Multimodal and hemispheric graph-theoretical brain network predictors of learning efficacy for frontal alpha asymmetry neurofeedback.

EEG neurofeedback using frontal alpha asymmetry (FAA) has been widely used for emotion regulation, but its effectiveness is controversial. Studies indicated that individual differences in neurofeedback training can be traced to neuroanatomical and neurofunctional features. However, they only focused on regional brain structure or function and overlooked possible neural correlates of the brain network. Besides, no neuroimaging predictors for FAA neurofeedback protocol have been reported so far. We designed a single-blind pseudo-controlled FAA neurofeedback experiment and collected multimodal neuroimaging data from healthy participants before training. We assessed the learning performance for evoked EEG modulations during training (L1) and at rest (L2), and investigated performance-related predictors based on a combined analysis of multimodal brain networks and graph-theoretical features. The main findings of this study are described below. First, both real and sham groups could increase their FAA during training, but only the real group showed a significant increase in FAA at rest. Second, the predictors during training blocks and at rests were different: L1 was correlated with the graph-theoretical metrics (clustering coefficient and local efficiency) of the right hemispheric gray matter and functional networks, while L2 was correlated with the graph-theoretical metrics (local and global efficiency) of the whole-brain and left the hemispheric functional network. Therefore, the individual differences in FAA neurofeedback learning could be explained by individual variations in structural/functional architecture, and the correlated graph-theoretical metrics of learning performance indices showed different laterality of hemispheric networks. These results provided insight into the neural correlates of inter-individual differences in neurofeedback learning. Supplementary Information: The online version contains supplementary material available at 10.1007/s11571-023-09939-x.

Impact of painful physical symptoms on first-episode major depressive disorder in adults with subthreshold depressive symptoms: A prospective cohort study.

OBJECTIVE: To investigate the impact of baseline painful physical symptoms (PPS) on subsequent first-episode major depressive disorder (MDD) in adults with subthreshold depressive symptoms, including subgroup analyses to assess whether the associations differ in individuals with and without physical diseases. METHODS: A total of 2343 adults with subthreshold depressive symptoms were recruited at 34 primary health care centers. PPS were measured at baseline. First-episode MDD during follow-up was diagnosed by professional psychiatrists using the Mini-International Neuropsychiatric Interview. RESULTS: Baseline PPS showed independent impacts on first-episode MDD in adults with subthreshold depressive symptoms without physical diseases, but not in those with physical diseases. A non-linear association (P < 0.001) was observed between PPS burden and the risk of first-episode MDD. The HRs for first-episode MDD exhibited a rapidly increasing trend between PPS burden scores of 10-16, and maintained consistently high when scores exceeded 16. The analyses for specific PPS revealed that headache, neck pain, and heart or chest pain were independently associated with first-episode MDD in participants without physical diseases, the HRs were 1.57 (1.15-2.36), 1.53 (1.02-2.30), and 1.69 (1.14-2.50), respectively. Further network analysis demonstrated that heart or chest pain serves as a bridge symptom among the seven specific PPS and first-episode MDD in those without physical diseases. CONCLUSION: PPS burden and heart or chest pain may be significant indicators for first-episode MDD in adults with subthreshold depressive symptoms without physical diseases. Future studies should investigate whether interventions targeting PPS can prevent episode MDD in this subthreshold population.

Evaluation of a novel instrument for detecting bipolar disorders in China: The Rapid Mood Screener (RMS).

OBJECTIVE: Bipolar disorder is easily misdiagnosed with major depressive disorder (MDD). The Rapid Mood Screener (RMS) was developed to address this unmet clinical need. This study aims to translate and evaluated the reliability and validity of the RMS in Chinese adults with bipolar I/II disorder (BD-I/II). METHODS: Brislin's translation and Delphi method were conducted to formulate the RMS-Chinses version (RMS-C). Patients with MDD (N = 99), BD-I (N = 77) and BD-II (N = 78) were included to assess the validity and reliability of RMS-C. The area under the curve (AUC) was computed to ascertain the ability of the Mood Disorder Questionnaire (MDQ) and RMS-C to distinguish BD-I and BD-II from MDD. The optimal cut-off scores for classification were also calculated by the maximum sensitivity and specificity. RESULTS: The intraclass correlation coefficient of the RMS-C was 0.82 (95%CI, 0.71-0.89). The content validity index by six items were 0.71, 0.86, 1.00, 0.86, 1.00, and 1.00 in turn, and by scales was 0.90. The AUCs of the RMS-C in both BD-I/II, BD-I alone and BD-II alone were 0.83 (95 % CI, 0.78-0.89), 0.82 (95 % CI, 0.75-0.89) and 0.85 (95 % CI, 0.79-0.91), respectively, and were comparably to the MDQ. The optimal RMS-C values of the presence of BD-I and BD-II were >4 and 3, respectively. CONCLUSION: The RMS-C is a valid, simple self-administer screening tool to help identify BD-I or BD-II in persons experiencing a depressive episode. Validating the impact of screening with the RMS-C on health outcomes and health economics is warranted.

Mediating role of personality traits in the association between multi-dimensional adverse childhood experiences and depressive symptoms among older adults: A 9-year prospective cohort study.

BACKGROUND: To explore the mediating role of personality traits in the correlation between multi-dimensional adverse childhood experiences (ACEs) and depressive symptoms in older adults. METHODS: This cohort study used data from the English Longitudinal Study of Ageing, and included 4050 older adults without depressive symptoms in 2010-2011. Multi-dimensional ACEs were evaluated in 2006-2007. Personality traits were assessed using the Midlife Development Inventory in 2010-2011. Depressive symptoms were measured using the 8-item version of the Center for Epidemiologic Studies Depression Scale during 2012-2019. Cox proportional hazard model was used to explore the associations between ACEs and depressive symptoms. The package named "mediation" in R was used to test mediating role of personality traits. RESULTS: ACEs in each dimension significantly increased the risk of depressive symptoms (all P-values < 0.05). The association of maltreatment (18.18 %) and household dysfunction (19.69 %) with depressive symptoms was significantly mediated by neuroticism. The correlation between poor parent-child bonding and depressive symptoms was significantly mediated by neuroticism (19.43 %), conscientiousness (4.84 %), and extroversion (8.02 %). LIMITATIONS: ACEs were retrospectively assessed based on participants' memories, which may induce recall bias. CONCLUSIONS: Maltreatment and household dysfunction may induce depressive symptoms by increasing neuroticism. Poor parent-child bonding may induce depressive symptoms by increasing neuroticism and reducing conscientiousness and extraversion. In addition to reducing the occurrence of ACEs, reducing neuroticism of individuals with maltreatment and household dysfunction in childhood, and reducing neuroticism, and increasing conscientiousness and extraversion of individuals with poor parent-child bonding in childhood might help to decrease their risk of depressive symptoms.

Olanzapine Promotes the Occurrence of Metabolic Disorders in Conditional TCF7L2-Knockout Mice.

Objectives: Schizophrenia (SCZ) patients display higher incidence of metabolic syndrome (MetS) and comorbidity of type II diabetes. Both atypical antipsychotics and genetic variants are believed to predispose the patients with the risk, but their interplay remains largely unknown. TCF7L2 is one of the most common genes strongly associated with glucose homeostasis which also participates in the pathogenesis of schizophrenia. In this study, we aimed to explore the regulatory roles of TCF7L2 in atypical antipsychotics-induced MetS. Methods: Mice with pancreatic ß-cell-specific Tcf7l2 deletion (CKO) were generated. The CKO mice and control littermates were subjected to olanzapine (4 mg/kg/day) or saline gavage for 6 weeks. Metabolic indices, ß cell mass, and the expressing levels of TCF7L2 and GLP-1R in the pancreatic tissue were closely monitored. Results: Tcf7l2 CKO mice displayed a spectrum of core features of MetS, which included remarkably increased rate of weight gain, higher fasting insulin, higher values of blood lipids (cholesterol, triglyceride, and low-density lipoprotein), impaired glucose tolerance, and hypertrophy of adipocytes. Notably, these effects could be further exacerbated by olanzapine. In addition, Tcf7l2 CKO mice with the olanzapine group showed significantly decreased expressions of GLP-1R protein and a trend of reduced pancreatic ß-cell mass. RT-qPCR revealed that the CKO mice presented a significantly less transcription of Sp5, an important element of the Wnt signaling pathway. Conclusion: Our study illustrates that mice with pancreatic ß-cell-targeted Tcf7l2 deletion were more vulnerable to suffer metabolic abnormalities after olanzapine administration. This impairment may be mediated by the reduced expression of GLP-1R.

Altered task-modulated functional connectivity during emotional face processing in euthymic bipolar patients: A whole-brain psychophysiological interaction study.

BACKGROUND: Patients with bipolar disorder (BD) show deficits of facial emotion processing even in the euthymic phase. However, the large-scale functional brain network mechanism underlying the emotional deficit of BD remains unclear. Specifically, it is of importance to understand how the task-modulated functional connectivity (FC) was alternated over distributed brain networks in BD. METHODS: In this study, we analyzed functional MRI data of a face-matching task from 29 euthymic BD patients and 29 healthy controls (HC), and performed whole-brain psychophysiological interaction (PPI) analysis to obtain task-modulated FC. Abnormal FC patterns were identified through support vector machine-based classification. The topological organization of task-modulated FC networks was estimated by the graph theoretical analysis and compared between BD and HC. RESULTS: BD exhibited widely distributed aberrant task-modulated FC patterns not only in core neurocognitive intrinsic brain networks (the fronto-parietal, cingulo-opercular, and default mode networks), but also in the cerebellum and primary processing networks (sensorimotor and visual). Furthermore, the local efficiency of the frontal-parietal network was significantly increased in BD. LIMITATIONS: The modest sample size. Only face pictures with negative emotion were used. Only unidirectional task-modulated FC was investigated. CONCLUSIONS: BD patients showed a widely distributed aberrant task-modulated FC pattern. Particularly, the fronto-parietal network, as one of the core neurocognitive intrinsic brain networks, was the primary network that demonstrated changes of both FC strength and local efficiency in BD. These findings on the task-modulated FC between these intrinsic brain networks might be considered an endophenotype of the BD condition persistent in the euthymic state.

PCSK9 mediates dyslipidemia induced by olanzapine treatment in schizophrenia patients.

RATIONALE: It is controversial whether dyslipidemia induced by antipsychotics in schizophrenia patients is due to weight gain or direct effects of drug treatment. However, recent evidence showed that olanzapine can cause acute dyslipidemia independent of weight change, and the underlying mechanism remains unclear. OBJECTIVE: To study the role of proprotein convertase subtilisin/kexin type 9 (PCSK9) in olanzapine-induced dyslipidemia, we analyzed in schizophrenic patients and in experimental models involving mice and cells to understand the mechanism. METHODS: Disturbances in lipid homeostasis caused by 8-week olanzapine treatment were prospectively evaluated in first-episode schizophrenic patients. Additionally, mice were administered olanzapine for 5 or 8 weeks to delineate liver actions for PCSK9 contributing to olanzapine-induced dyslipidemia. RESULTS: Olanzapine directly affected lipid metabolism, suggesting dyslipidemia is independent of weight gain in schizophrenia patients. Olanzapine administration significantly increased plasma PCSK9, which was positively correlated with the increment in low-density lipoprotein cholesterol (LDL-C) (r=0.77, p<0.001). Increased expression of PCSK9 in liver tissue of olanzapine-treated mice occurred prior to olanzapine-induced LDL-C abnormality. Hepatic sterol regulatory element binding protein-2 (SREBP-2) protein levels increased in mice treated with olanzapine but largely declined in olanzapine (10µM) treated HepG2 cells, which suggested high concentration of olanzapine-induced PCSK9 increase was not SREBP-2-dependent. However, expressions of sterol regulatory element binding protein-1c (SREBP-1c) significantly increased in the higher dose treated groups, which was consistent with PCSK9 increases. Activation of SREBP-1c after high-dose olanzapine treatment promotes PSCK9 expression, and consequently the degradation of low-density lipoprotein receptors results in LDL-C increase. CONCLUSIONS: Lipid disturbances caused by olanzapine are independent of weight gain. The study explored the relationship between SREBP-1c and PCSK9 in regulating lipoprotein metabolism after olanzapine treatment in vitro and in vivo. Further exploration of olanzapine-induced PCSK9 regulatory mechanisms may help identify control points for inhibition of olanzapine-mediated dyslipidemia.

Sex difference in lipid levels in first-diagnosed drug-naïve depression patients: A case-control and 12-weeks follow-up study.

AIM: Patients with depression have a high prevalence of developing dyslipidemia. In this study, we aim to investigate the difference of serum lipids, including total cholesterol (TCH), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG), between the depressed patients and healthy controls. Sex differences in lipids and their psychological correlations were also included. METHODS: The study included 56 healthy controls (males/females = 26/30) and 110 first-diagnosed drug-naïve outpatients (males/females = 35/75). A total of 42 patients (males/females = 14/28) were followed for 3 months. RESULTS: A significant difference was found in TCH and LDL-C among healthy control and patients. Interestingly, female patients with first-diagnosed, drug-naïve depression had lower atherogenic indices than male patients. After 3 months of antidepressants therapy, female patients exhibited detrimental changes in serum lipids, namely increased TG and atherogenic index. Moreover, correlation analysis showed significant correlations between changes of depression inventory (HAMD and BDI) score and serum lipids (TCH, HDL-C) in depressed patients. CONCLUSION: We found that dyslipidemia was more common in female patients with depression during therapy with antidepressants. Moreover, the altered serum lipids and atherogenic index might be a hallmark of female patients. Further investigation of sex differences in lipid metabolism of depression is warranted.

Disease burden of schizophrenia patients visiting a Chinese regional mental health centre.

Aim & methods: A decision-analytic model was constructed to simulate a real-world cohort of Chinese patients visiting a Chinese regional mental health center for long-term health outcomes and direct medical costs. Results: When compared with age and gender-matched general population, the Chinese patients with schizophrenia were associated with reduced overall survival by 20.6 years (27.6 vs 48.2 years) and reduced quality-adjusted life years (QALY) by 18.4 QALY (18.4 vs 36.8 QALY), respectively, and increased lifetime direct medical costs by about three-times (US$84,324 vs 33,387 as of 31 December 2017) on average. Conclusion: The burden of schizophrenia was mainly driven by the mortality associated with relapsed schizophrenia and direct medical costs for schizophrenia in local mental health rehabilitation institutes.

L-theanine ameliorate depressive-like behavior in a chronic unpredictable mild stress rat model via modulating the monoamine levels in limbic-cortical-striatal-pallidal-thalamic-circuit related brain regions.

L-theanine, originally found in green tea, elicits various physiological effects, such as promoting relaxation, improving concentration and learning ability, and providing antianxiety-like and antidepressant-like properties. This study aims to investigate the effects of L-theanine (2 mg/kg) on monoamine levels in an animal model of depression. The effect of l-theanine on the symptoms of depression was examined through the open-field test, sucrose preference test, and forced swim test. The monoamine neurotransmitters that involve serotonin (5-HT), norepinephrine (NE), and dopamine (DA) were measured in the limbic-cortical-striatal-pallidal-thalamic (LCSPT)-circuit related brain regions, including the prefrontal cortex (PFC), nucleus accumbens (NAC), striatum (ST), amygdala, and hippocampus (HIP). L-theanine ameliorated the depressive-like behaviors in the chronic unpredictable mild stress (CUMS) rat model. In the PFC, NAC, and HIP, L-theanine administration significantly increased the levels of 5-HT, NE, and DA. In the ST, the levels of 5-HT and DA were increased after the administration of L-theanine. However, in the HIP, only the level of DA significantly changed after the treatment of L-theanine. Taken together, these results indicated that L-theanine has possibly antidepressant-like effects in the CUMS rat model, which could be mediated by the monoamine neurotransmitters in the LCSPT-circuit related brain regions.