Background Visual learning memory deficits are key issues in major depressive disorder (MDD), but the specific gut microbiota involved are not well understood. While gut dysbiosis and metabolic alterations in the frontolimbic region are linked to MDD, the influence of regional neurochemistry on the microbiota-cognition relationship remains unknown. Methods Visual learning memory was assessed in 38 MDD patients and 41 healthy controls (HC) using the Brief Visuospatial Memory Test-Revised. Gut microbiota were analyzed via 16S rRNA gene sequencing of fecal samples, and neurochemical ratios N-acetylaspartate/Creatine (NAA/Cr) and Choline/Creatine (Cho/Cr) in anterior cingulate cortex (ACC) and prefrontal white matter (PWM) were quantified using proton magnetic resonance spectroscopy. Results MDD exhibited visual learning memory deficits, elevated NAA/Cr in the right ACC, reduced NAA/Cr in the right PWM compared to HC. Ruminococcus abundance was increased in MDD and negatively correlated with visual learning memory. The relationship between Ruminococcus abundance and visual learning memory was moderated by NAA/Cr ratios in the ACC and PWM in a configuration-dependent manner. Specifically, the most pronounced negative association emerged when the ACC NAA/Cr ratio was high and the PWM NAA/Cr ratio was low. Conclusions The study indicates that simultaneous metabolic dysregulation in gray and white matter, shown by elevated ACC NAA/Cr and decreased PWM NAA/Cr, constitutes a “double hit” that exacerbated visual learning memory impairment associated with Ruminococcus in MDD. This dual impact underscores distinct yet interconnected vulnerabilities in gray and white matter, where microbiota-cognition associations are critically shaped by the broader neurochemical environment.

Objective It remains unclear whether individuals with bipolar disorder (BD) with suicidal attempt (SA) exhibit glymphatic dysfunction, or how such dysfunction may relate to personality traits. Methods In this study, magnetic resonance imaging (MRI) was used to evaluate glymphatic function by calculating multiple indices, including the diffusion tensor imaging along the perivascular space (DTI-ALPS) index, free-water (FW), perivascular space volume (PVS), and choroid plexus volume (CP), in 37 BD individuals with SA, 35 BD individuals without SA (NSA), and 35 healthy controls (HCs). Among BD individuals, SA was assessed using Beck Scale for Suicidal Ideation (SSI-Beck), and personality traits were evaluated via the Minnesota Multiphasic Personality Inventory-2 (MMPI-2). Results BD patients with SA scored higher on MMPI-2 for Hypochondriasis, Depression, and Schizophrenia than NSA and HCs. Furthermore, BD patients with SA exhibited lower ALPS index and higher FW than HCs, but no significant differences in ALPS index and FW between SA-NSA or NSA-HCs groups, nor in CP and PVS among three groups. In BD with SA, Schizophrenia scores showed a negative correlation with the right ALPS index, whereas Paranoia and Hypochondria scores were positively correlated with FW. Multivariate regression analysis revealed that the interaction between FW and Psychopathic Deviate independently predicted SSI-Beck scores in BD with SA. Conclusions This study demonstrates that glymphatic dysfunction and maladaptive personality traits in BD with SA may interact to exacerbate suicidal tendencies, suggesting glymphatic - targeting therapies as a potential strategy to reduce suicide risk.

This study aimed to characterise neurometabolic differences between bipolar disorder I (BD-I) and bipolar disorder II (BD-II), and to examine their associations with cognitive function. A total of 50 patients diagnosed with BD-I, 80 patients with BD-II, and 50 healthy controls (HCs) were recruited for this study. Metabolite concentrations—specifically N-acetylaspartate (NAA) and choline-containing compounds (Cho)—were measured in the prefrontal white matter (PWM), anterior cingulate cortex (ACC), and thalamus through proton magnetic resonance spectroscopy (¹H-MRS). Cognitive performance was evaluated using the MATRICS Consensus Cognitive Battery (MCCB). When compared to HCs, patients with BD-II showed significantly higher Cho/Cr ratios in the right PWM and left ACC, along with lower NAA/Cr ratios in the right thalamus; compared to BD-II patients, those with BD-I exhibited higher Cho/Cr ratios in the right PWM and lower NAA/Cr ratios in the right thalamus; among BD-I patients, the Cho/Cr ratio in the left ACC was negatively correlated with measures of information processing speed and attentional vigilance. This study demonstrates that BD-II patients exhibit greater cholinergic dysregulation in the left ACC and the right PWM, whereas BD-I patients show more pronounced neuronal dysfunction in the right thalamus. Furthermore, the left ACC Cho/Cr ratio was specifically associated with cognitive impairments in information processing speed and attentional vigilance, but only among patients with BD-I. This suggests that subtype-specific mechanisms underlie the relationship between neurometabolic abnormalities and cognitive deficits. Not applicable.

The underlying mechanism of major depressive disorder (MDD) with eating disorder (ED) remains unclear. We aim to clarify the characteristic changes of THs and brain neurometabolic alterations in ED, and to explore their relationships. The study included 28 individuals with MDD and ED, 81 individuals with MDD without ED, and 37 age-matched healthy controls (HCs). Serum TH levels were assessed, and 1H proton magnetic spectroscopy was utilized to determine the N-acetylaspartic acid to creatine (NAA/Cr) and choline-containing compounds to creatine ratios in the prefrontal cortex, anterior cingulate cortex, and thalamus. Subsequently, differential analysis, receiver operating characteristic (ROC) analysis, and correlation analysis were performed to explore their characteristics and interrelationships. In both MDD with ED and MDD without ED cohorts, free tri-iodothyronine (FT3) levels were significantly lower compared to HCs, whereas free thyroxine (FT4) and total thyroxine (TT4) levels were elevated. Significantly lower NAA/Cr ratios were observed in the right thalamus and higher NAA/Cr ratios in the left cerebellum in both MDD with ED and MDD without ED compared to HCs. Neurometabolic factors and THs levels achieved an ROC curve area of 0.830 in differentiating MDD with ED from MDD without ED. In addition, serum FT3 and TT4 levels showed a positive correlation with NAA/Cr in the eft cerebellum in cases of MDD with ED. Our findings reveal concurrent thyroid hormone irregularities and neurometabolic changes in the thalamic-cerebellum circuitry in MDD with ED, providing preliminary insights into the neurobiology of abnormal eating behaviors in depression. Given the cross-sectional design, these results are exploratory and require validation. Level of evidence Level IV, cross-sectional study.

Dysregulation of copper (Cu) metabolism may contribute to the pathogenesis of major depressive disorder (MDD) by disrupting hippocampal function. The aim of this study is to elucidate the neurobiological mechanisms through integrated clinical and animal experiments. A total of 85 MDD patients and 65 healthy controls (HCs) were recruited for this study. Serum Cu, ceruloplasmin (Cp) levels, and the relative mRNA expression of ATPase copper-transporting alpha (Atp7a) were measured. All participants underwent resting-state functional magnetic resonance imaging, and the Amplitude of Low-Frequency Fluctuation (ALFF) was calculated using subdivisions of the hippocampus (HPC). Cognitive function across seven domains was also assessed. In animal studies, mice were subjected to a chronic unpredictable mild stress (CUMS) model to develop depression. The Cu chelator tetrathiomolybdate (TTM) was then administered to investigate its impacts on Cu-related biochemical indices and brain structure in the HPC of the test group. We found that MDD patients exhibited increased serum Cu2+ levels, and decreased Cp level and Atp7a mRNA expression compared to HCs. A significant reduction in ALFF was observed in the right rostral hippocampus (rHPC) of MDD patients. Animal studies showed depressive-like mice had high Cu levels and Atp7a mRNA expression, with low Cp levels in HPC, accompanying hippocampal cytoarchitectural impairments. Systemic administration of Cu TTM effectively counteracted and reversed both the Cu dyshomeostasis and hippocampal structural damage associated with depression. Patients with MDD exhibit Cu metabolism dysregulation, with excess Cu²⁺ harming hippocampal neurons and contributing to the pathogenesis of depression. Consequently, modulating Cu homeostasis may represent a novel therapeutic target for MDD.

Background Increasing evidences show that inflammation might be involved in bipolar disorder (BD), but the association between abnormal brain function and inflammation in BD is still unclear. In this study, we tried to explore the disrupted brain functional network topology, peripheral inflammatory cytokine levels, and their correlations in unmedicated bipolar II depression (BDII-D).Methods In this study, 65 individuals with unmedicated BDII-D and 50 healthy controls (HCs) underwent resting-state magnetic resonance imaging scans. Graph theory analysis was performed to investigate the topological properties of the whole-brain functional connectome at both global and nodal levels. Besides, serum levels of 17 inflammatory cytokines were measured in both BDII-D and HCs. Correlations between topological properties, clinical variables, and peripheral inflammatory cytokine levels in BDII-D were calculated.Results Compared with HCs, at the global level, BDII-D showed significantly higher $ \lambda $ , decreased $ \gamma $ , $ \sigma $ , Eglo, and Eloc; at the nodal level, BDII-D showed decreased Enodal in the right olfactory cortex, left pallidum, and vermis. Besides, BDII-D showed higher levels of interleukin-8 (IL-8), interleukin-10 (IL-10), and granulocyte colony-stimulating factor (G-CSF) compared with the HCs. In BDII-D, $ \gamma $ and $ \sigma $ were significantly negatively correlated with the Hamilton Depression Rating Scale (HDRS) scores and number of episodes. Also, IL-8 level showed significant negative correlation with $ \gamma $ , $ \sigma $ , and Enodal of the left pallidum in BDII-D.Conclusions Reduced information segregation and integration, and lower nodal efficiency in the left pallidum were associated with proinflammatory cytokine IL-8 level and might contribute to severe depressive symptoms in unmedicated BDII-D.

Virtual Reality-based Eye movement desensitization and reprocessing therapy (VR-EMDR) has been proven effective in treating adults with major depressive disorder (MDD). However, its effectiveness in treating adolescents with MDD is less studied, and its underlying neuroimaging mechanism remains unknown. Sixty-eight adolescents with MDD and 29 adolescent healthy control (HC) were recruited. Adolescents with MDD were randomly allocated to the intervention group and the wait-list control group. The intervention group received 12-session of VR-EMDR, while another group received no psychotherapy. We used the Hamilton Depression Rating Scale-24 version (24-HDRS) to assess the patients’ depressive symptoms; the Das-Naglieri Cognitive Assessment System (CAS) to assess the patients’ neurocognitive performance; and the functional near-infrared spectroscopy (fNIRS) to assess the patients’ functional connectivity and small-world network attributes. After VR-EMDR, the linear mixed model (LMM) revealed significantly lower scores in 24-HDRS and average shortest path, and significantly higher scores in figure memory, successive processing, sentence repetition, sentence question, and total cognitive in the intervention group (all p < 0.05). Multiple linear regression analyses revealed that significant negative relationships can be found between average shortest path and figure memory, total cognition; a significant positive relationship can be found between global efficiency and successive processing (all p < 0.05). VR-EMDR can effectively improve depressive symptoms, neurocognitive performance, and change small-world network attributes in adolescents with MDD. Furthermore, the changes in average shortest path length and global efficiency may play potential roles in the improvement of cognitive function after VR-EMDR.

Importance:Accelerated intermittent theta burst stimulation (aiTBS) is an effective rapid-acting treatment for suicidal ideation in adults with major depressive disorder (MDD). However, evidence in adolescents remains limited, and whether dual-site frontal-cerebellar aiTBS enhances antisuicidal efficacy in this population is unknown. Objective:To investigate the clinical effectiveness and safety of dual-site aiTBS targeting the left dorsolateral prefrontal cortex (DLPFC) and cerebellum vs single-site DLPFC aiTBS for reducing suicidal ideation in adolescents with MDD. Design, Setting, and Participants:This double-blind, randomized clinical trial with a 1-month follow-up was conducted at the First Affiliated Hospital of Jinan University (Guangzhou, China) from September 2023 to May 2025. Adolescents (aged 12-18 years) with MDD and suicidal ideation and without comorbid medical or neurologic conditions were enrolled and randomly assigned to dual-site aiTBS or single-site aiTBS. Interventions:Patients received 5 daily sessions of aiTBS over 4 days. Dual-site aiTBS delivered active stimulation to both the left DLPFC and left cerebellum, while single-site aiTBS delivered active stimulation to the left DLPFC with sham stimulation to the left cerebellum. Main Outcome and Measure:The primary outcome was the change from baseline to day 4 in the Beck Scale for Suicide Ideation (BSI) score (range, 0-38; higher scores indicate greater severity of suicidal ideation), assessed with a linear mixed-effects model. Results:Of 79 adolescents assessed for eligibility, a total of 59 were included (45 females [76%]; mean [SD] age, 14.78 [1.72] years). Of these, 29 were randomized to the dual-site aiTBS group (23 [79%] female) and 30 to the single-site group (22 [73%] female). For the primary outcome, patients receiving dual-site aiTBS showed a significantly greater reduction in mean BSI scores compared with those receiving single-site aiTBS at day 4 (difference, 4.94 points [95% CI, 0.73-9.14 points]; t = 2.35; P = .02; Cohen d, 0.61 [95% CI, 0.09-1.13]). No serious adverse events in either group were observed. Conclusions and Relevance:This randomized clinical trial found that dual-site aiTBS targeting the left DLPFC and cerebellum was more effective than single-site left DLPFC aiTBS in reducing suicidal ideation for adolescents with MDD and was well tolerated. The findings suggest this protocol may be a promising strategy for rapid reduction of suicidal ideation in the adolescent population. Trial Registration:Chinese Clinical Trial Registry Identifier: ChiCTR2300068954.

This randomized clinical trial compares the efficacy of dual-site accelerated intermittent theta burst stimulation (aiTBS) to the left dorsolateral prefrontal cortex (DLPFC) and cerebellum vs to the DLPFC alone for reducing suicidal ideation in adolescents with major depressive disorder in China. QuestionIs dual-site accelerated intermittent theta burst stimulation (aiTBS) targeting the left dorsolateral prefrontal cortex (DLPFC) and cerebellum more effective than single-site DLPFC stimulation in alleviating suicidal ideation among adolescents with major depressive disorder (MDD)?FindingsIn this randomized clinical trial of 59 adolescents aged 12 to 18 years with MDD and suicidal ideation, dual-site aiTBS significantly reduced suicidal ideation after the 4-day treatment compared with single-site stimulation.MeaningThe findings indicate that dual-site aiTBS targeting both the DLPFC and cerebellum may provide a rapid and effective treatment option for suicidal ideation in adolescents with MDD. ImportanceAccelerated intermittent theta burst stimulation (aiTBS) is an effective rapid-acting treatment for suicidal ideation in adults with major depressive disorder (MDD). However, evidence in adolescents remains limited, and whether dual-site frontal-cerebellar aiTBS enhances antisuicidal efficacy in this population is unknown.ObjectiveTo investigate the clinical effectiveness and safety of dual-site aiTBS targeting the left dorsolateral prefrontal cortex (DLPFC) and cerebellum vs single-site DLPFC aiTBS for reducing suicidal ideation in adolescents with MDD.Design, Setting, and ParticipantsThis double-blind, randomized clinical trial with a 1-month follow-up was conducted at the First Affiliated Hospital of Jinan University (Guangzhou, China) from September 2023 to May 2025. Adolescents (aged 12-18 years) with MDD and suicidal ideation and without comorbid medical or neurologic conditions were enrolled and randomly assigned to dual-site aiTBS or single-site aiTBS.InterventionsPatients received 5 daily sessions of aiTBS over 4 days. Dual-site aiTBS delivered active stimulation to both the left DLPFC and left cerebellum, while single-site aiTBS delivered active stimulation to the left DLPFC with sham stimulation to the left cerebellum.Main Outcome and MeasureThe primary outcome was the change from baseline to day 4 in the Beck Scale for Suicide Ideation (BSI) score (range, 0-38; higher scores indicate greater severity of suicidal ideation), assessed with a linear mixed-effects model.ResultsOf 79 adolescents assessed for eligibility, a total of 59 were included (45 females [76%]; mean [SD] age, 14.78 [1.72] years). Of these, 29 were randomized to the dual-site aiTBS group (23 [79%] female) and 30 to the single-site group (22 [73%] female). For the primary outcome, patients receiving dual-site aiTBS showed a significantly greater reduction in mean BSI scores compared with those receiving single-site aiTBS at day 4 (difference, 4.94 points [95% CI, 0.73-9.14 points]; t = 2.35; P = .02; Cohen d, 0.61 [95% CI, 0.09-1.13]). No serious adverse events in either group were observed.Conclusions and RelevanceThis randomized clinical trial found that dual-site aiTBS targeting the left DLPFC and cerebellum was more effective than single-site left DLPFC aiTBS in reducing suicidal ideation for adolescents with MDD and was well tolerated. The findings suggest this protocol may be a promising strategy for rapid reduction of suicidal ideation in the adolescent population.Trial RegistrationChinese Clinical Trial Registry Identifier: ChiCTR2300068954

INTRODUCTION:Gender dysphoria (GD) causes distress from gender-sex incongruence with elevated suicide risk, yet its neuropathology remains unclear. The thalamic-cortical functional connectivity (FC) in transgender women (TW) is unexplored. We investigated thalamo-cortical FC and its mediating role in TW's symptom-cognition relationships. METHODS:We retrospectively analysed resting-state fMRI from 44 TW, 40 cisgender men (CM), and 42 cisgender women (CW), between October 2021 and January 2024. Clinical symptoms (GIDYQ-AA) and cognition (MCCB) were assessed. Seed-based thalamic subregion FC and mediation analyses were performed. RESULTS:Relative to CW, TW and CM exhibited increased FC in multiple thalamo-prefrontal circuits. Compared to CM, TW showed decreased left mPFtha-left DLPFC FC (p = 0.026), and right rTtha-left DLPFC FC (p = 0.025). Compared to CM, right PPtha-right MOG FC (p = 0.023; p < 0.001), and right cTtha-right SOG FC (p = 0.008; p < 0.001) were increased in TW and CW. In TW, left rTtha-bilateral MPFC FC correlated with GIDYQ-AA scores, attention/vigilance, and composite. This FC fully mediated relationships between GD symptoms and both attention/vigilance (bootstrapped 95% CI = 1.861-11.688) and composite (bootstrapped 95% CI = 1.025-12.283). CONCLUSIONS:TW exhibit thalamo-cortical FC abnormalities and cognitive dysfunction. Critically, thalamus-MPFC dysconnectivity mediates GD symptom-related cognitive dysfunction, revealing a novel neural pathway. Validation in larger, diverse samples is needed.

Background Subthreshold depression (StD) is considered a prodromal stage of major depressive disorder (MDD). This study aims to investigate the neurobiological mechanisms of StD by analyzing functional connectivity (FC) and cognitive function in comparison to MDD.Methods A total of 153 StD individuals, 188 MDD patients, and 110 healthy controls (HCs) were studied using resting-state functional magnetic resonance imaging (fMRI). Whole-brain FC was calculated using seeds from the default mode network (DMN), salience network (SN), executive control network, and affective network (AN). Cognitive function was assessed across seven domains.Results StD showed only a deficit in social cognition, while MDD exhibited multidomain cognitive impairments compared to HCs. Both MDD and StD exhibited reduced FC between the right anterior insula (AI) and the left inferior frontal gyrus (IFG), and increased FC between the right subcallosal cingulate cortex and the left posterior cingulate cortex (PCC), key areas of the SN and AN, compared to HCs. MDD particularly showed decreased connectivity between the left PCC and the left middle temporal gyrus, and within the left PCC, while no abnormal FC of the DMN was found in StD. Altered AI-IFG FC was positively correlated with social cognition in StD.Conclusions Abnormal connectivity patterns of the SN and AN may contribute to the development of depressive symptoms in StD and MDD, while altered FC of the DMN may be involved in the onset of the disease. A social cognition deficit appeared first in StD, relating to the abnormal connectivity of the SN.

Our study investigated the neuropsychological mechanisms underlying BD comorbid with BPD by examining childhood trauma and metabolic changes in the cerebellum. We found that BD & BPD patients reported higher levels of physical abuse and demonstrated distinct cerebellar metabolic profiles characterized by elevated NAA/Cr and Cho/Cr ratios in the right cerebellum compared to BD patients without BPD. Notably, these ratio changes were driven by significantly increased absolute NAA concentrations and decreased creatine levels, whereas absolute choline concentrations and NAA/Cho ratios remained unchanged. Physical abuse was inversely correlated with the right cerebellar Cho/Cr ratio. These findings suggest that childhood trauma may interact with cerebellar energy metabolic dysfunction-characterized by neuronal hypermetabolism (elevated NAA) and compromised energy buffering (reduced Cr)-in the pathophysiology of this comorbidity. This study provides new insights into the biological underpinnings linking early-life adversity and cerebellar neurochemical alterations in BD & BPD.

Background Major depressive disorder (MDD) with atypical features often characterized with increased misdiagnosis and poor response to standard treatment. This research explores the neurobiological mechanisms underlying atypical depression (AD) by examining spontaneous brain activity and childhood trauma contrasting these findings with non-atypical depression (NAD). Methods A total 93 youth patients with MDD (31 with AD and 62 NAD) and 52 healthy controls (HCs) were studied using resting-state functional magnetic resonance imaging (fMRI). We employed the amplitude of low-frequency fluctuation (ALFF) method alongside a sliding-window dynamic analysis to investigate temporal variations in local brain activity. Childhood trauma was evaluated using the Childhood Trauma Questionnaire (CTQ). Results Both the youth AD and NAD exhibited increased dynamic ALFF (dALFF) in the midbrain, and decreased static ALFF (sALFF) in the left lingual gyrus (LG) and the bilateral anterior cingulate cortex (ACC) when compared to HCs. Both MDD groups exhibited increased sALFF in the left cerebellum relative to HCs, whereas AD demonstrated decreased sALFF in the left inferior temporal gyrus (ITG) when compared to NAD. The elevated sALFF in the left cerebellum was inversely correlated with CTQ emotional and physical neglect scores in AD. Conclusions Abnormal spontaneous brain activity in the midbrain, LG, ACC, and cerebellum may represent inherent characteristics of MDD, regardless of atypical features. Childhood trauma may be an early risk factor for MDD, which is not sufficient to distinguish between atypical and non-atypical phenotypes.

BACKGROUND:Previous studies indicated that the notion that 20-40 % of patients with major depressive disorder (MDD) have cognitive impairments (CI). The mechanism of cognitive deficits in MDD is largely unknown. Recent evidence suggests that metabolic changes may be associated with poorer cognitive outcomes in MDD. METHOD:We recruited 105 right-handed, untreated youth with MDD patients, and 68 demographically matched healthy controls (HCs), and underwent the MATRICS Consensus Cognitive Battery (MCCB) assessment and proton magnetic resonance spectroscopy (1H-MRS) scan in the anterior cingulate gyrus (ACC) and putamen. Differential and association analysis was performed to investigate the relationship between cognitive performance and neurometabolism ratios of ACC and putamen in MDD groups. RESULTS:Thirty-nine patients defined as CI group (>1.5 SD below the normal mean of MCCB in two or more MCCB domains) and 67 patients for NCI (without CI) group. The CI group exhibited significantly higher Cho/Cr ratios in the right ACC when compared to the NCI group and HCs groups. Both CI and NCI groups showed significantly higher Cho/Cr ratios in the left putamen compared to the HCs. Meanwhile, the number of episodes were positively correlated with the Cho/Cr ratios in the left putamen (r = 0.35, p = 0.035) in CI group. CONCLUSION:Our findings suggest that both CI and NCI MDD may experience putamen dysfunction. Additionally, the frequency of depressive episodes appears to have a cumulative effect on alterations in the Cho/Cr ratios in the putamen. Concurrently, an increased Cho/Cr ratio in the ACC is linked to widespread cognitive deficits in MDD patients. These results may point to a subgroup of patients who could benefit from interventions aimed at modulating brain functional status.

Currently, bipolar disorder diagnosis is primarily based on clinical interviews. Magnetoencephalography signals reflect changes in the brain’s magnetic field induced by neuronal activity. As a result, the combination of magnetoencephalography and network science holds great promise for identifying bipolar disorder biomarkers. However, the existing methods remain limited in capturing the complexity of nodes and their connections within resting-state brain networks, making it difficult to fully reveal underlying pathological mechanisms. In this work, we measured the uncertainty associated with a subgraph, an information-theoretic metric called “subgraph entropy,” and used it to identify individuals with bipolar disorder. This method enabled a more accurate characterization of brain network complexity, facilitating the identification of regions closely associated with disease states. The results showed that subgraph entropy features significantly contributed to the classification of bipolar disorder, particularly within the beta frequency band. In addition, two special forms of subgraph entropy, namely node entropy and edge entropy, were examined to identify important brain regions and functional connectivity in bipolar disorder patients across multiple frequency bands. Notably, in the beta frequency band, the method based on edge entropy achieved 0.8462 accuracy, 0.7308 specificity, and 0.9231 sensitivity through leave-one-out cross-validation, effectively distinguishing individuals with bipolar disorder from healthy controls.

Background: Differentiating between patients with bipolar disorder (BD) and major depressive disorder (MDD) is clinically challenging. This study aimed to explore the potential of radiomic textural features for discriminating BD and MDD. Methods: A total 253 subjects (114 patients with BD, 139 patients with MDD) with T1-weighted MRI data were recruited. Radiomics features and gray matter volume (GMV) features were extracted from each brain region. A novel high-level MSN_II feature method based on radiomic features was proposed. And a total of 21 MSN features (5 MSN_I and 16 MSN_II) based on different combinations of the 5 types of radiomic textural feature were calculated. Classification models were constructed using various combinations of MSNs or GMV, and their performance and stability was evaluated through 2000 repeated experiments. Results: The model built with combined features (GMV and GMV + MSN_II_GLCM_GLSZM_NGTDM) showed the best classification performance (AUC = 0.896 +/- 0.058, ACC = 0.831 +/- 0.064) in the validation cohort. After MANOVA analysis and FDR correlation, the MSN_II_GLCM_GLSZM_NGTDM values in 4 regions (right rectus gyrus, right temporal pole: middle temporal gyrus, Vermis3 and Vermis10) showed significant difference between BD and MDD. Limitation: The main limitation of this study is that the data is derived from a single center without an external independent test set. Conclusions: Incorporating the high-level MSN_II based on radiomics features can improve the classification performance compared to models solely relying on GMV features alone. This result implied the potential application of the proposed high level MSN method and radiomics textural features on the MDD and BD clinical studies.

BACKGROUND:Early-onset depression (EOD) and late-onset depression (LOD) are prevalent subtypes of major depressive disorder (MDD), but the clinical distinction between EOD and LOD remains blurred due to nonspecific symptoms and lack of biomarkers. This study aims to elucidate the characteristics in cognitive function and biochemical metabolism of EOD and LOD, and to identify biological factors influencing age of onset (AOO). METHODS:Seventy patients with MDD (40 with EOD and 30 with LOD) and sixty-eight age-matched healthy controls (HC) were included in this study. Participants were evaluated for clinical features, cognitive function, and serum trace elements levels. Proton magnetic resonance spectroscopy (1H-MRS) was employed to quantify neurometabolites levels, including N-acetyl aspartate (NAA), choline (Cho), and creatine (Cr). RESULTS:Patients with LOD experienced more episodes and severe depressive symptoms than those with EOD (p = 0.025, p < 0.001). EOD patients performed significantly worse than LOD patients on social cognition (p = 0.005), while LOD patients performed worse than EOD patients on reasoning and problem solving (p = 0.005). Additionally, LOD patients displayed higher ceruloplasmin (Cp) levels compared to EOD patients (p = 0.004), but no difference was found in neurometabolic levels between EOD and LOD. Multiple linear regression indicated a positive correlation between serum Cp levels and AOO of depression (p < 0.001), while bilateral thalamic NAA/Cr showed a negative correlation with AOO (p = 0.012, p = 0.016). CONCLUSIONS:Patients with EOD were characterized by social cognition impairments, while patients with LOD were marked by reasoning and problem-solving deficits. Serum Cp levels demonstrated an AOO-related effect and served as a positive predictor for the AOO of depression. Furthermore, a negative correlation has been established between bilateral thalamic NAA/Cr and the AOO of MDD. LIMITATIONS:The limited sample size and the challenge in distinguishing whether observed results are attributed to age or AOO effects.

BACKGROUND:Cognitive impairments in major depressive disorder (MDD) affect patients' social functioning, with underlying mechanisms involving gut microbiota and inflammatory factors remaining unclear. METHODS:The study analyzed cognitive function, gut microbiota changes, and inflammatory factor levels in 39 unmedicated MDD patients and 41 healthy controls, employing correlation and moderation effect analysis. RESULTS:MDD patients scored lower than controls in cognitive functions like information processing speed, attention/vigilance, verbal learning, visual learning and social cognition. They showed reduced gut microbiota diversity and increased levels of inflammatory markers (TNF-α, IL-1, IL-6, IL-17, IL-27, IL-33). Sellimonas abundance correlated negatively with attention/vigilance, moderated by TNF-α, IL-27, and IL-33. This relationship was stronger at lower inflammation levels. CONCLUSIONS:MDD patients exhibit multi-domain cognitive dysfunction alongside pro-inflammatory states and disrupted gut microbiota. The abundance of Sellimonas significantly predicts attention/vigilance deficits. Inflammatory factors modulate the impact of gut microbiota on cognitive function, suggesting chronic low-grade inflammation as a key risk factor for cognitive impairment in MDD.

Background: The therapeutic effects of vortioxetine on mood and cognition have been documented in major depressive disorder (MDD). This study aims to examine whether vortioxetine can improve brain glymphatic system function and connections among functional brain networks and to explore the underlying relationships among these changes. Methods: A total of 34 patients with MDD and 41 healthy controls (HCs) were recruited in the study. All participants underwent mood and cognitive assessment, and diffusion tensor imaging (DTI) and resting-state functional MRI scans at baseline and 8-week follow-up. The DTI analysis along the perivascular space (DTI-ALPS) index, and functional connectivity (FC) were assessed. Cognitive assessment was conducted using the Chinese version of Measurement Consensus Cognitive Battery (MCCB). Correlation analysis was subsequently performed to explore underlying association among these indexes. Results: Compared to HCs, patients with MDD showed decreased DTI-ALPS indexes at baseline; patients with MDD showed increased the default mode network (DMN) FC between the posterior cingulate cortex (PCC)-precuneus; patients with MDD displayed decreased attention/vigilance, verbal learning, visual learning, social cognition, and global cognition. Treatment with vortioxetine, patients with MDD displayed reduced depressive symptoms, increased DTI-ALPS indexes, decreased DMN FC, and improved attention/vigilance, verbal learning, visual learning, social cognition, and global cognition. Moreover, the increased DTI-ALPS indexes correlated with improved global cognition, and decreased DMN FC in MDD, respectively. Conclusions: The current study indicated vortioxetine improves glymphatic system function and brain connections within the DMN in MDD. Furthermore, the restoration of glymphatic function is linked to improved brain function and cognition. Trial Registration: ClinicalTrials.gov identifier: ChiCTR2200057820.