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Background and aim Postpartum depression (PPD) is a familiar problem which is associated with about 10–20% of women after child delivery. Fish oil (FO) has a therapeutic potentials to many diseases including mood disorders. However, there is paucity of data on the effects of FO supplementation on PPD rat model. Hence, this study aimed at investigating the potentials of FO in ameliorating depressive-like behaviors in PPD rat by evaluating the involvement of NLRP3-inflammasome. Experimental procedure Thirty six virgin adult female rats (n = 6) were randomly divided into six groups; Group 1–3 were normal control (NC), Sham (SHAM) and ovariectomized group (OVX) respectively whereas group 4–6 were PPD rats forced-fed once daily with distilled water (PPD), fish oil (PPD + FO; 9 g/kg) and Fluoxetine (PPD + FLX; 15 mg/kg) respectively from postpartum day 1 and continued for 10 consecutive days. Rats behaviors were evaluated on postpartum day 10 through open field test (OFT) and forced swimming test (FST), followed by biochemical analysis of NLRP3 inflammasome proteins pathway in their brain and determination of neutrophil to lymphocyte ratio (NLR). Results PPD-induced rats exhibited high immobility and low swimming time in FST with increased inflammatory status; NLR, IL-1β and NFкB/NLRP3/caspase-1 activity in their hippocampus. However, administration of FO or fluoxetine reversed the aforementioned abnormalities. Conclusion In conclusion, 10 days supplementation with FO ameliorated the depressive-like behaviors in PPD rats by targeting the NFкB/NLRP3/caspase-1/IL-1β activity. This has shed light on the potential of NLRP3 as a therapeutic target in treatment of PPD in rats., Graphical abstract Image 1, Highlights • Pioneer study on 10 days effect of Menhaden fish oil in post partum depression rat model. • Menhaden fish oil attenuates post partum depression in rat model. • Menhanden fish oil acted through NLRP3 inflammasome pathways.

Highlights • There are no quantitative markers of major depression that associates with brain. • Switching strategy during verbal fluency can be calculated via machine learning. • Switching between semantic clusters is related to cognitive function in depression. • It is associated with cortical thickness in frontal, temporal and occipital regions. • It is associated with fractional anisotropy in right long antero-posterior tracts., Background The search of biomarkers in the field of depression requires easy implementable tests that are biologically rooted. Qualitative analysis of verbal fluency tests (VFT) are good candidates, but its cerebral correlates are unknown. Methods We collected qualitative semantic and phonemic VFT scores along with grey and white matter anatomical MRI of depressed (n = 26) and healthy controls (HC, n = 25) women. Qualitative VFT variables are the “clustering score” (i.e. the ability to produce words within subcategories) and the “switching score” (i.e. the ability to switch between clusters). The clustering and switching scores were automatically calculated using a data-driven approach. Brain measures were cortical thickness (CT) and fractional anisotropy (FA). We tested for associations between CT, FA and qualitative VFT variables within each group. Results Patients had reduced switching VFT scores compared to HC. Thicker cortex was associated with better switching score in semantic VFT bilaterally in the frontal (superior, rostral middle and inferior gyri), parietal (inferior parietal lobule including the supramarginal gyri), temporal (transverse and fusiform gyri) and occipital (lingual gyri) lobes in the depressed group. Positive association between FA and the switching score in semantic VFT was retrieved in depressed patients within the corpus callosum, right inferior fronto-occipital fasciculus, right superior longitudinal fasciculus extending to the anterior thalamic radiation (all p

Alexander disease (AxD) is a rare and fatal neurodegenerative disorder caused by mutations in the gene encoding glial fibrillary acidic protein (GFAP). In this report, a mouse model of AxD (GFAPTg;Gfap+/R236H) was analyzed that contains a heterozygous R236H point mutation in murine Gfap as well as a transgene with a GFAP promoter to overexpress human GFAP. Using label-free quantitative proteomic comparisons of brain tissue from GFAPTg;Gfap+/R236H versus wild-type mice confirmed upregulation of the glutathione metabolism pathway and indicated proteins were elevated in the peroxisome proliferator-activated receptor (PPAR) signaling pathway, which had not been reported previously in AxD. Relative protein-level differences were confirmed by a targeted proteomics assay, including proteins related to astrocytes and oligodendrocytes. Of particular interest was the decreased level of the oligodendrocyte protein, 2-hydroxyacylsphingosine 1-beta-galactosyltransferase (Ugt8), since Ugt8-deficient mice exhibit a phenotype similar to GFAPTg;Gfap+/R236H mice (e.g., tremors, ataxia, hind-limb paralysis). In addition, decreased levels of myelin-associated proteins were found in the GFAPTg;Gfap+/R236H mice, consistent with the role of Ugt8 in myelin synthesis. Fabp7 upregulation in GFAPTg;Gfap+/R236H mice was also selected for further investigation due to its uncharacterized association to AxD, critical function in astrocyte proliferation, and functional ability to inhibit the anti-inflammatory PPAR signaling pathway in models of amyotrophic lateral sclerosis (ALS). Within Gfap+ astrocytes, Fabp7 was markedly increased in the hippocampus, a brain region subjected to extensive pathology and chronic reactive gliosis in GFAPTg;Gfap+/R236H mice. Last, to determine whether the findings in GFAPTg;Gfap+/R236H mice are present in the human condition, AxD patient and control samples were analyzed by Western blot, which indicated that Type I AxD patients have a significant fourfold upregulation of FABP7. However, immunohistochemistry analysis showed that UGT8 accumulates in AxD patient subpial brain regions where abundant amounts of Rosenthal fibers are located, which was not observed in the GFAPTg;Gfap+/R236H mice., Graphical abstract, Highlights • Models of AxD provide insight into functions of astrocytes related to neuropathology. • PPAR pathway found upregulated in AxD mice may be neuroprotective. Fatty acid binding protein (Fabp7) was upregulated in AxD mice and human CNS samples. • Depleted levels in the classical constituents of myelin were observed in AxD mice. • UGT8 may be related to myelin deficits in AxD., In Brief The article contains the first whole brain proteomic survey from a mouse model of Alexander disease (AxD). Several novel findings include activation of the PPAR signaling pathway, which has been reported to be protective in models of amyotrophic lateral sclerosis (ALS). Another finding related to the gliosis phenotype in AxD mice was the upregulation of fatty acid binding protein 7 (FABP7), which induces an NF-κB inflammatory response and counteracts the anti-inflammatory effects of PPAR signaling.

Highlights • A clinically relevant method of predicting MDD treatment efficacy is needed. • The present investigation applies dynamic FDG-PET using blood as a reference. • FDG-PET was assessed in the raphe nuclei, ventral prefrontal cortex and insula. • Regional pretreatment metabolism does not relate to symptom severity decrease. • Predictive FDG-PET signal may not be generalizable to heterogeneous MDD cohorts., There is critical need for a clinically useful tool to predict antidepressant treatment outcome in major depressive disorder (MDD) to reduce suffering and mortality. This analysis sought to build upon previously reported antidepressant treatment efficacy prediction from 2-[18F]-fluorodeoxyglucose - Positron Emission Tomography (FDG-PET) using metabolic rate of glucose uptake (MRGlu) from dynamic FDG-PET imaging with the goal of translation to clinical utility. This investigation is a randomized, double-blind placebo-controlled trial. All participants were diagnosed with MDD and received an FDG-PET scan before randomization and after treatment. Hamilton Depression Rating Scale (HDRS-17) was completed in participants diagnosed with MDD before and after 8 weeks of escitalopram, or placebo. MRGlu (mg/(min*100 ml)) was estimated within the raphe nuclei, right insula, and left ventral Prefrontal Cortex in 63 individuals. Linear regression was used to examine the association between pretreatment MRGlu and percent decrease in HDRS-17. Additionally, the association between percent decrease in HDRS-17 and percent change in MRGlu between pretreatment scan and post-treatment scan was examined. Covariates were treatment type (SSRI/placebo), handedness, sex, and age. Depression severity decrease (n = 63) was not significantly associated with pretreatment MRGlu in the raphe nuclei (β = -2.61e-03 [-0.26, 0.25], p = 0.98), right insula (β = 0.05 [-0.23, 0.32], p = 0.72), or ventral prefrontal cortex (β = 0.06 [-0.23, 0.34], p = 0.68) where β is the standardized estimated coefficient, with a 95% confidence interval, or in whole brain voxelwise analysis (family-wise error correction, alpha = 0.05). MRGlu percent change was not significantly associated with depression severity decrease (n = 58) before multiple comparison correction in the RN (β = 0.20 [-0.07, 0.47], p = 0.15), right insula (β = 0.24 [-0.03, 0.51], p = 0.08), or vPFC (β = 0.22 [-0.06, 0.50], p = 0.12). We propose that FDG-PET imaging does not indicate a clinically relevant biomarker of escitalopram or placebo treatment response in heterogeneous major depressive disorder cohorts. Future directions include focusing on potential biologically-based subtypes of major depressive disorder by implementing biomarker stratified designs.

Controlling unmodified serotonin levels in brain synapses is a primary objective when treating major depressive disorder - a disease that afflicts ~20% of the world's population. Roughly 60% of patients respond poorly to first-line treatments and thus new therapeutic strategies are sought. Toward this end, we have constructed isoform-specific inhibitors of the human cytosolic sulfotransferase 1A3 (SULT1A3) - the isoform responsible for sulfonating ~80% of the serotonin in extracellular brain fluid. The inhibitor design includes a core ring structure, which anchors the inhibitor into a SULT1A3-specific binding pocket located outside the active site, and a sidechain crafted to act as a latch to inhibit turnover by fastening down the SULT1A3 active-site cap. The inhibitors are allosteric, they bind with nanomolar affinity and are highly specific for the 1A3 isoform. The cap-stabilizing effects of the latch can be accurately calculated and are predicted to extend throughout the cap and into the surrounding protein. A free energy correlation demonstrates that the percent inhibition at saturating inhibitor varies linearly with cap stabilization - the correlation is linear because the rate-limiting step of the catalytic cycle, nucleotide release, scales linearly with the fraction of enzyme in the cap-open form. Inhibitor efficacy in cultured cells was studied using a human mammary epithelial cell line that expresses SULT1A3 at levels comparable to those found in neurons. The inhibitors perform similarly in ex vivo and in vitro studies; consequently, SULT1A3 turnover can now be potently suppressed in an isoform-specific manner in human cells.

Objective This study aimed to assess the immediate stress and psychological impact experienced by healthcare workers and other personnel during the Coronavirus disease (COVID-19) pandemic. Method The sample consisted of 2554 hospital workers (i.e., physicians, nurses, allied health professionals, and auxiliary staff members) who were working in Yeungnam University Hospital in Daegu, South Korea. The Impact of Event Scale-Revised (IES-R) was administered to the hospital workers twice over a 2 week interval. A high-risk group, identified on the basic of first total IES-R, was assessed further with the Mini International Neuropsychiatric Interview (MINI) and the Clinical Global Impressions-Severity (CGI—S) scale and was offered periodic psychiatric consultations on a telephone. Results The participating nurses and auxiliary staff members had significantly higher IES-R scores (p, Highlights • The healthcare workers reported experiencing high levels of psychological stress during the pandemic period. • Higher levels of stress were reported by the nonmedical staff workers than by the physicians. • These findings underscore the need to provide sufficient information and support to nurses, other staff members. • Psychiatrists will play an important role in implementing rapid and effective psychiatric interventions during a pandemic.

BackgroundDepressive and neurocognitive disorders are debilitating conditions that account for the leading causes of years lived with disability worldwide. Overcoming these disorders is an extremely important public health problem today. However, there are no biomarkers that are objective or easy-to-obtain in daily clinical practice, which leads to difficulties in assessing treatment response and developing new drugs. Due to advances in technology, it has become possible to quantify important features that clinicians perceive as reflective of disorder severity. Such features include facial expressions, phonic/speech information, body motion, daily activity, and sleep. The overall goal of this proposed study, the Project for Objective Measures Using Computational Psychiatry Technology (PROMPT), is to develop objective, noninvasive, and easy-to-use biomarkers for assessing the severity of depressive and neurocognitive disorders.MethodsThis is a multi-center prospective study. DSM-5 criteria for major depressive disorder, bipolar disorder, and major and minor neurocognitive disorders are inclusion criteria for the depressive and neurocognitive disorder samples. Healthy samples are confirmed to have no history of psychiatric disorders by Mini-International Neuropsychiatric Interview, and have no current cognitive decline based on the Mini Mental State Examination. Participants go through approximately 10-minute interviews with a psychiatrist/psychologist, where participants talk about non-specific topics such as everyday living, symptoms of disease, hobbies, etc. Interviews are recorded using RGB and infrared cameras, and an array microphone. As an option, participants are asked to wear wrist-band type devices during the observational period. The interviews take place ≤10 times within up to five years of follow-up. Various software is used to process the raw video, voice, infrared, and wearable device data. A machine learning approach is used to predict the presence of symptoms, severity, and the improvement/deterioration of symptoms.DiscussionThe PROMPT goal is to develop objective digital biomarkers for assessing the severity of depressive and neurocognitive disorders in the hopes of guiding decision-making in clinical settings as well as reducing the risk of clinical trial failure. Challenges may include the large variability of samples, which makes it difficult to extract the features that commonly reflect disorder severity.Trial RegistrationUMIN000021396, University Hospital Medical Information Network (UMIN)

The 18 kDa translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor, is predominately localized to the outer mitochondrial membrane in steroidogenic cells. Brain TSPO expression is relatively low under physiological conditions, but is upregulated in response to glial cell activation. As the primary index of neuroinflammation, TSPO is implicated in the pathogenesis and progression of numerous neuropsychiatric disorders and neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), multiple sclerosis (MS), major depressive disorder (MDD) and obsessive compulsive disorder (OCD). In this context, numerous TSPO-targeted positron emission tomography (PET) tracers have been developed. Among them, several radioligands have advanced to clinical research studies. In this review, we will overview the recent development of TSPO PET tracers, focusing on the radioligand design, radioisotope labeling, pharmacokinetics, and PET imaging evaluation. Additionally, we will consider current limitations, as well as translational potential for future application of TSPO radiopharmaceuticals. This review aims to not only present the challenges in current TSPO PET imaging, but to also provide a new perspective on TSPO targeted PET tracer discovery efforts. Addressing these challenges will facilitate the translation of TSPO in clinical studies of neuroinflammation associated with central nervous system diseases., Graphical abstract The 18 kDa translocator protein (TSPO) expression in the central nervous system is upregulated in response to glial cell activation. There is a great potential for the future application of TSPO radioligands as diagnostic and prognostic tools, as well as for assessing therapeutic interventions for neurologic diseases.Image 1

Highlights • Deep brain stimulation (DBS) benefits from precise targeting of white matter tracts. • Better to increase spatial vs. angular resolution for separating parallel tracts. • Scanning time trade-off between angular & spatial resolution depends on local anatomy. • We recommend increased spatial resolution dMRI for tract-guided internal capsule DBS., Given the restricted total scanning time for clinical neuroimaging, it is unclear whether clinical diffusion MRI protocols would benefit more from higher spatial resolution or higher angular resolution. In this work, we investigated the relative benefit of improving spatial or angular resolution in diffusion MRI to separate two parallel running white matter tracts that are targets for deep brain stimulation: the anterior thalamic radiation and the supero-lateral branch of the medial forebrain bundle. Both these tracts are situated in the ventral anterior limb of the internal capsule, and recent studies suggest that targeting a specific tract could improve treatment efficacy. Therefore, we scanned 19 healthy volunteers at 3T and 7T according to three diffusion MRI protocols with respectively standard clinical settings, increased spatial resolution of 1.4 mm, and increased angular resolution (64 additional gradient directions at b = 2200s/mm2). We performed probabilistic tractography for all protocols and quantified the separability of both tracts. The higher spatial resolution protocol improved separability by 41% with respect to the clinical standard, presumably due to decreased partial voluming. The higher angular resolution protocol resulted in increased apparent tract volumes and overlap, which is disadvantageous for application in precise treatment planning. We thus recommend to increase the spatial resolution for deep brain stimulation planning to 1.4 mm while maintaining angular resolution. This recommendation complements the general advice to aim for high angular resolution to resolve crossing fibers, confirming that the specific application and anatomical considerations are leading in clinical diffusion MRI protocol optimization.

Highlights • Stimulation closer to tracts was associated with better outcome in DBS for depression. • Lead placement was consistent across (non)responders w.r.t. anatomical landmarks. • Tractography-guided surgery needed to ensure tracts lie within activated tissue., Background Deep brain stimulation (DBS) is an innovative treatment for treatment-refractory depression. DBS is usually targeted at specific anatomical landmarks, with patients responding to DBS in approximately 50% of cases. Attention has recently shifted to white matter tracts to explain DBS response, with initial open-label trials targeting white matter tracts yielding much higher response rates (>70%). Objective/Hypothesis Our aim was to associate distance to individual white matter tracts around the stimulation target in the ventral anterior limb of the internal capsule to treatment response. Methods We performed diffusion magnetic resonance tractography of the superolateral branch of the medial forebrain bundle and the anterior thalamic radiation in fourteen patients that participated in our randomized clinical trial. We combined the tract reconstructions with the postoperative images to identify the DBS leads and estimated the distance between tracts and leads, which we subsequently associated with treatment response. Results Stimulation closer to both tracts was significantly correlated to a larger symptom decrease (r = 0.61, p = 0.02), suggesting that stimulation more proximal to the tracts was beneficial. Biophysical modelling indicated that 37.5% of tracts were even outside the volume of activated tissue. There was no difference in lead placement with respect to anatomical landmarks, which could mean that differences in treatment response were driven by individual differences in white matter anatomy. Conclusions Our results suggest that deep brain stimulation of the ventral anterior limb of the internal capsule could benefit from targeting white matter bundles. We recommend acquiring diffusion magnetic resonance data for each individual patient.

Background Anxiety and depression are common, debilitating and costly. These disorders are influenced by multiple risk factors, from genes to psychological vulnerabilities and environmental stressors, but research is hampered by a lack of sufficiently large comprehensive studies. We are recruiting 40,000 individuals with lifetime depression or anxiety and broad assessment of risks to facilitate future research. Methods The Genetic Links to Anxiety and Depression (GLAD) Study (www.gladstudy.org.uk) recruits individuals with depression or anxiety into the NIHR Mental Health BioResource. Participants invited to join the study (via media campaigns) provide demographic, environmental and genetic data, and consent for medical record linkage and recontact. Results Online recruitment was effective; 42,531 participants consented and 27,776 completed the questionnaire by end of July 2019. Participants’ questionnaire data identified very high rates of recurrent depression, severe anxiety, and comorbidity. Participants reported high rates of treatment receipt. The age profile of the sample is biased toward young adults, with higher recruitment of females and the more educated, especially at younger ages. Discussion This paper describes the study methodology and descriptive data for GLAD, which represents a large, recontactable resource that will enable future research into risks, outcomes, and treatment for anxiety and depression., Highlights • Online recruitment of 40,000 individuals with lifetime depression or anxiety. • Detailed online phenotyping combined with genetic and clinical data. • The study sample is severe, highly comorbid, with chronic psychopathology. • The study protocol enables recall of participants for future research and trials.

Background Deep brain stimulation (DBS) of the superolateral branch of the medial forebrain bundle (slMFB) emerges as a - yet experimental - treatment for major depressive disorder (MDD) and other treatment refractory psychiatric diseases. First experiences have been reported from two open label pilot trials in major depression (MDD) and long-term effectiveness for MDD (50 months) has been reported. Objective To give a detailed description of the surgical technique for DBS of the superolateral branch of the medial forebrain bundle (slMFB) in MDD. Methods Surgical experience from bilateral implantation procedures in n = 24 patients with MDD is reported. The detailed procedure of tractography-assisted targeting together with detailed electrophysiology in 144 trajectories in the target region (recording and stimulation) is described. Achieved electrode positions were evaluated based on postoperative helical CT and fused to preoperative high resolution anatomical magnetic resonance imaging (MRI; Philips Medical Systems, Best, Netherlands), including the pre-operative diffusion tensor imaging (DTI) tractographic information (StealthViz DTI, Medtronic, USA; Framelink 5.0, Medtronic, USA). Midcommissural point (MCP) coordinates of effective contact (EC) location, together with angles of entry into the target region were evaluated. To investigate incidental stimulation of surrounding nuclei (subthalamic nucleus, STN; substantia nigra, SNr; and red nucleus, RN) as a possible mechanism, a therapeutic triangle (TT) was defined, located between these structures (based on MRI criteria in T2) and evaluated with respect to EC locations. Results Bilateral slMFB DBS was performed in all patients. We identified an electrophysiological environment (defined by autonomic reaction, passive microelectrode recording, acute effects and oculomotor effects) that helps to identify the proper target site on the operation table. Postoperative MCP-evaluation of effective contacts (EC) shows a significant variability with respect to localization. Evaluation of the TT shows that responders will typically have their active contacts inside the triangle and that surrounding nuclei (STN, SNr, RN) are not directly hit by EC, indicating a predominant white matter stimulation. The individual EC position within the triangle cannot be predicted and is based on individual slMFB (tractography) geometry. There was one intracranial bleeding (FORESEE I study) during a first implantation attempt in a patient who later received full bilateral implantation. Typical oculomotor side effects are idiosyncratic for the target region and at inferior contacts. Conclusion The detailed surgical procedure of slMFB DBS implantation has not been described before. The slMFB emerges as an interesting region for the treatment of major depression (and other psychiatric diseases) with DBS. So far it has only been successfully researched in open label clinical case series and in 15 patients published. Stimulation probably achieves its effect through direct white-matter modulation of slMFB fibers. The surgical implantation comprises a standardized protocol combining tractographic imaging based on DTI, targeting and electrophysiological evaluation of the target region. To this end, slMFB DBS surgery is in technical aspects comparable to typical movement disorder surgery. In our view, slMFB DBS should only be performed under tractographic assistance., Graphical abstract Unlabelled Image, Highlights • The slMFB is an emerging target for DBS in therapy refractory Depression. • The therapeutic effect is related to modulation of white matter. • Surgery for slMFB DBS is tractography assisted surgery. • DBS of the slMFB is in many aspects similar to movement disorder surgery.

Highlights • Connectivity analyses complemented with a metric exploring switching in brain activity. • Lower insula-salience connectivity predicts insufficient antidepressant response. • This same insula region is activated less when switching from task to a rest. • This could be a potential biomarkers for predicting future antidepressant response., Insufficient response to treatment is the main cause of prolonged suffering from major depressive disorder (MDD). Early identification of insufficient response could result in faster and more targeted treatment strategies to reduce suffering. We therefore explored whether baseline alterations within and between resting state functional connectivity networks could serve as markers of insufficient response to antidepressant treatment in two years of follow-up. We selected MDD patients (N = 17) from the NEtherlands Study of Depression and Anxiety (NESDA), who received ≥ two antidepressants, indicative for insufficient response, during the two year follow-up, a group of MDD patients who received only one antidepressant (N = 32) and a healthy control group (N = 19) matched on clinical characteristics and demographics. An independent component analysis (ICA) of baseline resting-state scans was conducted after which functional connectivity within the components was compared between groups. We observed lower connectivity of the right insula within the salience network in the group with ≥ two antidepressants compared to the group with one antidepressant. No difference in connectivity was found between the patient groups and healthy control group. Given the suggested role of the right insula in switching between task-positive mode (activation during attention-demanding tasks) and task-negative mode (activation during the absence of any task), we explored whether right insula activation differed during switching between these two modes. We observed that in the ≥2 antidepressant group, the right insula was less active compared to the group with one antidepressant, when switching from task-positive to task-negative mode than the other way around. These findings imply that lower right insula connectivity within the salience network may serve as an indicator for prospective insufficient response to antidepressants. This result, supplemented by the diminished insula activation when switching between task and rest related networks, could indicate an underlying mechanism that, if not sufficiently targeted by current antidepressants, could lead to insufficient response. When replicated, these findings may contribute to the identification of biomarkers for early detection of insufficient response.

Screen-based sedentary behaviors and emotional disorders are associated with one another in youth. Yet, the direction of the association is unclear, as is whether specific types of screen-based sedentary behaviors and emotional disorder symptoms are more closely linked. This study estimated the bi-directional associations between two types of screen-based sedentary behaviors and four types of self-reported emotional disorder symptoms, and tested whether physical activity buffered these associations in a Los Angeles high school student cohort (N = 2525, baseline Mage = 14.6 years). Participants completed baseline (9th Grade, 2013) and 12-month follow-up (10th grade, 2014) surveys reporting on: television viewing and computer/videogame use (≥4 h/day; yes/no), physical activity (≥60 min/day for ≥5 days/week), and Major Depressive Disorder (MDD), Generalized Anxiety Disorder (GAD), Panic Disorder (PD), and Social Phobia (SP) symptoms (meet/exceed [sub]clinical symptom threshold; yes/no). After adjusting for baseline screen-based sedentary behavior and covariates, students with (sub)clinical baseline MDD and GAD were at increased odds of high computer/videogame use one year later (OR = 1.36[95%CI, 1.07–1.73]; OR = 1.36[95%CI,1.09–1.71], respectively). Baseline SP was marginally related to increased computer/videogame use at follow-up (OR = 1.33[95%CI,1.04–1.69]). Greater baseline computer/videogame use was associated with increased odds of (sub)clinical GAD (OR = 1.54[95%CI,1.23–1.94]) and (sub)clinical SP (OR = 1.64[95%CI 1.27–2.12]) at follow-up; these associations were suppressed among baseline physically active students. Television viewing was unrelated to emotional disorder symptoms and PD was not associated with screen-based sedentary behaviors. Thus, only reciprocal associations between computer/videogame use, SP, and GAD during a one-year period of adolescence were observed. Interventions reducing computer/videogame use and increasing physical activity may improve adolescent emotional health., Highlights • Computer/videogames relate to emotional health, independent of television viewing. • Computer/videogames specifically relate to generalized anxiety and social phobia. • Findings provide evidence of bi-directionality of the above associations. • Physical activity weakened the computer/videogame-emotional health associations.

Background Numerous cognitive and emotional functions are executed asymmetrically between the left and right hemispheres. Right hemisphere hyperactivity/left hemisphere hypoactivity often appears to be a feature in neuroimaging studies of depression. However, few studies have evaluated abnormalities in structural asymmetry in untreated patients with major depressive disorder (MDD). Methods In this study, 3-dimensional high-resolution structural magnetic resonance images were acquired from 35 treatment-naïve patients with MDD (mean age = 28.9 years, 22 females) and 35 normal controls. The asymmetry index in cortical thickness and subcortical volume were calculated based on an automated surface-based technique. Results Abnormalities in structural asymmetry in patients with MDD were mainly located in the cortical-striatal-pallidal-thalamic circuit, including the superior frontal cortex, rostral middle frontal cortex, caudal middle frontal cortex, nucleus accumbens, pallidum and thalamus. No significant correlation was observed between symptom severity and asymmetric measurements. Conclusion These findings provide further evidence for the altered morphological interhemispheric imbalances in depression and these alterations were independent of depressive symptom severity, suggesting that cerebral asymmetry could be an appropriate indicator of morphological variations in mental disease., Highlights • Cortical asymmetric changes in depression mainly involved the frontal cortex. • Clinical variables were not associated with cerebral asymmetry. • Cerebral asymmetry could be an indicator of morphological variations in depression.

Highlights • The Brain/MINDS beyond project plans to collect multi-site/scanner brain MRI data. • Prospective harmonization of MRI was achieved by standardizing scanning protocols. • The preliminary data showed moderate reliability of brain connectome data. • Completing traveling subject plan will allow robust statistical harmonization. • Scanning protocols are publicly available and data will also be shared by 2024., Psychiatric and neurological disorders are afflictions of the brain that can affect individuals throughout their lifespan. Many brain magnetic resonance imaging (MRI) studies have been conducted; however, imaging-based biomarkers are not yet well established for diagnostic and therapeutic use. This article describes an outline of the planned study, the Brain/MINDS Beyond human brain MRI project (BMB-HBM, FY2018 ~ FY2023), which aims to establish clinically-relevant imaging biomarkers with multi-site harmonization by collecting data from healthy traveling subjects (TS) at 13 research sites. Collection of data in psychiatric and neurological disorders across the lifespan is also scheduled at 13 sites, whereas designing measurement procedures, developing and analyzing neuroimaging protocols, and databasing are done at three research sites. A high-quality scanning protocol, Harmonization Protocol (HARP), was established for five high-quality 3 T scanners to obtain multimodal brain images including T1 and T2-weighted, resting-state and task functional and diffusion-weighted MRI. Data are preprocessed and analyzed using approaches developed by the Human Connectome Project. Preliminary results in 30 TS demonstrated cortical thickness, myelin, functional connectivity measures are comparable across 5 scanners, suggesting sensitivity to subject-specific connectome. A total of 75 TS and more than two thousand patients with various psychiatric and neurological disorders are scheduled to participate in the project, allowing a mixed model statistical harmonization. The HARP protocols are publicly available online, and all the imaging, demographic and clinical information, harmonizing database will also be made available by 2024. To the best of our knowledge, this is the first project to implement a prospective, multi-level harmonization protocol with multi-site TS data. It explores intractable brain disorders across the lifespan and may help to identify the disease-specific pathophysiology and imaging biomarkers for clinical practice.

Evidence indicates meditation facilitates affective regulation and reduces negative affect. It also influences resting-state functional connectivity between affective networks and the posterior cingulate (PCC)/precuneus, regions critically implicated in self-referential processing. However, no longitudinal study employing active control group has examined the effect of meditation training on affective processing, PCC/precuneus connectivity, and their association. Here, we report that eight-week meditation, but not relaxation, training ‘neutralized’ affective processing of positive and negative stimuli in healthy elderly participants. Additionally, meditation versus relaxation training increased the positive connectivity between the PCC/precuneus and the pons, the direction of which was largely directed from the pons to the PCC/precuneus, as revealed by dynamic causal modeling. Further, changes in connectivity between the PCC/precuneus and pons predicted changes in affective processing after meditation training. These findings indicate meditation promotes self-referential affective regulation based on increased regulatory influence of the pons on PCC/precuneus, which new affective-processing strategy is employed across both resting state and when evaluating affective stimuli. Such insights have clinical implications on interventions on elderly individuals with affective disorders., Highlights • Meditation training in the elderly “neutralized” affective processing • Meditation training in the elderly increased pons-to-PCC resting-state connectivity • Meditation promotes affective regulation via increased influence of pons on PCC. As an increasingly popular practice, meditation is considered to facilitate affective regulation and positive mind state. Here we report meditation training versus active control ‘neutralized’ elderly participants' positive and negative affective processing, and led to more positive resting-state connectivity from the pontine nuclei, which regulates affective processing, to the posterior cingulate/precuneus which engages in self-referential processing. Further, the change in pons-to-posterior cingulate connectivity predicted change in affective processing in the meditation, but not active control, group. These findings indicate that meditation enhances affective regulatory capacities, with a neural basis of increased influence of the pontine nuclei on the posterior cingulate/precuneus.

Ketamine has been reported to exert a prophylactic effect against stress-induced depressive-like behavior by modulating the guanosine-based purinergic system. However, the molecular pathways underlying its prophylactic effect and whether guanosine also elicits a similar effect remain to be determined. Here, we investigated the prophylactic effect of ketamine and guanosine against corticosterone (CORT – 20 mg/kg, p.o.)-induced depressive-like behavior in mice. Furthermore, we characterized if the prophylactic response may be associated with mTORC1-driven signaling in the hippocampus and prefrontal cortex. A single administration of ketamine (5 mg/kg, i.p.), but not guanosine (1 or 5 mg/kg, p.o.), given 1 week before the pharmacological stress prevented CORT-induced depressive-like behavior in the tail suspension test (TST) and splash test (SPT). Fluoxetine treatment for 3 weeks did not prevent CORT-induced behavioral effects. A single administration of subthreshold doses of ketamine (1 mg/kg, i.p.) plus guanosine (5 mg/kg, p.o.) partially prevented the CORT-induced depressive-like behavior in the SPT. Additionally, CORT reduced Akt (Ser473) and GSK-3β (Ser9) phosphorylation and PSD-95, GluA1, and synapsin immunocontent in the hippocampus, but not in the prefrontal cortex. No alterations on mTORC1/p70S6K immunocontent were found in both regions in any experimental group. CORT-induced reductions on PSD-95, GluA1, and synapsin immunocontent were prevented only by ketamine treatment. Collectively, these findings suggest that ketamine, but not guanosine, exerts a prophylactic effect against depressive-like behavior, an effect associated with the stimulation of long-lasting pro-synaptogenic signaling in the hippocampus., Highlights • CORT induces depressive-like behavior and hippocampal synaptogenic markers deficits. • Ketamine prevents CORT-induced behavioral and hippocampal synaptogenic alterations. • Guanosine or fluoxetine are unable to prevent the alterations induced by CORT. • Ketamine plus guanosine partially prevent CORT-induced reduced self-care behavior.

Background Incomplete hippocampal inversion (IHI), also called malrotation, is a frequent atypical anatomical pattern of the hippocampus. Because of the crucial implication of the hippocampus in Major Depressive Disorder (MDD) and the neurodevelopmental hypothesis of MDD, we aimed to assess the prevalence of IHI in patients with MDD, the link of IHI with hippocampal volume (HV) and the impact of IHI on the predictive value of HV for response and remission after antidepressant treatment. Methods IHI (right and left, partial and total and IHI scores) and HV were assessed in 60 patients with a current Major Depressive Episode (MDE) in a context of MDD and 60 matched controls. Patients were prospectively assessed at baseline and after one, three and six months of antidepressant treatment for response and remission. Results The prevalence of IHI did not significantly differ between MDD patients (right = 23.3%; left = 38.3%) and controls (right = 16.7%; left = 33.3%). IHI was not significantly associated with MDD clinical characteristics. IHI alone did not predict response and remission after antidepressant treatment. However, an interaction between left HV and left IHI predicted six-month response (p = 0.04), HDRS score decrease (p = 0.02) and both three-month (p = 0.04) and six-month (p = 0.03) remission. A case-control design in 30 matched patients with or without left IHI confirmed that interaction. In patients without left IHI, left HV at baseline were smaller in six-month non-remitters as compared to remitters (2.2(± 0.43) cm3 vs 2.97(± 0.5) cm3 p = 0.02), and in six-month non-responders as compared to responders (2.18(± 0.42) cm3 vs 2.86(± 0.54) cm3, p = 0.03). In patients with left IHI, no association was found between left HV at baseline and antidepressant response and remission. Conclusion IHI is not more frequent in MDD patients than in controls, is not associated with HV, but is a confounder that decreases the predictive value of hippocampal volume to predict response or remission after antidepressant treatment. IHI should be systematically assessed in future research studies assessing hippocampal volume in MDD., Highlights • Incomplete hippocampal inversion (IHI) is not significantly more frequent in MDD than in controls. • IHI is not significantly associated with MDD clinical characteristics. • Hippocampal volume predicts antidepressant efficacy in MDD patients without IHI. • Hippocampal volume does not predict antidepressant efficacy in patients with IHI.

Purpose Our aim is to examine which risk factors have a greater impact in women than in men on the risk of major depressive disorder (MDD) and whether factors differ between a possible recurrent MDD and a first onset of MDD. Methods Prospective cohort study of general practice attendees in seven countries, who were followed up at 6 and 12 months (predictD). Absolute risk differences (interaction contrast) across sex for onset of DSM-IV MDD after 6 or 12 months of follow-up were estimated for 35 risk factors from 7101 participants without MDD at baseline. Results A total of 599 participants (80% female) had an onset of MDD at 6 or 12 months. Most risk factors had a greater impact in women than in men on the risk of MDD and were not restricted to a specific class of risk factors. After we stratified for a history of depressive symptoms, we found that the impact of risk factors across sex was generally stronger on possible recurrent MDD than on a first onset of MDD. Conclusions Our findings may partly account for the observed difference in incidence of MDD between men and women.

Major depressive disorder (MDD) and bipolar disorder (BD) are severe psychiatric diseases with overlapping symptomatology. Although previous studies reported abnormal brain structures in MDD or BD patients, the disorder-specific underlying neural mechanisms remain poorly understood. The purpose of this study was to investigate the whole-brain gray matter morphological patterns in unmedicated patients with MDD or BD and to identify the shared and disease-specific brain morphological alterations in these two disorders. We acquired high-resolution brain structural MRI data from a sample of 36 MDD patients, 32 BD patients, and 30 healthy controls. Using FreeSurfer, we estimated their brain cortical thickness (CT) and compared between-group difference in multiple locations across the continuous cortical surface. Compared to the healthy controls, both the MDD and BD patient groups showed significantly reduced CT in the left inferior temporal cortex (ITC). However, compared to the MDD patients, the BD patients showed a significantly thinner CT in the left rostral middle frontal region. In addition, compared to the healthy controls, the BD patients displayed thinner CT in the left ITC, left frontal pole (FPO), left superior frontal, right lateral occipital, right pars triangularis (PTRI) and right lateral orbitofrontal regions. Further analysis revealed a significantly positive correlation between the mean CT in the left FPO and the onset age, but a negative correlation between the mean CT in the right PTRI and the number of episodes, in the BD patients. Our findings revealed that the BD and MDD patients had variations in CT that were in common, but many more that were distinct, suggesting potential differences in their neural mechanisms., Highlights • We found thinner CT in the left ITC in both MDD and BD groups compared to controls. • We detected thinner CT in the left rMFC in the BD group compared to the MDD group. • The BD group had more pronounced abnormality in CT primarily in the PFC than the MDD group. • Clinical variables of BD group were associated with decreased CT in the left FPO and right PTRI. This study aims to detect abnormal cortical thickness in patients with major depressive disorder (MDD) or bipolar disorder (BD), and to identify the shared and disease-specific brain morphological alterations in these two disorders. The two patient groups showed several common but more distinct variation patterns in cortical thickness, and the BD patients had lower cortical thickness in widespread brain areas than the MDD and the controls. These findings may have potential clinical implications for distinguishing BD from MDD patients.

Astrocytes control tissue equilibrium and hence define the homoeostasis and function of the CNS (central nervous system). Being principal homoeostatic cells, astroglia are fundamental for various forms of neuropathology, including AD (Alzheimer's disease). AD is a progressive neurodegenerative disorder characterized by the loss of cognitive functions due to specific lesions in mnesic-associated regions, including the mPFC (medial prefrontal cortex). Here, we analyzed the expression of GS (glutamine synthetase) and GLT-1 (glutamate transporter-1) in astrocytes in the mPFC during the progression of AD in a triple-transgenic mouse model (3xTg-AD). GS is an astrocyte-specific enzyme, responsible for the intracellular conversion of glutamate into glutamine, whereas the removal of glutamate from the extracellular space is accomplished mainly by astroglia-specific GLT-1. We found a significant decrease in the numerical density (Nv, cells/mm3) of GS-positive astrocytes from early to middle ages (1–9 months; at the age of 1 month by 17%, 6 months by 27% and 9 months by 27% when compared with control animals) in parallel with a reduced expression of GS (determined by Western blots), which started at the age of 6 months and was sustained up to 12 months of age. We did not, however, find any changes in the expression of GLT-1, which implies an intact glutamate uptake mechanism. Our results indicate that the decrease in GS expression may underlie a gradual decline in the vital astrocyte-dependent glutamate–glutamine conversion pathway, which in turn may compromise glutamate homoeostasis, leading towards failures in synaptic connectivity with deficient cognition and memory.

Despite converging evidence that major depressive illness is associated with both memory impairment and hippocampal pathology, findings vary widely across studies and it is not known whether these changes are regionally specific. In the present study we acquired brain MRIs (magnetic resonance images) from 31 unmedicated patients with MDD (major depressive disorder; mean age 39.2±11.9 years; 77% female) and 31 demographically comparable controls. Three-dimensional parametric mesh models were created to examine localized alterations of hippocampal morphology. Although global volumes did not differ between groups, statistical mapping results revealed that in MDD patients, more severe depressive symptoms were associated with greater left hippocampal atrophy, particularly in CA1 (cornu ammonis 1) subfields and the subiculum. However, previous treatment with atypical antipsychotics was associated with a trend towards larger left hippocampal volume. Our findings suggest effects of illness severity on hippocampal size, as well as a possible effect of past history of atypical antipsychotic treatment, which may reflect prolonged neuroprotective effects. This possibility awaits confirmation in longitudinal studies.

Background Depression often co-occurs in late-life in the context of declining cognitive functions, but it is not clear whether specific depression symptom dimensions are differentially associated with cognitive abilities. Methods The study sample comprised 3107 community-dwelling older adults from the Longitudinal Aging Study Amsterdam (LASA). We applied a Multiple Indicators Multiple Causes (MIMIC) model to examine the association between cognitive abilities and latent dimensions of the Center for Epidemiologic Studies Depression Scale (CES-D), while accounting for differential item functioning (DIF) due to age, gender and cognitive function levels. Results A factor structure consisting of somatic symptoms, positive affect, depressed affect, and interpersonal difficulties fitted the data well. Higher levels of inductive reasoning were significantly associated with lower levels of depressed affect and somatic symptoms, whereas faster processing speed was significantly associated with lower levels of somatic symptoms. DIF due to age and gender was found, but the magnitude of the effects was small and did not alter substantive conclusions. Limitations Due to the cross-sectional context of this investigation, the direction of influence between depression symptom levels and cognitive function levels cannot be established. Furthermore, findings are relevant to non-clinical populations, and they do not clarify whether certain DIF effects may be found only at high or low levels of depression. Conclusions Our findings suggest differential associations between late-life depression dimensions and cognitive abilities in old age, and point towards potential etiological mechanisms that may underline these associations. These findings carry implications for the prognosis of cognitive outcomes in depressed older adults., Highlights • Better inductive reasoning was associated with lower severity of depressed affect. • Better inductive reasoning was associated with lower severity of somatic symptoms. • Faster processing speed was associated with lower severity of somatic symptoms. • DIF due to age and gender was statistically significant but of small magnitude. • No DIF due to level of cognitive functioning was found.

Abnormalities in functional limbic–anterior cingulate–prefrontal circuits associated with emotional reactivity, evaluation and regulation have been implicated in the pathophysiology of major depressive disorder (MDD). However, existing knowledge about structural alterations in depression is equivocal and based on cohorts of limited sample size. This study used voxel-based morphometry (VBM) and surface-based cortical thickness to investigate the structure of these circuits in a large and well-characterized patient cohort with MDD. Non-geriatric MDD outpatients (n = 102) and age- and gender-matched healthy control participants (n = 34) provided T1-weighted magnetic resonance imaging data during their baseline visit as part of the International Study to Predict Optimized Treatment for Depression. Whole-brain VBM volumetric and surface-based cortical thickness assessments were performed voxel-wise and compared (at p, Highlights • Focal gray matter volume decrease in depression exceeded loss via aging 11–50 years. • Gray matter differences were found in regions with established roles in depression. • Structural change findings support the idea of depression as a network abnormality. • Hippocampal gray matter volume loss likely has no role in non-geriatric depression. • Amygdala gray matter volume loss likely plays no role in depression pathophysiology.

Highlights • Astrocytes are active dynamic signalling players of the brain. • Dysfunctions of astrocytes can contribute to the pathogenesis of brain disorders. • A common pathological hallmark of several CNS diseases is reactive astrogliosis. • Targeting astrocytes represent an alternative approach to develop new therapies., Astrocytes are key active elements of the brain that contribute to information processing. They not only provide neurons with metabolic and structural support, but also regulate neurogenesis and brain wiring. Furthermore, astrocytes modulate synaptic activity and plasticity in part by controlling the extracellular space volume, as well as ion and neurotransmitter homeostasis. These findings, together with the discovery that human astrocytes display contrasting characteristics with their rodent counterparts, point to a role for astrocytes in higher cognitive functions. Dysfunction of astrocytes can thereby induce major alterations in neuronal functions, contributing to the pathogenesis of several brain disorders. In this review we summarize the current knowledge on the structural and functional alterations occurring in astrocytes from the human brain in pathological conditions such as epilepsy, primary tumours, Alzheimer’s disease, major depressive disorder and Down syndrome. Compelling evidence thus shows that dysregulations of astrocyte functions and interplay with neurons contribute to the development and progression of various neurological diseases. Targeting astrocytes is thus a promising alternative approach that could contribute to the development of novel and effective therapies to treat brain disorders.

Background The Euro-D depression scale consists of symptom clusters that may be differentially related to demographic and cognitive characteristics in older adults. This hypothesis needs further investigation and the role of measurement bias on substantive conclusions remains to be established. Method The study sample comprised 10,405 community-dwelling older adults from six Latin American countries. We applied a Multiple Indicators Multiple Causes (MIMIC) model for a concurrent investigation of measurement bias and of the association between Euro-D symptom clusters and background variables. Results The factorial validity of Euro-D, with a two-dimensional structure – affective suffering and motivation disturbance, was consistently supported in all countries. Although complete measurement invariance could not be assumed across countries, measurement bias was minor. Both Euro-D factors were unrelated to age, but related to gender, as well as to impairment in memory and verbal fluency. Gender differences were larger for affective suffering than for motivation disturbance, whereas differences in verbal fluency impairment were more strongly related to motivation disturbance. Limitations Our analytic strategies could only examine invariance at the level of indicator thresholds. The generalisability of current findings needs to be examined in clinical populations. A wider set of cognitive tests is needed. We did not examine the compositional factors that could have accounted for the variation in Euro-D scores across countries, as this was beyond the aims of the paper. Conclusion The current study adds evidence for the construct validity of Euro-D and for the possible differential association of depression symptom-clusters with gender and verbal fluency in older adults. An understanding of the heterogeneity of late-life depression may carry clinical implications for the diagnosis and treatment of depression in old age., Highlights • The Euro-D factor structure was invariant across Latin American countries. • Measurement bias was minor and did not alter substantive conclusions. • Depression domains were differentially related to gender and cognitive function. • Depression domains were unrelated to age. • Cognitive function levels confounded the effect of age on depression domains.