and IV) and creatine kinase activities in prefrontal cortex, hippocampus and striatum. Our results showed that both acute and chronic treatments with memantine or imipramine altered respiratory chain complexes and creatine kinase activities in rat brain; however, these alterations were different with relation to protocols (acute or chronic), complex, dose and brain area. Finally, these findings further support the hypothesis that the effects of imipramine and memantine could be involve mitochondrial function modulation.

Mémoire émotionnelle du soi

Emotion shapes autobiographical memory (AM) by tagging events that are relevant for the narrative self, which may be viewed as a hierarchical network of interconnected goals. Subsequent AM retrieval is a reconstruction process that grounds the self by providing coherent narratives organized to elicit a sense of identity across the time. The lateral and medial prefrontal cortices underlie reconstruction and self-referential processing, respectively, whereas the lateral and medial temporal cortices underlie semantic and episodic aspects, respectively. Additionally, the posterior cortical midline structures and the amygdala are involved in visual and emotional aspects, respectively. These regions have been found to display aberrant functioning in major depression. Accordingly, major depression is associated with impairments of AM retrieval combining mood-congruency, overgenerality, intrusive memories and third-person visual perspective.

Association of Plasma Interleukin-18 Levels with Emotion Regulation and μ-Opioid Neurotransmitter Function in Major Depression and Healthy Volunteers

Alterations in central neurotransmission and immune function have been documented in major depression (MDD). Central and peripheral endogenous opioids are linked to immune functioning in animal models, stress-activated, and dysregulated in MDD. We examined the relationship between μ-opioid receptor (OR)-mediated neurotransmission and a proinflammatory cytokine (interleukin [IL]-18). We studied 28 female subjects (14 MDDs, 14 control subjects) with positron emission tomography and [(11)C] carfentanil (μ-OR selective) during neutral and sadness states. With a simple regression model in SPM2 (Wellcome Trust, London, England) we identified brain regions where baseline μ-OR availability (nondisplaceable binding potential [BP(ND)]) and sadness-induced changes in μ-OR BP(ND) were associated with baseline IL-18. Baseline IL-18 was greater in MDDs than control subjects [t(25) = 2.13, p = .04]. In control subjects IL-18 was correlated with negative emotional ratings at baseline and during sadness induction. In MDDs, IL-18 was positively correlated with baseline regional μ-OR BP(ND) and with sadness-induced μ-opioid system activation in the subgenual anterior cingulate, ventral basal ganglia, and amygdala. This study links plasma IL-18 with sadness-induced emotional responses in healthy subjects, the diagnosis of MDD, and μ-opioid functioning, itself involved in stress adaptation, emotion regulation, and reward. This suggests that IL-18 represents a marker associated with emotion regulation/dysregulation at least in part through central opioid mechanisms.

A psychoneuroimmunological review on cytokines involved in antidepressant treatment response

The literature exploring the role that cytokine functioning plays in the pathogenesis and treatment of depressive illness is reviewed. The review focuses on the influence of antidepressants on cytokines, and on how treatment response might be affected by genetic variants of cytokines. The authors systematically reviewed the scientific literature on the subject over the last 20 years, searching PubMed, PsychInfo, and Cochrane databases. Antidepressants modulate cytokine functioning, and these mechanisms appear to directly influence treatment outcome in depression. Antidepressants appear to normalize serum levels of major inflammatory cytokines, including interleukin (IL)-1beta, IL-6, tumor necrosis factor alpha (TNF-alpha), and interferon gamma (IFN-gamma). Antidepressants are postulated to modulate cytokine functioning through their effects on intracellular cyclic adenosyl monophosphate (cAMP), serotonin metabolism, the hypothalamo-pituitary-adrenocortical (HPA) axis or through a direct action on neurogenesis. Preliminary research shows that cytokine genotypes and functioning may be able to help predict antidepressant treatment response. Current literature demonstrates an association between antidepressant action and cytokine functioning in major depression. Improved understanding of the specific pharmacologic and pharmacogenetic mechanisms is needed. Such knowledge may serve to enhance our understanding of depression, leading to promising new directions in the pathology, nosology, and treatment of depression.

The role of cognitive impairment in general functioning in major depression

The association between cognitive performance and general functioning in depression is controversial. The present study evaluated the association between cognitive dysfunction and major depressive disorder (MDD, N = 70) as compared with age- and gender-matched healthy controls ( n = 206) and its relationship to general functioning (physical and mental health quality of life, activities of daily living, and employment status) in participants with current MDD ( n = 26) and those with previous MDD only ( n = 44). Participants were assessed clinically using the Mini International Neuropsychiatric Interview (M.I.N.I.) for the depression groups and the Diagnostic Interview for Psychoses (DIP-DM) for the control group. Measures to evaluate cognition and quality of lifes comprised the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), the Short Form-36 Health Survey Questionnaire, and the Activities/Instrumental Activities of Daily Living (ADL/IADL); employment status was also assessed in MDD. The results showed that a) while individuals with current depression had worse cognitive performance in all domains than healthy controls, those individuals with previous depression had lasting cognitive impairments in the domains of immediate memory and attention as compared with healthy controls; b) individuals with current depression had lower scores in the visuospatial/constructional and attention domains and the total score than individuals with previous depression; c) individuals in the depression group as a whole who were currently unemployed had significantly lower scores in all domains (except attention) of cognitive function; d) cognitive function was not related to either physical or mental quality of life or impairments of activities of daily living (ADL, IADL); e) that unemployment in previous depression was related to poor cognitive function similar to those with current depression. The results indicate that MDD may have detrimental and lasting effects on cognitive performance partly related to poorer general functioning.

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.

Longitudinal Assessment of Neuropsychological Function in Major Depression

Neuropsychological impairment is a core component of major depression, yet its relationship to clinical state is unclear. The aims of the present review were to determine which neuropsychological domains and tasks were most sensitive to improvement in clinical state in major depression and to highlight the methodological issues in such research. Studies that included a baseline and at least one follow-up neuropsychological testing session in adults with major depression were identified using MEDLINE, Web of Science and ScienceDirect databases. Thirty studies were included in the review. Findings in younger adult populations suggested that improvement in mood was most strongly related to improved verbal memory and verbal fluency, while measures of executive functioning and attention tended to remain impaired across treatment. In late-life major depression, improved psychomotor speed was most closely related to treatment response, but there was much inconsistency between study findings, which may be due to methodological issues. In major depression, particular neuropsychological domains are more strongly related to clinical state than others. The findings from the present review suggest that the domains most sensitive to clinical state are verbal learning and memory, verbal fluency and psychomotor speed. In contrast, measures of attention and executive functioning perhaps represent more trait-like markers of major depression. With further methodologically sound research, the changes in neuropsychological function associated with treatment response may provide a means of evaluating different treatment strategies in major depression.