Graph convolutional network with attention mechanism improve major depressive depression diagnosis based on plasma biomarkers and neuroimaging data.

BACKGROUND: The absence of clinically-validated biomarkers or objective protocols hinders effective major depressive disorder (MDD) diagnosis. Compared to healthy control (HC), MDD exhibits anomalies in plasma protein levels and neuroimaging presentations. Despite extensive machine learning studies in psychiatric diagnosis, a reliable tool integrating multi-modality data is still lacking. METHODS: In this study, blood samples from 100 MDD and 100 HC were analyzed, along with MRI images from 46 MDD and 49 HC. Here, we devised a novel algorithm, integrating graph neural networks and attention modules, for MDD diagnosis based on inflammatory cytokines, neurotrophic factors, and Orexin A levels in the blood samples. Model performance was assessed via accuracy and F1 value in 3-fold cross-validation, comparing with 9 traditional algorithms. We then applied our algorithm to a dataset containing both the aforementioned protein quantifications and neuroimages, evaluating if integrating neuroimages into the model improves performance. RESULTS: Compared to HC, MDD showed significant alterations in plasma protein levels and gray matter volume revealed by MRI. Our new algorithm exhibited superior performance, achieving an F1 value and accuracy of 0.9436 and 94.08 %, respectively. Integration of neuroimaging data enhanced our novel algorithm's performance, resulting in an improved F1 value and accuracy, reaching 0.9543 and 95.06 %. LIMITATIONS: This single-center study with a small sample size requires future evaluations on a larger test set for improved reliability. CONCLUSIONS: In comparison to traditional machine learning models, our newly developed MDD diagnostic model exhibited superior performance and showed promising potential for inclusion in routine clinical diagnosis for MDD.

Repetitive Transcranial Magnetic Stimulation (rTMS) Improves Cognitive Impairment and Intestinal Microecological Dysfunction Induced by High-Fat Diet in Rats.

Consuming a high-fat diet (HFD) is widely recognized to cause obesity and result in chronic brain inflammation that impairs cognitive function. Repetitive transcranial magnetic stimulation (rTMS) has shown effectiveness in both weight loss and cognitive improvement, although the exact mechanism is still unknown. Our study examined the effects of rTMS on the brain and intestinal microecological dysfunction. rTMS successfully reduced cognitive decline caused by an HFD in behavioral assessments involving the Y maze and novel object recognition. This was accompanied by an increase in the number of new neurons and the transcription level of genes related to synaptic plasticity (spindlin 1, synaptophysin, and postsynaptic protein-95) in the hippocampus. It was reached that rTMS decreased the release of high mobility group box 1, activation of microglia, and inflammation in the brains of HFD rats. rTMS also reduced hypothalamic hypocretin levels and improved peripheral blood lipid metabolism. In addition, rTMS recovered the HFD-induced gut microbiome imbalances, metabolic disorders, and, in particular, reduced levels of the microvirus. Our research emphasized that rTMS enhanced cognitive abilities, resulting in positive impacts on brain inflammation, neurodegeneration, and the microbiota in the gut, indicating the potential connection between the brain and gut, proposing that rTMS could be a new approach to addressing cognitive deficits linked to obesity.

Microalgae-Based Hydrogel for Inflammatory Bowel Disease and Its Associated Anxiety and Depression.

Patients diagnosed with inflammatory bowel disease (IBD) exhibit a notable prevalence of psychiatric disorders, such as anxiety and depression. Nevertheless, the etiology of psychiatric disorders associated with IBD remains uncertain, and an efficacious treatment approach has yet to be established. Herein, an oral hydrogel strategy (SP@Rh-gel) is proposed for co-delivery of Spirulina platensis and rhein to treat IBD and IBD-associated anxiety and depression by modulating the microbiota-gut-brain axis. SP@Rh-gel improves the solubility, release characteristics and intestinal retention capacity of the drug, leading to a significant improvement in the oral therapeutic efficacy. Oral administration of SP@Rh-gel can reduce intestinal inflammation and rebalance the disrupted intestinal microbial community. Furthermore, SP@Rh-gel maintains intestinal barrier integrity and reduces the release of pro-inflammatory factors and their entry into the hippocampus through the blood-brain barrier, thereby inhibiting neuroinflammation and maintaining neuroplasticity. SP@Rh-gel significantly alleviates the colitis symptoms, as well as anxiety- and depression-like behaviors, in a chronic colitis mouse model. This study demonstrates the significant involvement of the microbiota-gut-brain axis in the development of IBD with psychiatric disorders and proposes a safe, simple, and highly efficient therapeutic approach for managing IBD and comorbid psychiatric disorders.

Comparisons of Accelerated Continuous and Intermittent Theta Burst Stimulation for Treatment-Resistant Depression and Suicidal Ideation.

BACKGROUND: Suicidal ideation is a substantial clinical challenge in treatment-resistant depression (TRD). Recent work demonstrated promising antidepressant effects in TRD patients with no or mild suicidal ideation using a specific protocol termed intermittent theta burst stimulation (iTBS). Here, we examined the clinical effects of accelerated schedules of iTBS and continuous TBS (cTBS) in patients with moderate to severe suicidal ideation. METHODS: Patients with TRD and moderate to severe suicidal ideation (n = 44) were randomly assigned to receive accelerated iTBS or cTBS treatment. Treatments were delivered in 10 daily TBS sessions (1800 pulses/session) for 5 consecutive days (total of 90,000 pulses). Neuronavigation was employed to target accelerated iTBS and cTBS to the left and right dorsolateral prefrontal cortex (DLPFC), respectively. Clinical outcomes were evaluated in a 4-week follow-up period. RESULTS: Accelerated cTBS was superior to iTBS in the management of suicidal ideation (pweek 1 = .027) and anxiety symptoms (pweek 1 = .01). Accelerated iTBS and cTBS were comparable in antidepressant effects (p < .001; accelerated cTBS: mean change at weeks 1, 3, 5 = 49.55%, 54.99%, 53.11%; accelerated iTBS: mean change at weeks 1, 3, 5 = 44.52%, 48.04%, 51.74%). No serious adverse events occurred during the trial. One patient withdrew due to hypomania. The most common adverse event was discomfort at the treatment site (22.73% in both groups). CONCLUSIONS: These findings provide the first evidence that accelerated schedules of left DLPFC iTBS and right DLPFC cTBS are comparably effective in managing antidepressant symptoms and indicate that right DLPFC cTBS is potentially superior in reducing suicidal ideation and anxiety symptoms.

Effect of prebiotics, probiotics, synbiotics on depression: results from a meta-analysis.

Accumulating studies have shown the effects of gut microbiota management tools in improving depression. We conducted a meta-analysis to evaluate the effects of prebiotics, probiotics, and synbiotics on patients with depression. We searched six databases up to July 2022. In total, 13 randomized controlled trials (RCTs) with 786 participants were included. The overall results demonstrated that patients who received prebiotics, probiotics or synbiotics had significantly improved symptoms of depression compared with those in the placebo group. However, subgroup analysis only confirmed the significant antidepressant effects of agents that contained probiotics. In addition, patients with mild or moderate depression could both benefit from the treatment. Studies with a lower proportion of females reported stronger effects for alleviating depressive symptoms. In conclusion, agents that manipulate gut microbiota might improve mild-to-moderate depression. It is necessary to further investigate the benefits of prebiotic, probiotic and synbiotic treatments relative to antidepressants and follow up with individuals over a longer time before these therapies are implemented in clinical practice.

Dysregulation of striatal dopamine D2/D3 receptor-mediated by hypocretin induces depressive behaviors in rats.

BACKGROUND: The dysregulation of the dopamine system contributes to depressive-like behaviors in rats, and the neurological functions regulated by hypocretin are severely affected in depression. However, whether suvorexant plays a role in alleviating depression by affecting the dopamine system is unclear. METHODS: To preliminarily explore the mechanism of suvorexant (10 mg/kg) in the treatment of depression, the mRNA and protein expression of TH, Drd2, Drd3, GluN2A, DAT, and GluN2B in the striatum of rats was quantified by qPCR and western blotting. The plasma hypocretin-1 and dopamine levels and the striatal dopamine levels were determined by ELISA. RESULTS: i) Compared to those of the control group, chronic unpredictable mild stress (CUMS) rats showed depressive-like behaviors, which were subsequently reversed by treatment with suvorexant. ii) The mRNA and protein expressions of TH, Drd2, Drd3, GluN2A, and GluN2B in the striatum of CUMS were significantly increased compared with those in the controls, but decreased after suvorexant treatment. iii) Compared with those in the control group, the plasma and striatal dopamine levels of CUMS decreased while plasma hypocretin-1 levels increased, which was reversed after suvorexant treatment. LIMITATIONS: i) The suvorexant is a dual hypocretin receptor antagonist; however, the responsible receptor is unclear. ii) We only focused on related factors in the striatum but did not explore other brain regions, nor did we directly explore the relationship among these factors. CONCLUSION: Depressive-like behaviors induced by CUMS can be reversed by suvorexant, and the therapeutic effects of suvorexant may be mediated by affecting the dopamine system.

YY1 (Yin-Yang 1), a transcription factor regulating systemic inflammation, is involved in cognitive impairment of depression.

AIM: Clinical and preclinical studies suggest that alterations in the peripheral and brain immune system are associated with the pathophysiology of depression, also leading to changes in local glucose metabolism in the brain. Here, the authors identified Yin-Yang 1 (YY1), a transcription factor closely associated with central and peripheral inflammation. METHODS: Plasma levels of YY1, interleukin (IL) 6, and IL-1ß in major depressive disorder (MDD) were collected before and after treatment with vortioxetine, and correlation with clinical and cognitive scores was studied. Chronic unpredictable mild stress was treated with vortioxetine. Micropositron emission tomography (microPET) was used to analyze glucose metabolism and mRNA, and the protein level of the YY1-nuclear factor κB (NF-κB)-IL-1ß inflammatory pathway were measured in related brain regions. RESULTS: Plasma levels of YY1 and IL-1ß were significantly increased in MDD and decreased after treatment with vortioxetine. Meanwhile, the level of YY1 in plasma was negatively correlated with cognitive functions in patients with MDD and positively correlated with the level of IL-1ß in plasma. Compared with the control group, in chronic unpredictable mild stress rats, (microPET) analysis showed that the decrease of glucose metabolism in the hippocampus, entorhinal cortex, amygdala, striatum, and medial prefrontal cortex was reversed after treatment. mRNA and protein level of related molecular in YY1-NF-κB-IL-1ß inflammatory pathway decreased in the hippocampus and was reversed by vortioxetine. CONCLUSION: The current study suggests that the YY1-NF-κB-IL-1ß inflammatory pathway may play an essential role in both mood changes and cognitive impairment in depression, and may be associated with changes in glucose metabolism in emotion regulation and cognition. These findings provide new evidence for the inflammatory mechanisms of depression.

The role of reelin in the pathological mechanism of depression from clinical to rodents.

Major depressive disorder (MDD) is a devastating mental illness and the leading cause of disability worldwide. Previous studies have suggested that synaptic plasticity in the hippocampus plays an important role in depression pathogenesis. Reelin is expressed mainly in the frontal lobe and hippocampus, and is closely associated with neurodevelopment and synaptic plasticity. However, few studies have investigated its role in MDD combining clinical trials and animal experiments. We show that in a clinical trial, plasma reelin levels decreased in patients with first-episode drug-naïve MDD and increased after treatment; further, plasma reelin levels allowed to distinguish drug-naïve patients with first-episode MDD from healthy individuals. In rats, chronic mild and unpredictable stress led to a decrease in both reelin mRNA and protein levels in the hippocampus, which could be reversed by vortioxetine. Subsequent experiments confirmed that the reelin-ApoER2-NR2A /NR2B pathway regulates hippocampal synaptic plasticity and may be involved in depression or antidepressant responses. Our work contributes to a deeper understanding of MDD pathogenesis and provides new evidence that reelin should be considered a potential therapeutic target for MDD.

Overnutrition Induced Cognitive Impairment: Insulin Resistance, Gut-Brain Axis, and Neuroinflammation.

Overnutrition-related obesity has become a worldwide epidemic, and its prevalence is expected to steadily rise in the future. It is widely recognized that obesity exerts negative impacts on metabolic disorders such as type 2 diabetes mellitus (T2DM) and cardiovascular diseases. However, relatively fewer reports exist on the impairment of brain structure and function, in the form of memory and executive dysfunction, as well as neurogenerative diseases. Emerging evidence indicates that besides obesity, overnutrition diets independently induce cognitive impairments via multiple mechanisms. In this study, we reviewed the clinical and preclinical literature about the detrimental effects of obesity or high-nutrition diets on cognitive performance and cerebral structure. We mainly focused on the role of brain insulin resistance (IR), microbiota-gut-brain axis, and neuroinflammation. We concluded that before the onset of obesity, short-term exposure to high-nutrition diets already blunted central responses to insulin, altered gut microbiome composition, and activated inflammatory mediators. Overnutrition is linked with the changes in protein expression in brain insulin signaling, leading to pathological features in the brain. Microbiome alteration, bacterial endotoxin release, and gut barrier hyperpermeability also occur to trigger mental and neuronal diseases. In addition, obesity or high-nutrition diets cause chronic and low-grade systematic inflammation, which eventually spreads from the peripheral tissue to the central nervous system (CNS). Altogether, a large number of unknown but potential routes interact and contribute to obesity or diet-induced cognitive impairment. The challenge for future research is to identify effective interventions involving dietary shifts and personalized therapy targeting the underlying mechanisms to prevent and improve cognition deficits.

A pilot exploration of multi-omics research of gut microbiome in major depressive disorders.

The pathophysiology of major depressive disorder (MDD) remains obscure. Recently, the microbiota-gut-brain (MGB) axis's role in MDD has an increasing attention. However, the specific mechanism of the multi-level effects of gut microbiota on host metabolism, immunity, and brain structure is unclear. Multi-omics approaches based on the analysis of different body fluids and tissues using a variety of analytical platforms have the potential to provide a deeper understanding of MGB axis disorders. Therefore, the data of metagenomics, metabolomic, inflammatory factors, and MRI scanning are collected from the two groups including 24 drug-naïve MDD patients and 26 healthy controls (HCs). Then, the correlation analysis is performed in all omics. The results confirmed that there are many markedly altered differences, such as elevated Actinobacteria abundance, plasma IL-1ß concentration, lipid, vitamin, and carbohydrate metabolism disorder, and diminished grey matter volume (GMV) of inferior frontal gyrus (IFG) in the MDD patients. Notably, three kinds of discriminative bacteria, Ruminococcus bromii, Lactococcus chungangensis, and Streptococcus gallolyticus have an extensive correlation with metabolome, immunology, GMV, and clinical symptoms. All three microbiota are closely related to IL-1ß and lipids (as an example, phosphoethanolamine (PEA)). Besides, Lactococcus chungangensis is negatively related to the GMV of left IFG. Overall, this study demonstrate that the effects of gut microbiome exert in MDD is multifactorial.

Aberrant Development of Cross-Frequency Multiplex Functional Connectome in First-Episode, Drug-Naive Major Depressive Disorder and Schizophrenia.

Introduction: Both major depressive disorder (MDD) and schizophrenia (SCH) are characterized by neurodevelopmental abnormalities; however, transdiagnostic and diagnosis-specific patterns of such abnormalities have rarely been examined, particularly in large-scale functional brain networks via advanced multilayer network models. Methods: Here, we collected resting-state functional magnetic resonance imaging data from 45 MDD patients, 64 SCH patients, and 48 healthy controls (HCs; 13-45 years old), and we constructed functional networks in different frequency intervals. The frequency-dependent networks were then fused by multiplex network models, followed by graph-based topological analyses. Results: We found that functional networks of the patients showed common neurodevelopmental abnormalities in the right ventromedial parietooccipital sulcus (opposite correlations with age to HCs), whereas functional networks of the MDD patients exhibited specific alterations in the left superior parietal lobule and right precentral gyrus with respect to cross-frequency interactions. These findings were quite different from those from brain networks within each frequency interval, which revealed SCH-specific neurodevelopmental abnormalities in the right superior temporal gyrus (opposite correlations with age to the other two groups) in 0.027-0.073 Hz, and SCH-specific alterations in the left superior temporal gyrus and bilateral insula in 0.073-0.198 Hz. Finally, multivariate analysis of age prediction revealed that the subcortical network lost prediction ability in both patient groups, whereas the visual network exhibited additional prediction ability in the MDD patients. Discussion and Conclusion: Altogether, these findings demonstrate transdiagnostic and diagnosis-specific neurodevelopmental abnormalities and alterations in large-scale functional brain networks between MDD and SCH, which have important implications for understanding shared and unique neural mechanisms underlying the diseases.

Changes of Hypocretin (Orexin) System in Schizophrenia: From Plasma to Brain.

Hypocretin (also called orexin) regulates various functions, such as sleep-wake rhythms, attention, cognition, and energy balance, which show significant changes in schizophrenia (SCZ). We aimed to identify alterations in the hypocretin system in SCZ patients. We measured plasma hypocretin-1 levels in SCZ patients and healthy controls and found significantly decreased plasma hypocretin-1 levels in SCZ patients, which was mainly due to a significant decrease in female SCZ patients compared with female controls. In addition, we measured postmortem hypothalamic hypocretin-1-immunoreactivity (ir), ventricular cerebrospinal fluid (CSF) hypocretin-1 levels, and hypocretin receptor (Hcrt-R) mRNA expression in the superior frontal gyrus (SFG) in SCZ patients and controls We observed a significant decrease in the amount of hypothalamic hypocretin-1 ir in SCZ patients, which was due to decreased amounts in female but not male patients. Moreover, Hcrt-R2 mRNA in the SFG was decreased in female SCZ patients compared with female controls, while male SCZ patients showed a trend of increased Hcrt-R1 mRNA and Hcrt-R2 mRNA expression compared with male controls. We conclude that central hypocretin neurotransmission is decreased in SCZ patients, especially female patients, and this is reflected in the plasma.

Distinguishing hypochondriasis and schizophrenia using regional homogeneity: a resting-state fMRI study and support vector machine analysis.

OBJECTIVE: A few former studies suggested that there are partial overlaps in abnormal brain structure and cognitive function between hypochondriasis (HS) and schizophrenia (SZ). But their differences in brain activity and cognitive function were unclear. METHODS: Twenty-one HS patients, 23 SZ patients, and 24 healthy controls (HC) underwent resting-state functional magnetic resonance imaging (rs-fMRI) with the regional homogeneity analysis (ReHo), subsequently exploring the relationship between ReHo value and cognitive functions. The support vector machines (SVM) were used on effectiveness evaluation of ReHo for differentiating HS from SZ. RESULTS: Compared with HC, HS showed significantly increased ReHo values in right middle temporal gyrus (MTG), left inferior parietal lobe (IPL), and right fusiform gyrus (FG), while SZ showed increased ReHo in left insula, decreased ReHo values in right paracentral lobule. Additionally, HS showed significantly higher ReHo values in FG, MTG, and left paracentral lobule, but lower in insula than SZ. The higher ReHo values in insula were associated with worse performance in MATRICS consensus cognitive battery (MCCB) in HS group. SVM analysis showed a combination of the ReHo values in insula and FG was able to satisfactorily distinguish the HS and SZ patients. CONCLUSION: Our results suggested that the altered default mode network (DMN), of which abnormal spontaneous neural activity occurs in multiple brain regions, might play a key role in the pathogenesis of HS, and the resting-state alterations of insula are closely related to cognitive dysfunction in HS. Furthermore, the combination of the ReHo in FG and insula was a relatively ideal indicator to distinguish HS from SZ.

Gray Matter Volume and Functional Connectivity in Hypochondriasis: A Magnetic Resonance Imaging and Support Vector Machine Analysis.

Objective: Patients with hypochondriasis hold unexplainable beliefs and a fear of having a lethal disease, with poor compliances and treatment response to psychotropic drugs. Although several studies have demonstrated that patients with hypochondriasis demonstrate abnormalities in brain structure and function, gray matter volume (GMV) and functional connectivity (FC) in hypochondriasis still remain unclear. Methods: The present study collected T1-weighted and resting-state functional magnetic resonance images from 21 hypochondriasis patients and 22 well-matched healthy controls (HCs). We first analyzed the difference in the GMV between the two groups. We then used the regions showing a difference in GMV between two groups as seeds to perform functional connectivity (FC) analysis. Finally, a support vector machine (SVM) was applied to the imaging data to distinguish hypochondriasis patients from HCs. Results: Compared with the HCs, the hypochondriasis group showed decreased GMV in the left precuneus, and increased GMV in the left medial frontal gyrus. FC analyses revealed decreased FC between the left medial frontal gyrus and cuneus, and between the left precuneus and cuneus. A combination of both GMV and FC in the left precuneus, medial frontal gyrus, and cuneus was able to discriminate the hypochondriasis patients from HCs with a sensitivity of 0.98, specificity of 0.93, and accuracy of 0.95. Conclusion: Our study suggests that smaller left precuneus volumes and decreased FC between the left precuneus and cuneus seem to play an important role of hypochondriasis. Future studies are needed to confirm whether this finding is generalizable to patients with hypochondriasis.

Linking peripheral IL-6, IL-1ß and hypocretin-1 with cognitive impairment from major depression.

BACKGROUND: Cognitive impairment has long challenged the patients with major depressive disorder (MDD), hypocretins and inflammation have recently been implicated in cognitive function. However, limited studies have compressively assessed their associations with cognitive impairment in MDD. METHODS: A total of 100 MDD patients and 100 healthy controls (HC) were recruited for this study. They were tested with HAMD, HAMA, and MCCB scales. The plasma level of selected inflammatory factors (IL-1ß, IL-6, and TNF-α) and hypocretin-1 were determined using enzyme-linked immunosorbent assay (ELISA). Correlation analysis was performed to explore the relationship between the plasma level of the factors and clinical performances. RESULTS: Patients with MDD showed cognitive impairment in each MCCB subdomain except working memory compared with HC. The levels of IL-6, IL-1ß and hypocretin-1 in MDD patients were higher than HC. Besides, IL-1ß levels was negatively correlated with overall cognitive function in the combined group. Hypocretin-1 was positively correlated with socially cognitive impairment in MDD patients. A negative correlation between plasma hypocretin-1 levels and HAMA scales was also observed in MDD patients. LIMITATION: The study was cross-sectional, thereby limiting causal inference, and had a relatively small sample size. There are no subcategories for MDD based on characteristics. CONCLUSION: IL-1ß, IL-6 and Hypocretin-1 were reported as potential factors involved in MDD pathology. Hypocretin-1 could contribute to the biological mechanisms of anxiety relief. Hypocretin-1, therefore, may be important in exploring the pathological mechanisms of social cognitive impairment in MDD patients. Conclusively, this study provides new insights for exploring cognitive impairment in depression.