Multi-modal morphometric association study of subclinical depressive symptoms using voxel-based morphometry, cortical thickness, and diffusion tensor imaging (DTI).

BACKGROUND: Case-control studies in major depression have established numerous regional grey and white matter effects in fronto-limbic brain regions. Yet, brain structural studies of dimensional depressive psychopathology within the subclinical spectrum are still limited, in particular for multi-modal imaging approaches. METHODS: Using voxel-based and surface-based morphometry (cortical thickness) in combination with diffusion tensor imaging (DTI) in a large non-clinical sample (N = 300), we correlated grey and white matter structural variation with subclinical depressive symptoms assessed with Beck's Depression inventory (BDI). RESULTS: We found a significant decrease of axial diffusivity associated with higher BDI scores in the left hippocampal part of the cingulum bundle (p < 0.05, threshold free cluster enhanced [TFCE] p-value) and some grey matter trend results e.g., a non-linear negative correlation of cortical thickness with depressive symptom load in the right pre/postcentral cortex (pFWE = 0.054, family wise error [FWE] peak level corrected) and a trend in grey matter volume decrease in women in the inferior frontal gyrus (pFWE = 0.054). LIMITATIONS: Since all grey matter effects disappear after FWE correction, we assume more stable effects in a larger, less homogenous sample enriched by help-seeking subjects covering a wider range of subclinical psychopathology. CONCLUSION: Our study adds correlations between single depressive symptoms and brain structure to a growing literature. Since subclinical depression is increasingly recognised to be relevant in our understanding of manifest depression, early detection and identification of potential brain correlates of minor depressive symptoms has the potential to expand and reveal possible biomarkers and early psychological treatment.

Individualized prediction of cognitive test scores from functional brain connectome in patients with first-episode late-life depression.

BACKGROUND: In the realm of cognitive screening, the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) are widely utilized for detecting cognitive deficits in patients with late-life depression (LLD), However, the interindividual variability in neuroimaging biomarkers contributing to individual-specific symptom severity remains poorly understood. In this study, we used a connectome-based predictive model (CPM) approach on resting-state functional magnetic resonance imaging data from patients with LLD to establish individualized prediction models for the MoCA and the MMSE scores. METHODS: We recruited 135 individuals diagnosed with first-episode LLD for this research. Participants underwent the MMSE and MoCA tests, along with resting-state functional magnetic resonance imaging scans. Functional connectivity matrices derived from these scans were utilized in CPM models to predict MMSE or MoCA scores. Predictive precision was assessed by correlating predicted and observed scores, with the significance of prediction performance evaluated through a permutation test. RESULTS: The negative model of the CPM procedure demonstrated a significant capacity to predict MoCA scores (r = -0.309, p = 0.002). Similarly, the CPM procedure could predict MMSE scores (r = -0.236, p = 0.016). The predictive models for cognitive test scores in LLD primarily involved the visual network, somatomotor network, dorsal attention network, and ventral attention network. CONCLUSIONS: Brain functional connectivity emerges as a promising predictor of personalized cognitive test scores in LLD, suggesting that functional connectomes are potential neurobiological markers for cognitive performance in patients with LLD.

Effects of lockdowns on neurobiological and psychometric parameters in unipolar depression during the COVID-19 pandemic.

Defying the COVID-19 pandemic required restriction measures of unprecedented scale, that may induce and exacerbate psychiatric symptoms across the population. We aimed to assess in vivo dynamic effects of mitigation strategies on human brain neurobiology, neuroplastic as well as psychometric parameters. Three structural magnetic resonance imaging measurements, serum brain-derived neurotrophic factor (sBDNF) analyses, and psychometric assessments (Beck Depression Inventory-II and Perceived Stress Questionnaire-20) were performed in healthy individuals and patients with a recurrent major depressive disorder in the period from September 2020 to July 2021. Group differences and changes over time in structural imaging, neuroplastic and psychometric parameters were assessed with linear mixed models. Analysis of data from 18 patients with a recurrent major depressive disorder and 28 healthy individuals showed clinically relevant scores for depression and stress in the patient group as well as significant cross-sectional differences in depression scores (F = 30.89, p < 0.001) and three subscales of the Perceived Stress Questionnaire (Worries: F = 19.19, p < 0.001, Tension: F = 34.44, p < 0.001, Joy: F = 12.05, p = 0.001). Linear mixed models revealed no significant changes over time in cortical thickness of the prefrontal cortex, anterior cingulate cortex, hippocampus, and amygdala (F = 0.29, p > 0.1) and no interaction with group (F = 0.28, p > 0.1). Further, analysis revealed no main effect of time and no interaction of time x group in depressive symptoms, perceived stress subscales, and sBDNF (all p > 0.1). Despite the limited sample size, the strength of this investigation lies in the multimodal assessment of peri-pandemic lockdown effects. Nine months of varying restrictions measures did not result in observable changes in brain morphology nor impact depressive symptoms in either psychiatric patients with a recurrent major depressive disorder or healthy individuals. While these neurobiological and psychometric data stand in contrast to initial expectations about the effects of restriction measures, they might inform future investigations of longitudinal effects of restriction measures on mental health.

Modulatory effects of aerobic training on the degree centrality of brain functional activity in subthreshold depression.

BACKGROUND: Aerobic training has been shown to effectively prevent the progression of depressive symptoms from subthreshold depression (StD) to major depressive disorder (MDD), and understanding how aerobic training promotes changes in neuroplasticity is essential to comprehending its antidepressant effects. Few studies, however, have quantified the alterations in spontaneous brain activity before and after aerobic training for StD. METHODS: Participants included 44 individuals with StD and 34 healthy controls (HCs). Both groups underwent moderate aerobic training for eight weeks, and resting state functional magnetic resonance imaging (rs-fMRI) data were collected before and after training. The degree centrality (DC) changes between the two groups and the DC changes in each group before and after training were quantified. RESULTS: The rs-fMRI results showed that compared with the HCs, the DC values of the StD group in the orbital region of the left inferior frontal gyrus significantly depreciated at baseline. After aerobic training, the results of the follow-up examination revealed no significant difference in the DC values between the two groups. In addition, compared with baseline, the StD group exhibited an significant decrease in the DC values of the left dorsolateral superior frontal gyrus; while the HCs group exhibited an significant decrease in the DC values of the left thalamus. No statistically significant connection was seen between changes in DC values and psychological scale scores in the StD group. CONCLUSIONS: Our findings suggest that regular aerobic training can enhance brain plasticity in StD. In addition, we demonstrated that DC is a relevant and accessible method for evaluating the functional plasticity of the brain induced by aerobic training in StD.

Upregulation of KLK8 contributes to CUMS-induced hippocampal neuronal apoptosis by cleaving NCAM1.

Neuronal apoptosis has been well-recognized as a critical mediator in the pathogenesis of depressive disorders. Tissue kallikrein-related peptidase 8 (KLK8), a trypsin-like serine protease, has been implicated in the pathogenesis of several psychiatric disorders. The present study aimed to explore the potential function of KLK8 in hippocampal neuronal cell apoptosis associated with depressive disorders in rodent models of chronic unpredictable mild stress (CUMS)-induced depression. It was found that depression-like behavior in CUMS-induced mice was associated with hippocampal KLK8 upregulation. Transgenic overexpression of KLK8 exacerbated, whereas KLK8 deficiency attenuated CUMS-induced depression-like behaviors and hippocampal neuronal apoptosis. In HT22 murine hippocampal neuronal cells and primary hippocampal neurons, adenovirus-mediated overexpression of KLK8 (Ad-KLK8) was sufficient to induce neuron apoptosis. Mechanistically, it was identified that the neural cell adhesion molecule 1 (NCAM1) may associate with KLK8 in hippocampal neurons as KLK8 proteolytically cleaved the NCAM1 extracellular domain. Immunofluorescent staining exhibited decreased NCAM1 in hippocampal sections obtained from mice or rats exposed to CUMS. Transgenic overexpression of KLK8 exacerbated, whereas KLK8 deficiency largely prevented CUMS-induced loss of NCAM1 in the hippocampus. Both adenovirus-mediated overexpression of NCAM1 and NCAM1 mimetic peptide rescued KLK8-overexpressed neuron cells from apoptosis. Collectively, this study identified a new pro-apoptotic mechanism in the hippocampus during the pathogenesis of CUMS-induced depression via the upregulation of KLK8, and raised the possibility of KLK8 as a potential therapeutic target for depression.

Lipopolysaccharide-induced endotoxaemia during adolescence promotes stress vulnerability in adult mice via deregulation of nuclear factor erythroid 2-related factor 2 in the medial prefrontal cortex.

RATIONALE: Sepsis is a severe inflammatory response to infection that leads to long-lasting cognitive impairment and depression after resolution. The lipopolysaccharide (LPS)-induced endotoxaemia model is a well-established model of gram-negative bacterial infection and recapitulates the clinical characteristics of sepsis. However, whether LPS-induced endotoxaemia during adolescence can modulate depressive and anxiety-like behaviours in adulthood remains unclear. OBJECTIVES: To determine whether LPS-induced endotoxaemia in adolescence can modulate the stress vulnerability to depressive and anxiety-like behaviours in adulthood and explore the underlying molecular mechanisms. METHODS: Quantitative real-time PCR was used to measure inflammatory cytokine expression in the brain. A stress vulnerability model was established by exposure to subthreshold social defeat stress (SSDS), and depressive- and anxiety-like behaviours were evaluated by the social interaction test (SIT), sucrose preference test (SPT), tail suspension test (TST), force swimming test (FST), elevated plus-maze (EPM) test, and open field test (OFT). Western blotting was used to measure Nrf2 and BDNF expression levels in the brain. RESULTS: Our results showed that inflammation occurred in the brain 24 h after the induction of LPS-induced endotoxaemia at P21 but resolved in adulthood. Furthermore, LPS-induced endotoxaemia during adolescence promoted the inflammatory response and the stress vulnerability after SSDS during adulthood. Notably, the expression levels of nuclear factor erythroid 2-related factor 2 (Nrf2) and BDNF in the mPFC were decreased after SSDS exposure in mice treated with LPS during adolescence. Activation of the Nrf2-BDNF signalling pathway by sulforaphane (SFN), an Nrf2 activator, ameliorated the effect of LPS-induced endotoxaemia during adolescence on stress vulnerability after SSDS during adulthood. CONCLUSIONS: Our study identified adolescence as a critical period during which LPS-induced endotoxaemia can promote stress vulnerability during adulthood and showed that this effect is mediated by impairment of Nrf2-BDNF signalling in the mPFC.

The Greater Impact of Paternal, Compared to Maternal, Hereditary Background on Depressive-Like Behavior in Wistar Kyoto Rats with Different Amino Acid Metabolism in the Pup Brain.

In the pathogenesis of depression, heredity is believed to be a major factor. However, the mechanism by which heredity contributes to the onset of depression is not fully understood. Wistar Kyoto (WKY) rats have been used as an animal model for depression because of their increased depression-like behavior compared to Wistar (WIS) rats. In the present study, pups crossbred from WKY × WIS rats were used to evaluate locomotor activity in an open field test (OFT) and depression-like behavior in a forced swimming test (FST), with a focus on amino acid metabolism. Pups in the WKY♂ × WKY♀ group showed lower locomotor activity in the OFT and higher depression-like behavior in the FST than those in the WIS♂ × WIS♀ group. In addition, multiple regression analysis showed that the paternal strain had a greater effect than the maternal strain on locomotor activity and depression-like behavior in OFT and FST, respectively. Several amino acids in the brainstem, hippocampus, and striatum were significantly decreased through the influence of the WKY paternal strain, but not the WKY maternal strain. Based on these data from comparing WKY and WIS rats, we hypothesize that the hereditary effects of the WKY paternal strain on behavioral tests are partially caused by dysregulation of the amino acid metabolism in the brain.

Mirtazapine modulates Glutamate and GABA levels in the animal model of maternal depression. MRI and 1H MRS study in female rats.

We aimed to determine, using in vivo magnetic resonance, whether maternal depression induced by chronic unpredictable stress (CUS) in the pre-gestational period in female rats would be evidenced by structural or neurometabolic changes in the hippocampal region of the brain. At the same time, appropriate behavioral tests were also administered after a relatively long two-month period of a stress paradigm. The objective of the study was not only to study an animal model of CUS using magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (1H MRS) focused on the hippocampus, but also to use this technique to verify the effectiveness of mirtazapine antidepressant treatment. In the group with CUS, we found a significant decrease in the relative concentration of γ-aminobutyric acid (GABA/tCr) and glutamate+glutamine (Glx/tCr) compared to the control group, while we did not observe any statistically significant change in hippocampal volumes. Moreover, the forced swim test revealed an increase in depression-like behavior. The most important finding was the return of GABA/tCr and Glx/tCr levels to control levels during mirtazapine treatment; however, behavioral tests did not demonstrate any effects from mirtazapine treatment. In vivo1H MRS confirmed mirtazapine modulation of CUS in an animal model more robustly than behavioral tests.

Disrupted intrinsic functional brain network in patients with late-life depression: Evidence from a multi-site dataset.

BACKGROUND: Late-life depression (LLD) is a common and serious mental disorder, whose neural mechanisms are not yet fully understood. In this study, we aimed to characterize LLD-related changes in intrinsic functional brain networks using a large, multi-site sample. METHODS: Using resting-state functional magnetic resonance imaging, the edge-based functional connectivity (FC) as well as multiple topological brain network metrics at both global and nodal levels were compared between 206 LLD patients and 210 normal controls (NCs). RESULTS: Compared with NCs, the LLD patients had extensive alterations in the intrinsic brain FCs, especially significant decreases in FCs within the default mode network (DMN) and within the somatomotor network (SMN). The LLD patients also showed alterations in several global brain network metrics compared with NCs, including significant decreases in global efficiency, local efficiency, clustering coefficient, and small-worldness, as well as a significantly increased characteristic path length. Moreover, significant alterations in nodal network metrics (increased nodal betweenness and decreased nodal efficiency) were found in patients with LLD, which mainly involved the DMN and SMN. Post-hoc subgroup analyses indicated that the above changes in FC strengths were present in both first-episode, drug-naïve (FEDN) and non-FEDN patients, and were correlated with depression severity in the FEDN patients. Moreover, changes in FC strengths were found in both the early/late-onset (depression starts before/after the age of 50) patients, while altered topological metrics were found in only the late-onset patients. CONCLUSIONS: These results may help to strengthen our understanding of the underlying neural mechanisms and biological heterogeneity in LLD.

Lack of bombesin receptor-activated protein homologous protein impairs hippocampal synaptic plasticity and promotes chronic unpredictable mild stress induced behavioral changes in mice.

Bombesin receptor-activated protein (BRAP) and its homologous protein in mice, which is encoded by bc004004 gene, were expressed abundantly in brain tissues with unknown functions. We treated bc004004-/- mice with chronic unpredictable mild stress (CUMS) to test whether those mice were more vulnerable to stress-related disorders. The results of forced swimming test, sucrose preference test, and open field test showed that after being treated with CUMS for 28 days or 35 days both bc004004-/- and bc004004+/+ mice exhibited behavioural changes and there was no significant difference between bc004004+/+ and bc004004-/-. However, behavioural changes were observed only in bc004004-/- mice after being exposed to CUMS for 21 days, but not in bc004004+/+ after 21-day CUMS exposure, indicating that lack of BRAP homologous protein may cause vulnerability to stress-related disorders in mice. In addition, bc004004-/- mice showed a reduction in recognition memory as revealed by novel object recognition test. Since memory changes and stress related behavioural changes are all closely related to the hippocampus function we further analyzed the changes of dendrites and synapses of hippocampal neurons as well as expression levels of some proteins closely related to synaptic function. bc004004-/- mice exhibited decreased dendritic lengths and increased amount of immature spines, as well as altered expression pattern of synaptic related proteins including GluN2A, synaptophysin and BDNF in the hippocampus. Those findings suggest that BRAP homologous protein may have a protective effect on the behavioural response to stress via regulating dendritic spine formation and synaptic plasticity in the hippocampus.

Large-scale lesion symptom mapping of depression identifies brain regions for risk and resilience.

Understanding neural circuits that support mood is a central goal of affective neuroscience, and improved understanding of the anatomy could inform more targeted interventions in mood disorders. Lesion studies provide a method of inferring the anatomical sites causally related to specific functions, including mood. Here, we performed a large-scale study evaluating the location of acquired, focal brain lesions in relation to symptoms of depression. Five hundred and twenty-six individuals participated in the study across two sites (356 male, average age 52.4 ± 14.5 years). Each subject had a focal brain lesion identified on structural imaging and an assessment of depression using the Beck Depression Inventory-II, both obtained in the chronic period post-lesion (>3 months). Multivariate lesion-symptom mapping was performed to identify lesion sites associated with higher or lower depression symptom burden, which we refer to as 'risk' versus 'resilience' regions. The brain networks and white matter tracts associated with peak regional findings were identified using functional and structural lesion network mapping, respectively. Lesion-symptom mapping identified brain regions significantly associated with both higher and lower depression severity (r = 0.11; P = 0.01). Peak 'risk' regions include the bilateral anterior insula, bilateral dorsolateral prefrontal cortex and left dorsomedial prefrontal cortex. Functional lesion network mapping demonstrated that these 'risk' regions localized to nodes of the salience network. Peak 'resilience' regions include the right orbitofrontal cortex, right medial prefrontal cortex and right inferolateral temporal cortex, nodes of the default mode network. Structural lesion network mapping implicated dorsal prefrontal white matter tracts as 'risk' tracts and ventral prefrontal white matter tracts as 'resilience' tracts, although the structural lesion network mapping findings did not survive correction for multiple comparisons. Taken together, these results demonstrate that lesions to specific nodes of the salience network and default mode network are associated with greater risk versus resiliency for depression symptoms in the setting of focal brain lesions.

Deficiency of astrocyte CysLT1R ameliorates depression-like behaviors in mice by modulating glutamate synaptic transmission.

Our previous study suggests that hippocampal cysteinyl leukotriene receptor 1 (CysLT1R) could be involved in depression. Herein we hypothesize that CysLT1R may regulate depression by affecting synaptic glutamate cycling based on existence of CysLT1R in the astrocytes that participate in occurrence of depression. We found that CysLT1R expression was significantly increased in the astrocyte of chronic unpredictable mild stress (CUMS)-induced depression-like mice, CysLT1R astrocyte-specific conditional knockout (AcKO) significantly improved depression-like behaviors, as indicated by decreased immobility time in the forced swimming test and tail suspension test and increased sucrose preference in the sucrose preference test, and knockdown of CysLT1R in the astrocyte of dentate gyrus (DG), the region with the most significant increase of CysLT1R in the astrocyte of depression-like mice, produced similar effects. Correspondingly, overexpression of CysLT1R in the astrocyte of DG induced depression-like behaviors in mice. The further study showed that CysLT1R AcKO ameliorated synaptic plasticity impairment, as reflected by increased synapse, LTP and PSD95, and promoted glutamate transporter 1 (GLT-1) expression by inhibiting NF-κB p65 nuclear translocation mediated by ß-arestin2 and clatrhin, subsequently decreased glutamate in synaptic cleft and GluN2B on postsynaptic membrane in depression-like mice. The present study also showed that GLT-1 agonist or NF-κB inhibitor ameliorated depressive-like behaviors induced by overexpression of the astrocyte CysLT1R of DG. Our study demonstrated that astrocyte CysLT1R regulated depression by modulating glutamate synaptic transmission, suggesting that CysLT1R could be a potential target for developing novel drugs of anti-depression.

Positive effects of running exercise on astrocytes in the medial prefrontal cortex in an animal model of depression.

Depression is one of the most common mental illnesses and seriously affects all aspects of life. Running exercise has been suggested to prevent or alleviate the occurrence and development of depression; however, the underlying mechanisms of these effects remain unclear. Independent studies have indicated that astrocytes play essential roles and that the medial prefrontal cortex (mPFC) is an important brain region involved in the pathology underlying depression. However, it is unknown whether running exercise achieves antidepressant effects by affecting the number of astrocytes and glutamate transport function in the mPFC. Here, animal models of depression were established using chronic unpredictable stress (CUS), and depression-like behavior was assessed by the sucrose preference test. After successfully establishing the depression model, experimental animals performed running exercise. Glial fibrillary acidic protein-positive (GFAP+ ) cell number in the mPFC was precisely quantified using immunohistochemical and stereological methods, and the densities of bromodeoxyuridine-positive (BrdU+ ) and BrdU+ /GFAP+ cells in the mPFC were measured using a semiquantitative immunofluorescence assay. Changes in glutamate transporter gene expression in mPFC astrocytes were detected by mRNA sequencing and qRT-PCR. We found that running exercise reversed CUS-induced decreases in sucrose preference, increased astrocyte number and the density of newborn astrocytes, and reversed decreases in gene expression levels of GFAP, S100b, and the glutamate transporters GLT-1 and GLAST in the mPFC of CUS animals. These results suggested that changes in astrocyte number and glutamate transporter function may be potential meditators of the effects of running exercise in the treatment of depression.

Clinical and biological subtypes of late-life depression.

BACKGROUND: Late-life depression (LDD) results from multiple psychosocial and neurobiological changes occurring in later life. The current study investigated how patterns of clinical symptoms and brain structural features are classified into LDD subtypes. METHOD: Self-report scale of depression, behavioral rating of affective symptoms, and brain structural imaging of white matter change and cortical thickness were assessed in 541 older adults with no cognitive impairment or mild cognitive impairment. Latent profile analysis was used to identify distinct subtypes of depression. RESULTS: The latent profile analysis identified four classes with mild to severe depressive symptoms and two classes with minimal symptoms. While the classes primarily differed in the overall severity, the combinatory patterns of clinical symptoms and neuropathological signature distinguished the classes with similar severity. The classes were distinguished in terms of whether or not neurodegenerative risk accompanied the corresponding depressive symptoms. The presence of the negative self-scheme and cortical thinning pattern notably characterized the subtypes of LDD. LIMITATIONS: The underlying etiologies of the biological subtypes are still speculative, and the current study lacks clinical history that differentiates late- and early-onset depression. CONCLUSIONS: Our finding provides insight in identifying heterogeneities of depressive disorder in later life and suggests that self-report and behavioral symptom profile in combination with white matter lesion and cortical thickness effectively characterizes distinct subtypes of LDD.

Unraveling the mystery of white matter in depression: A translational perspective on recent advances.

BACKGROUND: Numerous cortical and subcortical structures have been studied extensively concerning alterations of their integrity as well as their neurotransmitters in depression. However, connections between these structures have received considerably less attention. OBJECTIVE: This systematic review presents results from recent neuroimaging as well as neuropathologic studies conducted on humans and other mammals. It aims to provide evidence for impaired white matter integrity in individuals expressing a depressive phenotype. METHODS: A systematic database search in accordance with the PRISMA guidelines was conducted to identify imaging and postmortem studies conducted on humans with a diagnosis of major depressive disorder, as well as on rodents and primates subjected to an animal model of depression. RESULTS: Alterations are especially apparent in frontal gyri, as well as in structures establishing interhemispheric connectivity between frontal regions. Translational neuropathological findings point to alterations in oligodendrocyte density and morphology, as well as to alterations in the expression of genes related to myelin synthesis. An important role of early life adversities in the development of depressive symptoms and white matter alterations across species is thereby revealed. Data indicating that stress can interfere with physiological myelination patterns is presented. Altered myelination is most notably present in regions that are subject to maturation during the developmental stage of exposure to adversities. CONCLUSION: Translational studies point to replicable alterations in white matter integrity in subjects suffering from depression across multiple species. Impaired white matter integrity is apparent in imaging as well as neuropathological studies. Future studies should focus on determining to what extent influencing white matter integrity is able to improve symptoms of depression in animals as well as humans.

Agomelatine rescues lipopolysaccharide-induced neural injury and depression-like behaviors via suppression of the Gαi-2-PKA-ASK1 signaling pathway.

BACKGROUND: Agomelatine has been shown to be effective in the treatment of depression, but the molecular mechanisms underlying its antidepressant effects have yet to be elucidated. Identification of these molecular mechanisms would not only offer new insights into the basis for depression but also provide the foundation for the development of novel treatments for this disorder. METHODS: Intraperitoneal injection of LPS was used to induce depression-like behaviors in rats. The interactions of the 5-HT2C reporter and Gαi-2 were verified by immunoprecipitation or immunofluorescence assay. Inflammatory related proteins, autophagy related proteins and apoptosis markers were verified by immunoblotting or immunofluorescence assay. Finally, electron microscopy analysis was used to observe the synapse and ultrastructural pathology. RESULTS: Here, we found that the capacity for agomelatine to ameliorate depression and anxiety in a lipopolysaccharide (LPS)-induced rat model of depression was associated with an alleviation of neuroinflammation, abnormal autophagy and neuronal apoptosis as well as the promotion of neurogenesis in the hippocampal dentate gyrus (DG) region of these rats. We also found that the 5-HT2C receptor is coupled with G alphai (2) (Gαi-2) protein within hippocampal neurons and, agomelatine, acting as a 5-HT2C receptor antagonist, can up-regulate activity of the Gαi-2-cAMP-PKA pathway. Such events then suppress activation of the apoptosis signal-regulating kinase 1 (ASK1) pathway, a member of the mitogen-activated protein kinase (MAPK) family involved in pathological processes of many diseases. CONCLUSION: Taken together, these results suggest that agomelatine plays a neuroprotective role in regulating neuroinflammation, autophagy disorder and apoptosis in this LPS-induced rat model of depression, effects which are associated with the display of antidepressant behaviors. These findings provide evidence for some of the potential mechanisms for the antidepressant effects of agomelatine.

Depression following ChAdOx1-S/nCoV-19 vaccine

We aimed to review the available reports of psychiatric adverse reactions to COVID vaccines. Electronic databases such as PubMed and Google scholar were combed to identify relevant reports. We found a total of 11 reports describing 14 cases of psychiatric reactions; these were mostly altered mental states, psychosis, mania, depression, and functional neurological disorder. The index case was commonly a young or middle-aged adult. All reports pertained to the use of either mRNA or vector-based vaccines. Symptom onset was within 10 days of vaccination in all cases; as such, this seems to be a high-risk period warranting vigilance.

Altered Functional Connectivity of Ventral Striatum Subregions in De-novo Parkinson's Disease with Depression.

Although various studies have reported a high prevalence of depression among Parkinson's disease (PD) patients, the pathophysiological mechanism of depression in PD (DPD) is still unclear. The core region of the reward network, the ventral striatum (VS), is critical in the occurrence and development of DPD. This study aimed to explore the altered functional connectivity (FC) of VS subregions in DPD. We recruited 20 DPD patients, 37 non-depressed PD (NDPD) patients, and 41 healthy controls (HC) matched in age, gender, and years of education. The patients' diagnosis with PD was de-novo. We then used resting-state functional magnetic resonance imaging to detect the FC differences of VS subregions among these groups. The FC between the left ventral caudate (vCa_L) and the left middle occipital gyrus (MOG.L) was significantly increased in DPD than in NDPD patients or HC. Compared with HC, NDPD patients exhibited significantly increased FCs between bilateral ventromedial putamen and the left paracentral lobule, the right ventromedial putamen (vmPu_R), and the right precentral gyrus, the vmPu_R, and the left precuneus. Besides, a significant negative correlation was found between the FC values of the vCa_L with the MOG.L and the HAMD-17 scores in the DPD group. The hyperconnectivity between vCa_L and the MOG.L might be viewed as a compensatory mechanism for depression in the early stage of PD. This study provides new insight into the neural mechanism of depression in the early stage of PD and contributes to explore the potential neuroimaging markers for DPD.

Longitudinal evidence on the development of socioeconomic inequalities in mental health due to the COVID-19 pandemic in Norway.

The economic and health consequences of the COVID-19 pandemic are unequally distributed. A growing literature finds evidence that those with low socioeconomic status have carried a greater burden in terms of both unemployment and infection risk. Against this background, it is natural to also expect increasing socioeconomic inequalities in mental health. We report from a population-based longitudinal study, assessing the mental health of more than 100,000 Norwegian adults during a period of more than 20 years, and into the COVID-19 pandemic. We find substantial, and equally high, increases in depressive symptoms across socioeconomic status. In addition, we show that the increase was particularly strong among women and those with lower levels of depressive symptoms prior to COVID-19.

Depressive symptoms reduce when dorsolateral prefrontal cortex-precuneus connectivity normalizes after functional connectivity neurofeedback.

Depressive disorders contribute heavily to global disease burden; This is possibly because patients are often treated homogeneously, despite having heterogeneous symptoms with differing underlying neural mechanisms. A novel treatment that can directly influence the neural circuit relevant to an individual patient's subset of symptoms might more precisely and thus effectively aid in the alleviation of their specific symptoms. We tested this hypothesis in a proof-of-concept study using fMRI functional connectivity neurofeedback. We targeted connectivity between the left dorsolateral prefrontal cortex/middle frontal gyrus and the left precuneus/posterior cingulate cortex, because this connection has been well-established as relating to a specific subset of depressive symptoms. Specifically, this connectivity has been shown in a data-driven manner to be less anticorrelated in patients with melancholic depression than in healthy controls. Furthermore, a posterior cingulate dominant state-which results in a loss of this anticorrelation-is expected to specifically relate to an increase in rumination symptoms such as brooding. In line with predictions, we found that, with neurofeedback training, the more a participant normalized this connectivity (restored the anticorrelation), the more related (depressive and brooding symptoms), but not unrelated (trait anxiety), symptoms were reduced. Because these results look promising, this paradigm next needs to be examined with a greater sample size and with better controls. Nonetheless, here we provide preliminary evidence for a correlation between the normalization of a neural network and a reduction in related symptoms. Showing their reproducibility, these results were found in two experiments that took place several years apart by different experimenters. Indicative of its potential clinical utility, effects of this treatment remained one-two months later.Clinical trial registration: Both experiments reported here were registered clinical trials (UMIN000015249, jRCTs052180169).