Models Of Major Depressive Disorder Research Articles

Major Depressive Disorder Among HIV Infected Youth in Uganda: Incidence, Persistence and Their Predictors.

Incidence and persistence of major depressive disorder (MDD) in children and adolescents with HIV (CA-HIV) in Uganda is described. 1339 CA-HIV attending care were enrolled and followed up for 12months. MDD was assessed using the DSM-5 referenced Child and Adolescent Symptom Inventory-5 (CASI-5), with a prevalence for MDD at baseline of 5% (95% CI 3.3-7.3). Kaplan-Meir method was used to estimate incidence of MDD and Cox models were fitted to investigate predictors of incident MDD. Cumulative incidence of MDD over 12months was 7.6 per 100 person-years 95% CI (6.2-9.4) and a rate of persistent MDD of 10/105 (9.5% CI 3.9-15.1). Significant independent predictors of incident MDD were: highest educational level of CA-HIV (protective), increasing depressive scores and decreasing CD4 Nadir. These finding have implications for what should constitute components of a mental health integration model in HIV youth services and for the future development of individualised mental health care.

Shared Transcriptional Signatures in Major Depressive Disorder and Mouse Chronic Stress Models

BackgroundMost of our knowledge of the biological basis of major depressive disorder (MDD) is derived from studies of chronic stress models in rodents. While these models capture certain aspects of the behavioral and neuroendocrine features of MDD, the extent to which they reproduce the molecular pathology of the human syndrome remains unknown. MethodsWe systematically compared transcriptional signatures in two brain regions implicated in depression—medial prefrontal cortex and nucleus accumbens—of humans with MDD and of 3 chronic stress models in mice: chronic variable stress, adult social isolation, and chronic social defeat stress. We used differential expression analysis combined with weighted gene coexpression network analysis to create interspecies gene networks and assess the capacity of each stress paradigm to recapitulate the transcriptional organization of gene networks in human MDD. ResultsOur results show significant overlap between transcriptional alterations in medial prefrontal cortex and nucleus accumbens in human MDD and the 3 mouse chronic stress models, with each of the chronic stress paradigms capturing distinct aspects of MDD abnormalities. Chronic variable stress and adult social isolation better reproduce differentially expressed genes, while chronic social defeat stress and adult social isolation better reproduce gene networks characteristic of human MDD. We also identified several gene networks and their constituent genes that are most significantly associated with human MDD and mouse stress models. ConclusionsThis study demonstrates the ability of 3 chronic stress models in mice to recapitulate distinct aspects of the broad molecular pathology of human MDD, with no one mouse model apparently better than another.

An Integrated Sleep and Reward Processing Model of Major Depressive Disorder

Major depressive disorder with comorbid sleep disturbance has been associated with negative outcomes, including lower rates of treatment response and a greater likelihood of depressive relapse compared to those without sleep disturbance. However, little, if any, research has been conducted to understand why such negative treatment outcomes occur when sleep disturbance is present. In this conceptual review, we argue that the relationship of sleep disturbance and negative treatment outcomes may be mediated by alterations in neural reward processing in individuals with blunted trait-level reward responsivity. We first briefly characterize sleep disturbance in depression, discuss the nature of reward processing impairments in depression, and summarize the sleep/reward relationship in healthy human subjects. We then introduce a novel Integrated Sleep and Reward model of the course and maintenance of major depressive disorder and present preliminary evidence of sleep and reward interaction in unipolar depression. Finally, we discuss limitations of the model and offer testable hypotheses and directions for future research.

A Robot Science Approach to a Consciousness Model of Major Depressive Disorder

Abstract In this study the authors focused on mental disorders as functional disorders of human consciousness from the viewpoints of cognitive science and information science. They further focused their study on depression, a disorder that is the most frequently seen of mental disorders and whose cause is unclear. The authors propose a model of consciousness for the pathogenesis of major depressive disorder, which is a typical disorder caused by depression. To construct this consciousness model, the authors adopted a consciousness module of their own development called Module of Nerves for Advanced Dynamics or MoNAD.

Toward a Comprehensive Developmental Model of Prescription Opioid Use Disorder.

To develop a comprehensive etiologic model of DSM-5 prescription opioid use disorder (POUD) based on Kendler and colleagues' development model for major depressive disorder. Data were drawn from the National Epidemiologic Survey on Alcohol and Related Conditions-III (2012-2013). Risk factors were divided into 4 developmental tiers (childhood/early adolescence, late adolescence, adulthood, past year). Hierarchical logistic regression models were used to examine the independent contribution of each risk factor. Separate models were built to predict 12-month nonmedical use of prescription opioids and risk of POUD among those with 12-month nonmedical use. After adjustment for other risk factors, the odds of past 12-month nonmedical use of prescription opioids were increased by history of trauma, social deviance, and use of drugs other than opioids in adulthood and by past-year pain, alcohol use disorder (AUD), tobacco use disorder, any Axis I disorder other than SUD, and number of stressful events. History of POUD in adulthood and pain, AUD, tobacco use disorder, and any Axis I disorder other than substance use disorders (SUD) in the past year increased the odds of 12-month POUD. History of SUD other than POUD in adulthood was associated with lower odds of POUD. For both outcomes, the effect of earlier development tiers was mediated by more proximal ones. A modification of Kendler and colleagues' model for major depressive disorder provides a useful foundation for a comprehensive developmental model of nonmedical opioid use and opioid use disorder.

Optogenetic and chemogenetic insights into the neurocircuitry of depression-like behaviour: A systematic review.

Major depressive disorder (MDD) and its treatment are challenges for global health. Optogenetics and chemogenetics are driving MDD research forward by unveiling causal relations between cell-type-specific control of neurons and depressive-like behaviour in rodents. Using a systematic search process, in this review, a set of 43 original studies applying optogenetic or chemogenetic techniques in rodent models of depression was identified. Our aim was to provide an examination of all available studies elucidating central neuronal mechanisms leading to depressive-like behaviour in rodents and thereby unveiling the most promising routes for future research. A complex interacting network of relevant structures, in which central circuitries causally related to depressive-like behaviour are implicated, has been identified. As most relevant structures emerge: medial prefrontal cortex, anterior cingulate cortex, amygdala, nucleus accumbens, ventral tegmental area, hippocampus and raphe nuclei. Further evidence, though examined by only few studies, emerges for structures like the lateral habenula, or medial dorsal thalamus. Most of the identified brain areas have previously been associated with MDD neuropathology, but now evidence can be provided for causal pathological mechanisms within a complex cortico-limbic reward circuitry. However, the studies also show conflicting results concerning the mechanisms underlying the causal involvement of specific circuitries. Comparability of studies is partly limited since even small deviations in methodological approaches lead to different outcomes. Factors influencing study outcomes were identified and need to be considered in future studies (e.g. frequency used for stimulation, time and duration of stimulation, limitations of applied animal models of MDD).

In vivo knockdown of astroglial glutamate transporters GLT-1 and GLAST increases excitatory neurotransmission in mouse infralimbic cortex: Relevance for depressive-like phenotypes

Alterations of energy metabolism and of astrocyte number/function in ventral anterior cingulate cortex (vACC) have been reported in major depressive disorder (MDD) patients and may contribute to MDD pathophysiology. We recently developed a mouse model of MDD mimicking these alterations. We knocked down the astroglial glutamate transporters GLAST and GLT-1 in infralimbic cortex (IL, rodent equivalent of vACC) using small interfering RNA (siRNA). GLAST and GLT-1 siRNA microinfusion in IL evoked a depressive-like phenotype, associated with a reduced serotonergic function and reduced forebrain BDNF expression. Neither effect occurred after siRNA application in the adjacent prelimbic cortex (PrL), thus emphasizing the critical role of vACC/IL in MDD pathogenesis. Here we examined the cellular/network basis of the changes induced in IL using intracellular recordings of layer V pyramidal neurons from mice microinjected with siRNA 24 h before. We analyzed (i) the electrophysiological characteristics of neurons; (ii) the synaptic transmission properties, by monitoring miniature, spontaneous and evoked EPSCs, and (iii) the gliotransmission, by monitoring slow inward currents (SICs), mediated by astrocytic glutamate release and activation of extra-synaptic NMDA receptors. GLT-1 and GLAST knockdown led to a more depolarized membrane potential and increased action potential firing rate of layer V pyramidal neurons, and enhanced excitatory synaptic transmission, as shown by the enhanced amplitude/frequency of spontaneous EPSCs. Gliotransmission was also increased, as indicated by the enhanced SIC amplitude/frequency. Hence, the depressive-like phenotype is associated with IL hyperactivity, likely leading to an excessive top-down inhibitory control of serotonergic activity through IL-midbrain descending pathways.

The relationship between PTSD factors and depression in a chronically homeless sample

ABSTRACT The relationship between post-traumatic stress disorder (PTSD) and major depressive disorder (MDD) is the subject of ongoing inquiry. Homeless adults with psychiatric illnesses are at risk for comorbid PTSD and MDD. However, the factor structures of commonly used screening tools for PTSD (PCL-5) and MDD (PHQ-9), and their interrelationships, have not been widely investigated in this population. The present article tests the factor structure of the PCL-5 and PHQ-9 in a sample of chronically homeless adults who reported lifetime trauma exposure and were enrolled into intensive community mental health services (N = 197). Confirmatory factor analysis was used to test six models of PTSD and four models of depression, although more complex models produced indefinite covariance matrices. The four-factor Dysphoria Model of PTSD and a two-factor model of MDD were considered the best models in this sample. Regression analyses tested the variance between PTSD and MDD symptom clusters. The PTSD dysphoria factor explained the most variance in depressive symptoms. Reexperiencing, avoidance, and arousal symptoms capture phenomena unique to the experience of PTSD among this psychiatric sample. These findings have implications for conceptualizing the underlying structures of PTSD and MDD among a moderately depressed sample of homeless adults with psychiatric illnesses.

USE OF SINGLE CELL GENOMIC TECHNOLOGY TO UNDERSTAND PSYCHIATRIC DISEASE

Alterations of energy metabolism and of astrocyte number/function in ventral anterior cingulate cortex (vACC) have been reported in major depressive disorder (MDD) patients and may contribute to MDD pathophysiology. We recently developed a mouse model of MDD mimicking these alterations. We knocked down the astroglial glutamate transporters GLAST and GLT-1 in infralimbic cortex (IL, rodent equivalent of vACC) using small interfering RNA (siRNA). GLAST and GLT-1 siRNA microinfusion in IL evoked a depressive-like phenotype, associated with a reduced serotonergic function and reduced forebrain BDNF expression. Neither effect occurred after siRNA application in the adjacent prelimbic cortex (PrL), thus emphasizing the critical role of vACC/IL in MDD pathogenesis. Here we examined the cellular/network basis of the changes induced in IL using intracellular recordings of layer V pyramidal neurons from mice microinjected with siRNA 24 h before. We analyzed (i) the electrophysiological characteristics of neurons; (ii) the synaptic transmission properties, by monitoring miniature, spontaneous and evoked EPSCs, and (iii) the gliotransmission, by monitoring slow inward currents (SICs), mediated by astrocytic glutamate release and activation of extra-synaptic NMDA receptors. GLT-1 and GLAST knockdown led to a more depolarized membrane potential and increased action potential firing rate of layer V pyramidal neurons, and enhanced excitatory synaptic transmission, as shown by the enhanced amplitude/frequency of spontaneous EPSCs. Gliotransmission was also increased, as indicated by the enhanced SIC amplitude/frequency. Hence, the depressive-like phenotype is associated with IL hyperactivity, likely leading to an excessive top-down inhibitory control of serotonergic activity through IL-midbrain descending pathways.

Mesenchymal Stromal Cells Modulate Peripheral Stress-Induced Innate Immune Activation Indirectly Limiting the Emergence of Neuroinflammation-Driven Depressive and Anxiety-like Behaviors

BackgroundHyperactivation of innate immunity has been implicated in the etiology of mood disorders, including major depressive disorder (MDD). Mesenchymal stromal cells (MSCs) have demonstrated potent immunomodulatory capabilities in the context of chronic inflammatory disease and injury but have yet to be evaluated in stress-based preclinical models of MDD. We sought to test the ability of intravenous MSCs to modulate innate immune activation and behavioral patterns associated with repeated social defeat (RSD). MethodsMurine RSD-induced innate immune activation as well as depressive and anxiety-like behaviors were assessed in unstressed, RSD, and RSD + human MSC groups. Biodistribution and fate studies were performed to inform potential mechanisms of action. ResultsMSCs reduced stress-induced circulating proinflammatory cytokines, monocytes, neuroinflammation, and depressive and anxiety-like behaviors. Biodistribution analyses indicated that infused MSCs distributed within peripheral organs without homing to the brain. Murine neutrophils targeted MSCs in the lungs within hours of administration. MSCs and recipient neutrophils were cleared by recipient macrophages promoting a switch toward a regulatory phenotype and systemic resolution of inflammation. ConclusionsPeripheral delivery of MSCs modulates central nervous system inflammatory processes and aberrant behavioral patterns in a stress-based rodent model of MDD and anxiety. Recent studies suggest that host immune cell–mediated phagocytosis of MSCs in vivo can trigger an immunomodulatory cascade, resulting in resolution of inflammation. Our data suggest that similar mechanisms may protect distal organs, including the brain, from systemic, stress-induced proinflammatory spikes and may uncover unexpected targets in the periphery for novel or adjunct treatment for a subset of patients with MDD.

Ketamine exerts a protective role in a cell-based model of major depressive disorder via the inhibition of apoptosis and inflammation and activation of the Krebs cycle.

Major depressive disorder (MDD) is one of the most common psychiatric disorders characterized by major depressive episodes. Although great efforts have been made to develop antidepressant drugs that target the monoaminergic system, these drugs are effective in only approximately 50% of MDD patients. In this study, we established a model of depression in PC12 cells using corticosterone to investigate the effect of ketamine and nuclear factor-κB (NF-κB) on the cell viability, apoptosis, levels of pro-inflammatory cytokines, apoptosis-related molecules, and enzymes of the Krebs cycle. PC12 cells were divided into control (no treatment, NC), ketamine treatment (KT), ketamine treatment with the inhibition of NF-κB (KI), and ketamine treatment with the overexpression of NF-κB (KO) group. Blood serum samples were collected from patients with MDD (n = 10) and healthy controls (n = 10) between 2015 and 2017. Ketamine significantly increased the viability and decreased the apoptosis of PC12 cells in KT and KI vs. NC group, but not in KO group. The levels of anti-apoptotic molecules and Krebs cycle enzymes were significantly increased in KI vs. KT group, while the levels of pro-apoptotic molecules and pro-inflammatory cytokines were decreased in KI vs. KT group. In addition, the levels of pro-inflammatory cytokines in the serum of MDD patients were significantly increased. The antidepressant effect of ketamine was enhanced in KI and reduced in KO group. Our results indicate that ketamine exerts its antidepressant effect via the inhibition of apoptosis and inflammation and the activation of the Krebs cycle in PC12 cells. NF-κB might be a potential therapeutic target in MDD.

Major Depressive Disorder in Neuroimaging: What is Beyond Fronto-limbic Model?

Background: The major depressive disorder (MDD) is a chronic illness with major manifestations in cognitive, social and occupational functions. The pathophysiological model is an intrigue issue for scientists to understand the origin of MDD. Objective: In the beginning, the cortico-limbic-striato-pallidal-thalamic model has been proposed to link the clinical symptoms with the abnormalities in brain structure and function. However, the model is still evolving due to recent advances in the neuroimaging techniques, especially for functional magnetic resonance imaging (fMRI). The recent findings in the fMRI studies in MDD showed the importance of fronto-limbic model for the modulations between cognitive function and primitive and negative emotions. Method: This review will focus on the literature of fMRI studies in MDD with findings not in the fronto-limbic structures. Results: Additional regions beyond the fronto-limbic model have been observed in some literature of MDD. Some regions in the parietal, temporal and occipital lobes have been shown with the alterations in gray matter, white matter and brain function. The importance of sensory detection, visuospatial function, language reception, motor response and emotional memories in these regions might provide the clues to understand the cognitive misinterpretations related to altered reception of outside information, behavioral responses related to biased cognition and emotional memories and clinical symptoms related to the significant alterations of interactions between different brain regions. Conclusion: Future studies to establish a more comprehensive model for MDD will be warranted, especially for the model beyond the fronto-limbic structures.

Effects of α7 nicotinic receptor positive allosteric modulator, PNU120596, on BDNF, NKCC1, and KCC2 expressions following LPS‐induced depressive‐like behavior in mice

Previous evidence indicates that neuroinflammation plays a critical role in the pathophysiology of major depressive disorder (MDD) by inducing neuronal excitability via dysregulation of microglial brain‐derived neurotrophic factor (BDNF), Na‐K‐Cl cotransporter‐1 (NKCC1), and K‐Cl cotransporter‐2 (KCC2). However, the role of microglial α7 nicotinic acetylcholine receptors (nAChRs), exhibiting anti‐inflammatory function during the activation, on these mediators is unknown. The objective of the present study was to determine the effects of PNU120596 on BDNF, NKCC1, and KCC2 expressions in lipopolysaccharide (LPS)‐induced mouse model of MDD using Western blot analysis, immunofluorescence staining, and real‐time polymerase chain reaction. We also examined the pharmacological interaction between PNU120596 and ANA12, an antagonist of TrkB which is the primary receptor for BDNF, on LPS‐induced depressive‐like behavior using forced swim test (FST), tail suspension test (TST), and Y‐maze test. Systemic administration of LPS (1 mg/kg, i.p.) significantly increased BDNF protein expression and mRNA ratio of NKCC1 to KCC2, and decreased KCC2 mRNA expression in the hippocampus and prefrontal cortex, the brain regions implicated in MDD. The PNU120596 (1 or 4 mg/kg, i.p.) dose‐dependently prevented the LPS‐induced dysregulated BDNF, NKCC1, and KCC2 expressions in these brain regions. Combination treatment with PNU120596 (1 mg/kg, i.p.) and ANA12 (0.25 mg/kg, i.p.) prevented LPS‐induced increased immobility time during FST and TST and LPS‐induced decreased spontaneous alternations (%) during Y‐maze test. Overall, our results suggest that PNU120596 prevented LPS‐induced depressive‐like behavior by decreasing neuronal excitability by targeting microglial α7 nAChR in the hippocampus and prefrontal cortex. (Supported in part by grant from Saudi Arabian Cultural Mission, USA).Support or Funding InformationSupported in part by grant from Saudi Arabian Cultural Mission, USA.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Examining the Coverage of Blood Vessels by Astrocyte Endfeet in an Animal Model of Major Depressive Disorder.

The use of immunofluorescent immunohistochemical methods has been instrumental to characterize the distribution and extents of colocalization of molecules located in various cellular compartments. Such information has been pivotal to formulate hypothesis about their roles in physiological and pathological conditions.In the brain, astrocytes interact with endothelial cells to form the blood-brain barrier (BBB). Astrocytes regulate features of the BBB through the tips of their processes, called astrocyte endfeet, which surround and contact brain microvessels. Any disruption in astrocyte endfeet can have dramatic consequences on the integrity of the BBB, with consequent development of brain disorders.Here we describe a method to characterize the integrity of astrocyte endfeet around blood vessels in an animal model of major depressive disorder (MDD) using confocal microscopy, Adobe Photoshop, and the AutoQuantX3 software.

M37 - TAKING A POLYGENIC APPROACH TO G⁎G AND G⁎E INTERACTIONS IN THE PREDICTION OF MDD

Background Major Depressive Disorder (MDD) is a complex heterogeneous disorder, with an estimated heritability of ~40%. Known environmental risk factors (e.g. neuroticism, cognition) also play an important role in the development of MDD. Despite the successful identification of many associated loci in the most recent MDD GWAS, this required a huge sample size and so these loci explain only a small fraction of the heritability, making clinical application challenging. One way of revealing greater aetiological insight, and potentially increasing disease prediction, is to detect gene-gene and gene-environment interactions. The identification of these interactions is challenging due to the huge model space involved (esp. for G⁎G). While these individual variant interactions may exist, there may also be interactions – more easily identified – between the overall polygenic risk of a disorder and that of other disorders or environmental risk factors. Here we aim to 1) use Polygenic Risk Scores (PRS) to identify global genetic interaction effects, and 2) build a predictive model of MDD case-control status utilizing the rich phenotypic data available in the UK Biobank. Methods To build and validate predictive models of MDD, we split the UK Biobank data into discovery GWAS, testing and validation datasets. The predictive model was developed via model selection techniques such as stepwise AIC/BIC and lasso regression, with a large number of PRS⁎PRS and PRS⁎E predictors. Results We identify several intriguing PRS interaction effects and increase out-of-sample prediction of MDD case/control status significantly via inclusion of PRS interactions.

Identification of Abnormal Circuit Dynamics in Major Depressive Disorder via Multiscale Neural Modeling of Resting-State fMRI.

Resting-state functional magnetic resonance imaging (rs-fMRI) studies have focused primarily on characterizing functional or effective connectivity of discrete brain regions. A major drawback of this approach is that it does not provide a mechanistic understanding of brain cognitive function or dysfunction at cellular and circuit levels. To overcome this limitation, we combined the methods of computational neuroscience with traditional macroscale connectomic analysis and developed a Multiscale Neural Model Inversion (MNMI) framework that links microscale circuit interaction with macroscale network dynamics and estimates both local coupling and inter-regional connections via stochastic optimization based on blood oxygen-level dependent (BOLD) rs-fMRI. We applied this method to the rs-fMRI data of 66 normal healthy subjects and 66 individuals with major depressive disorder (MDD) to identify potential biomarkers at both local circuit and global network level. Results suggest that the recurrent excitation and inhibition within the dorsal lateral prefrontal cortex (dlPFC) might be disrupted in MDD, consistent with the commonly accepted hypothetical model of MDD. In addition, recurrent excitation in the thalamus was found to be abnormally elevated, which may be responsible to abnormal thalamocortical oscillations often observed in MDD. Overall, our modeling approach holds the promise to overcome the limitation of traditional large-scale connectome modeling by providing hidden mechanistic insights into neuroanatomy, circuit dynamics and pathophysiology.

Modulation of gut microbiota by chlorogenic acid pretreatment on rats with adrenocorticotropic hormone induced depression-like behavior.

Gut microbiota dysbiosis has been implicated as a vital element in the development or exacerbation of mental disorders, such as major depressive disorder (MDD). Based on the current interest in the gut-brain axis, we investigate the effects of chlorogenic acid (CGA) on gut microbiota in a rat model of MDD. Depression was induced by the adrenocorticotropic hormone (ACTH, 100 μg per rat) in male Wistar rats, which were intervened with using saline or CGA (500 mg kg-1). Behavioral changes and serum parameters were assessed and fecal samples were analyzed by 16S rRNA gene sequencing. Our studies demonstrated that CGA pretreatment ameliorated depression-like behavior (SPT, FST, TST, and OFT) and serum biochemical levels (5-HT, DA, IL-6, and TNF-α) in ACTH-induced depression rats. In addition, CGA ameliorated the decrease in fecal microbiota diversity in ACTH-treated rats. In particular, at the genus level, the changes in the relative abundance of some key bacteria such as Desulfovibrionales, Desulfovibrio, Klebsiella, Burkholderiales, and Bifidobacterium were modulated by CGA pretreatment. These results indicated that CGA could modify the gut microbial community structure, which may contribute to its antidepressant effects.

Neurophysiologic Advance in Depressive Disorder.

Enormous efforts for near half-century have harvested a plenty of understanding on major depressive disorder (MDD), although the underlying mechanisms are still elusive. The available antidepressants are far from satisfaction due to long-delay action (LDA) of antidepressant efficacy and low response rates in MDD patients. Notably, discovery of a single low-dose ketamine-producing rapid-onset and sustained antidepressant efficacy has inspired new research direction. These new studies have revealed ketamine's NMDAR-dependent and NMDAR-independent mechanisms, most of which are well known to be the key bases of synaptic plasticity as well as learning and memory. In fact, animal models of MDD are all based on the principle of learning and memory, i.e., the change of a behavior, for which monoaminergic and glutamatergic systems are the major modulators and executors, respectively. Reconsidering MDD as an aberrant form of emotion-related learning and memory would endow us a clearer research direction for developing new techniques or ways to prevent, diagnose, and treat MDD.

A comprehensive regional neurochemical theory in depression: a protocol for the systematic review and meta-analysis of 1H-MRS studies in major depressive disorder

BackgroundMagnetic resonance spectroscopy (MRS) is a non-invasive analytical technique that investigates the presence and concentrations of brain metabolites. In the context of major depressive disorder (MDD), MRS has revealed regional biochemical changes in GABA, glutamate, and choline across different brain compartments. Technical and methodological advances in MRS data acquisition, in particular proton-based 1H-MRS, have resulted in a significant increase in the incidence of reports utilizing the technique for psychiatric disorder research and diagnosis. The most recent comprehensive meta-analysis reviewing MRS in MDD stems from 2006. Using contemporary systemic reviews and meta-analysis, the aim is to first test a neurochemical circuit-based theory of depression and then to determine if clinical scores relate to metabolite concentrations before and during treatment.MethodsRegion-specific metabolite changes in MDD will be assessed by systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Inclusion criteria will include participant age (18 to 65), English language studies, known regions of interest, and detailed documentation of 1H-MRS procedures. Reported brain regions will be standardized according neuroanatomical expertise allowing increased power of the meta-analysis. Regions of interest will initially include the hippocampus, thalamus, prefrontal cortex, anterior and posterior cingulate gyri, parietal lobe, and basal ganglia. Exclusion criteria will include comorbid psychiatric illness and drug use. Two independent reviewers will undertake all data extraction, while a third reviewer will check for reviewer discrepancies. Statistical analysis will be performed using STATA supplemented by Metan software and SPSS.DiscussionThis data will shed new light on the biochemical basis of depression in different brain regions, thereby highlighting the potential of MRS in identifying biomarkers and generating models of MDD and treatment response.Systematic review registrationPROSPERO CRD42018091494

An adaptive Network-Oriented cognitive model for Major Depression and its treatment

Abstract This paper presents an adaptive neurologically inspired cognitive model for Major Depressive Disorder. It is based on an (adaptive) temporal-causal network modelling approach incorporating a dynamic perspective on mental states and causal relations. The adaptive network model addresses how a Deep Brain Stimulation treatment used for this disorder can work by a Hebbian learning effect.