Optogenetic activation of the lateral habenulaD1R-ventral tegmental area circuit induces depression-like behavior in mice.

A number of different receptors are distributed in glutamatergic neurons of the lateral habenula (LHb). These glutamatergic neurons are involved in different neural pathways, which may identify how the LHb regulates various physiological functions. However, the role of dopamine D1 receptor (D1R)-expressing habenular neurons projecting to the ventral tegmental area (VTA) (LHbD1R-VTA) remains not well understood. In the current study, to determine the activity of D1R-expressing neurons in LHb, D1R-Cre mice were used to establish the chronic restraint stress (CRS) depression model. Adeno-associated virus was injected into bilateral LHb in D1R-Cre mice to examine whether optogenetic activation of the LHb D1R-expressing neurons and their projections could induce depression-like behavior. Optical fibers were implanted in the LHb and VTA, respectively. To investigate whether optogenetic inhibition of the LHbD1R-VTA circuit could produce antidepressant-like effects, the adeno-associated virus was injected into the bilateral LHb in the D1R-Cre CRS model, and optical fibers were implanted in the bilateral VTA. The D1R-expressing neuronal activity in the LHb was increased in the CRS depression model. Optogenetic activation of the D1R-expressing neurons in LHb induced behavioral despair and anhedonia, which could also be induced by activation of the LHbD1R-VTA axons. Conversely, optogenetic inhibition of the LHbD1R-VTA circuit improved behavioral despair and anhedonia in the CRS depression model. D1R-expressing glutamatergic neurons in the LHb and their projections to the VTA are involved in the occurrence and regulation of depressive-like behavior.

Risk factors of developing psychological problems among frontline healthcare professionals working in the COVID-19 pandemic era: a meta-analysis.

BACKGROUND: This study sought to evaluate the risk factors behind developing psychological problems as per specific mental health assessment instruments. This study focuses specifically on frontline healthcare professionals of the COVID-19 pandemic era, and evaluated the psychological assessment of frontline healthcare professionals. METHODS: Studies reporting on the psychological assessment of frontline healthcare professionals were retrieved from the PubMed, Embase, Web of Science, Ovid, EBSCO, and Cochrane Library databases. The recommended method was used to assess the risk of bias of the included studies. The random-effects method was applied when significant heterogeneity was observed. RESULTS: The combined results from the 20 included articles indicated that frontline healthcare professionals had a higher risk of developing anxiety in comparison with non-frontline healthcare workers, with similar levels of depression scoring were observed. Healthcare providers aged > 40 years had a lower probability of developing anxiety and seemed to experience minimal depression. Conversely, frontline workers had a higher incidence of anxiety than that of depression. Being single (not in a relationship) could influence the PHQ-9 scores instead of those concerning the GAD-7. The gender gap was not proven to be significantly wide between healthcare professionals with or without anxiety; however, being male was proven to be positively correlated with depression. CONCLUSION: In general, the risk factors for susceptibility to psychological problems among frontline healthcare professionals during the COVID-19 pandemic concerned those of a lower age, being single, being male, and being engage in frontline healthcare work.

Anatomical Connectivity-Based Strategy for Targeting Transcranial Magnetic Stimulation as Antidepressant Therapy.

OBJECTIVES: Abnormal activity of the subgenual anterior cingulate cortex (sACC) is implicated in depression, suggesting the sACC as a potentially effective target for therapeutic modulation in cases resistant to conventional treatments (treatment-resistant depression, TRD). We hypothesized that areas in the prefrontal cortex (PFC) with direct fiber connections to the sACC may be particularly effective sites for treatment using transcranial magnetic stimulation (TMS). The aim of this study was to identify PFC sites most strongly connected to the sACC. METHODS: Two neuroimaging data sets were used to construct anatomic and functional connectivity maps using sACC as the seed region. Data set 1 included magnetic resonance (MR) images from 20 healthy controls and Data set 2 included MR images from 15 TRD patients and 15 additional healthy controls. PFC voxels with maximum values in the mean anatomic connection probability maps were identified as optimal sites for TMS. RESULTS: Both right and left PFC contained sites strongly connected to the sACC, but the coordinates (in Montreal Neurological Institute space) of peak anatomic connectivity differed slightly between hemispheres. The left PFC site connected directly to the sACC both anatomically and functionally, while the right PFC site was functionally connected to the posterior cingulate cortex (PCC). CONCLUSIONS: Both left and right PFC are functionally connected to regions implicated in depression, the sACC and PCC, respectively. These bilateral PFC sites may be effective TMS targets to treat TRD.

Brain-derived neurotrophic factor blood levels after electroconvulsive therapy in patients with major depressive disorder: A systematic review and meta-analysis.

Some evidence pointed out that Electro-Convulsive Treatment (ECT) could increase the level of brain-derived neurotrophic factor (BDNF) in depressive patients. However, there are some disagreements. The purpose of the study is through a systematic review and meta-analysis to evaluate BDNF levels after ECT in patients with Major depressive disorder. Two independent researchers searched of published articles in the databases of Cochrane Library, PubMed, MEDLINE, EMBASE and WanFang Data, from January 1990 to March 2019. The following key words were used: "depression" or "depressive disorder", "major depressive disorder", "unipolar depression", "brain-derived neurotrophic factor" or "BDNF", and "electroconvulsive" or "ECT". A total of 22 studies met the inclusion criteria of the meta-analysis and included into our analysis. BDNF levels were increased among patients with MDD after ECT (P = 0.000) in plasma samples. The standardized mean difference (SMD) was 0.695 (95 % CI: 0.402-0.988). We also found BDNF levels increased on one week and one month after finishing ECT (SMD = 0.491, 95 %CI: 0.150,0.833, P = 0.005; and SMD = 0.812, 95 %CI: 0.326,1.298, P = 0.001, respectively). Our findings suggest that BDNF levels may increase after ECT and may possibly be used as an indicator of treatment response after one or more weeks of ECT in patients with depression. However, additional investigation of BDNF levels with different ECT durations are needed in responders and non-responders.

Identification of candidate genes and miRNAs associated with neuropathic pain induced by spared nerve injury.

Neuropathic pain (NP) is a complex, chronic pain condition caused by injury or dysfunction affecting the somatosensory nervous system. This study aimed to identify crucial genes and miRNAs involved in NP. Microarray data (access number GSE91396) were downloaded from the Gene Expression Omnibus (GEO). Murine RNA­seq samples from three brain regions [nucleus accumbens, (NAc); medial prefrontal cortex, (mPFC) and periaqueductal gray, (PAG)]were compared between the spared nerve injury (SNI) model and a sham surgery. After data normalization, differentially expressed RNAs were screened using the limma package and functional enrichment analysis was performed with Database for Annotation, Visualization and Integrated Discovery. The microRNA (miRNA/miR)­mRNA regulatory network and miRNA­target gene­pathway regulatory network were constructed using Cytoscape software. A total of 2,776 differentially expressed RNAs (219 miRNAs and 2,557 mRNAs) were identified in the SNI model compared with the sham surgery group. A total of two important modules (red and turquoise module) were found to be related to NP using weighed gene co­expression network analysis (WGCNA) for the 2,325 common differentially expressed RNAs in three brain regions. The differentially expressed genes (DEGs) in the miRNA­mRNA regulatory network were significantly enriched in 21 Gene Ontology terms and five pathways. A total of four important DEGs (CXCR2, IL12B, TNFSF8 and GRK1) and five miRNAs (miR­208a­5p, miR­7688­3p, miR­344f­3p, miR­135b­3p and miR­135a­2­3p) were revealed according to the miRNA­target gene­pathway regulatory network to be related to NP. Four important DEGs (CXCR2, IL12B, TNFSF8 and GRK1) and five miRNAs (miR­208a­5p, miR­7688­3p, miR­344f­3p, miR­135b­3p and miR­135a­2­3p) were differentially expressed in SNI, indicating their plausible roles in NP pathogenesis.

Identification of Biomarkers Related to Neuropathic Pain Induced by Peripheral Nerve Injury.

Our study aimed to explore the molecular mechanisms and novel target genes of neuropathic pain via bioinformatics analysis. Gene expression profiling of GSE30691 which was consisted of sciatic nerve lesion and sham control samples at 3 days, 7 days, 21 days, and 40 days (D3, D7, D21, and D40) after injury were downloaded from Gene Expression Omnibus. Differentially expressed genes (DEGs) were identified for all the four time points. Overlapped DEGs for all the four time points were used for functional and weighted co-expression modular analysis. Afterwards, protein-protein interaction (PPI) network was analyzed by MCODE (Molecular Complex Detection) and BiNGO. Pathway network was constructed according to the enriched pathways of PPI network and relevant pathways selected from the Comparative Toxicogenomics Database. There were 355 overlapped DEGs for all the four time points. Two co-expression modules had significant positive correlations with disease. The top ten hub DEGs in the PPI network were Fos, Tp53, Csk, Map2k2, Stat3, Ccl2, Pxn, Tgfb1, Notch1, and Prkacb. Fos, Dusp1, Tp53, Tgfb1, and Map2k2 participated in MAPK signaling pathway, while Csk participated in chemokine signaling pathway. The expressions of Fos, Tp53, Csk, and Map2k2 were significantly increased at D3. Tp53, Csk, and Map2k2 continued overexpressing until at D7, and an elevated tendency in Csk expression could be observed until at D21. The expression of Fos reached up to the highest at D40. Fos, Tp53, Csk, and Map2k2 might be the potential biomarkers related to neuropathic pain.

Aberrant functional connectivity density in patients with treatment-refractory obsessive-compulsive disorder: a pilot study.

OBJECTIVE: Functional connectivity (FC) is altered in patients with obsessive-compulsive disorder (OCD). Most previous studies have focused on the strength of FC in patients with OCD; few have examined the number of functional connections in these patients. The number of functional connections is an important index for assessing aberrant FC. In the present study, we used FC density (FCD) mapping to explore alterations in the number of functional connections in patients with treatment-refractory OCD (TROCD) using the FCD index. METHODS: Twenty patients with TROCD and 20 patients with OCD in clinical remission were enrolled in the study. Global FCD (gFCD) was adopted to compare the differences between the two groups of patients. RESULTS: The gFCD in the left middle temporal gyrus was lower in the patients with TROCD than in those with remitted OCD, suggesting that decreased information processing ability may play a significant role in TROCD. CONCLUSION: The left middle temporal gyrus is a key component of the emotional processing circuit and attentional processing circuit. Decreased information processing ability in this brain region may play a significant role in TROCD; however, further well-designed follow-up studies are needed to support this hypothesis.

A resting-state study of volumetric and functional connectivity of the habenular nucleus in treatment-resistant depression patients.

OBJECTIVE: To investigate the volumetric and functional connectivity of the habenular nucleus in treatment-resistant depression (TRD) patients using the resting-state functional magnetic resonance imaging (rs-fMRI) approach. METHODS: A total of 15 TRD patients, who visited the Mental Health Institute of the First Hospital Affiliated with Jilin University between August 2014 and March 2015, along with 15 normal subjects, were enrolled into this study for structural and functional imaging. Functional connectivity analysis was performed using bilateral habenular nuclei as the region of interest in contrast to whole-brain voxels. RESULTS: No significant difference of absolute volume was found in bilateral habenular nuclei between TRD patients and healthy controls, or after controlling for individual total intracranial volume. However, functional connectivity analysis showed increased connectivity between the right habenular nucleus with the medial superior frontal gyrus, anterior cingulate cortex and medial orbitofrontal gyrus, and decreased connectivity with the corpus callosum in the TRD group. For the left habenular nucleus seed, the brain region with increased functional connectivity in the inferior temporal gyrus and decreased functional connectivity in the insular was found in the TRD patients. CONCLUSION: Abnormal functional connectivity was present between the habenular nucleus and the default mode network in TRD patients. Dysfunction in habenular nucleus-related circuitry for processing negative emotion might form the pathological basis for TRD. Significant asymmetric functional connectivity was also found between bilateral habenular nuclei in TRD patients. Such asymmetry suggests potentially divergent strategy for intervention on bilateral habenular nucleus regions in the future management of depression.

Association of maternal diabetes with autism spectrum disorders in offspring: A systemic review and meta-analysis.

Studies on the association of maternal diabetes with autism spectrum disorders (ASDs) in offspring provide inconsistent findings; therefore an updated and comprehensive literature review and meta-analysis is necessary to perform in order to evaluate the available evidences.After searching databases systematically, we established the inclusion criteria and selected the eligible studies. In both overall and stratified analyses, the estimated effects were synthesized dependent on the presence or absence of heterogeneity.Twelve articles involving 16 studies were included and synthesized, demonstrating a significant association of maternal diabetes with ASDs among children (relative risk [RR] = 1.48). However, high heterogeneity was observed (I = 56.3%) and publication bias was identified. In terms of the analyses on reliable evidences from case-control studies, heterogeneity and publication bias disappeared, and the risk of ASDs was increased by 62% among diabetic mothers compared with non-diabetic mothers.Maternal diabetes, especially gestational diabetes mellitus, is associated with ASDs in offspring based on a limited number of convincing case-control studies. More large-scale population-based prospective studies are still needed to draw firm conclusions.

Efficacy, acceptability, and safety of adjunctive aripiprazole in treatment-resistant depression: a meta-analysis of randomized controlled trials.

BACKGROUND: Treatment-resistant depression (TRD) is common and potentially life-threatening in adults, and the benefits and risks of adjunctive aripiprazole in these patients remain controversial. Therefore, we conducted a meta-analysis of randomized controlled trials (RCTs) to assess the efficacy, acceptability, safety, and quality of life of adjunctive aripiprazole in patients with TRD. METHODS: RCTs published in PubMed, Web of Science, and Embase were systematically reviewed to evaluate the efficacy and safety profiles of TRD patients who were treated with adjunctive aripiprazole. The main outcome measures included response rate, remission rate, changes from baseline in Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impression-severity (CGI-S), Clinical Global Impression-improvement (CGI-I), 17-Item Hamilton Rating Scale for Depression (HAM-D17), Sheehan Disability scale (SDS), and Inventory of Depressive Symptomatology Self-Report Scale (IDS-SR), discontinuation due to adverse events, and adverse events. Risk ratio (RR) or weight mean difference with 95% confidence intervals (CIs) were pooled using a fixed-effects or random-effects model according to the heterogeneity among studies. RESULTS: A total of 8 RCTs involving 2,260 patients were included in this meta-analysis. Adjunctive aripiprazole was associated with a significantly higher remission rate (RR =1.64, 95% CI: 1.42 to 1.89; P<0.001) and response rate (RR =1.45, 95% CI: 1.13 to 1.87; P=0.004) than other treatments. Moreover, adjunctive aripiprazole had greater changes in MADRS score, CGI-S score, CGI-I score, HAM-D17 score, SDS score, and IDS-SR score. There were more patients treated with adjunctive aripiprazole who discontinued their treatments due to adverse events. The incidence of adverse events was significantly higher in the adjunctive aripiprazole group than in other treatment groups. CONCLUSION: The adjunctive aripiprazole showed benefits in improving the response rate, remission rate, and the quality of life in patients with TRD. However, clinicians should interpret these findings with caution due to the evidence of potential treatment-related side effects.

Efficacy and safety of olanzapine/fluoxetine combination in the treatment of treatment-resistant depression: a meta-analysis of randomized controlled trials.

BACKGROUND: Whether olanzapine/fluoxetine combination (OFC) is superior to olanzapine or fluoxetine monotherapy in patients with treatment-resistant depression (TRD) remains controversial. Thus, we conducted this meta-analysis of randomized controlled trials (RCTs) to compare the efficacy and safety of OFC with olanzapine or fluoxetine monotherapy for patients with TRD. MATERIALS AND METHODS: RCTs published in PubMed, Embase, Web of Science, and the ClinicalTrials.gov registry were systematically reviewed to assess the efficacy and safety of OFC. Outcomes included mean changes from baseline in Montgomery-Asberg Depression Rating Scale (MADRS), Clinical Global Impression-Severity (CGI-S), Hamilton Rating Scale for Anxiety (HAM-A), Brief Psychiatric Rating Scale (BPRS) scores, response rate, remission rate, and adverse events. Results were expressed with weighted mean difference (WMD) with 95% confidence intervals (CIs) and risk ratio (RR) with 95% CIs. RESULTS: A total of five RCTs with 3,020 patients met the inclusion criteria and were included in this meta-analysis. Compared with olanzapine or fluoxetine monotherapy, OFC was associated with greater changes from baseline in MADRS (WMD =-3.37, 95% CI: -4.76, -1.99; P<0.001), HAM-A (WMD =-1.82, 95% CI: -2.25, -1.40; P<0.001), CGI-S (WMD =-0.37, 95% CI: -0.45, -0.28; P<0.001), and BPRS scores (WMD =-1.46, 95% CI: -2.16, -0.76; P<0.001). Moreover, OFC had significantly higher response rate (RR =1.35, 95% CI: 1.12, 1.63; P=0.001) and remission rate (RR =1.71, 95% CI: 1.31, 2.23; P<0.001). The incidence of treatment-related adverse events was similar between the OFC and monotherapy groups (RR =1.01, 95% CI: 0.94, 1.08; P=0.834). CONCLUSION: OFC is more effective than olanzapine or fluoxetine monotherapy in the treatment of patients with TRD. Our results provided supporting evidence for the use of OFC in TRD. However, considering the limitations in this study, more large-scale, well-designed RCTs are needed to confirm these findings.

Altered Volume and Functional Connectivity of the Habenula in Schizophrenia.

The pathogenesis of schizophrenia (SCH) is associated with the dysfunction of monoamine neurotransmitters, the synthesis and release of which are mainly regulated by a key structure, the habenular (Hb) nucleus. However, little is known regarding whether SCH is associated with structural or functional alterations in the Hb. In this study, we combined structural and resting-state functional magnetic resonance imaging to investigate the changes in volume and functional connectivity of the Hb in 15 patients with SCH vs. 16 age- and gender-matched healthy controls (HCs). Morphologically, the absolute volume of the bilateral Hb was significantly lower in the SCH patients than in the HCs. Functionally, the bilateral Hb showed significantly enhanced functional connectivity with the left medial prefrontal cortex (mPFC) in the SCH patients. Additionally, the SCH patients exhibited increased functional connectivity of the left Hb with the left lingual gyrus and right inferior frontal gyrus (IFG). A further exploratory analysis revealed that the SCH patients showed increased functional connectivity between the right Hb and several subcortical regions related to dopaminergic pathways, including the left ventral striatum, caudate and putamen. Finally, the increased functional connectivity of the right Hb with the mPFC was positively correlated with the Brief Psychiatric Rating Scale (BPRS) scores in the patients. Together, these results suggest that the altered volume and functional connectivity of the Hb may be involved in the pathogenesis of SCH and thus that the Hb may serve as a potential target in developing new therapeutic strategies in SCH.

Prevalence and Recognition of Depressive Disorder in Three Medical Outpatient Departments of General Hospitals in Beijing, China.

This purpose of this study was to explore the prevalence and recognition of depressive disorders in cardiology, gastroenterology, and neurology outpatient departments of general hospitals. Patients screened with a Hospital Anxiety and Depression Scale score of 8 or higher were interviewed by psychiatrists using Mini-International Neuropsychiatric Interview (MINI). Prevalence of depressive disorders within the cohort was determined, sociodemographic data were analyzed for correlations to a depression diagnosis, and comparisons between the surveys and the clinical diagnosis were done to assess recognition of depressive disorders by physicians. Of the patients screened for this study (1552 cases), 12.8% were diagnosed with depressive disorders by MINI, with major depressive disorder, depression due to general medical conditions, and dysthymia having prevalence values of 10.8%, 1.4%, and 0.6%, respectively. As compared with MINI, physicians only recognized 27.6% of any of the depressive disorders. Among the complaints examined, both mood problems and sleeping problems predicted the probability of recognition.