Exploring Schizophrenia Classification Through Multimodal MRI and Deep Graph Neural Networks: Unveiling Brain Region-Specific Weight Discrepancies and Their Association With Cell-Type Specific Transcriptomic Features.

BACKGROUND AND HYPOTHESIS: Schizophrenia (SZ) is a prevalent mental disorder that imposes significant health burdens. Diagnostic accuracy remains challenging due to clinical subjectivity. To address this issue, we explore magnetic resonance imaging (MRI) as a tool to enhance SZ diagnosis and provide objective references and biomarkers. Using deep learning with graph convolution, we represent MRI data as graphs, aligning with brain structure, and improving feature extraction, and classification. Integration of multiple modalities is expected to enhance classification. STUDY DESIGN: Our study enrolled 683 SZ patients and 606 healthy controls from 7 hospitals, collecting structural MRI and functional MRI data. Both data types were represented as graphs, processed by 2 graph attention networks, and fused for classification. Grad-CAM with graph convolution ensured interpretability, and partial least squares analyzed gene expression in brain regions. STUDY RESULTS: Our method excelled in the classification task, achieving 83.32% accuracy, 83.41% sensitivity, and 83.20% specificity in 10-fold cross-validation, surpassing traditional methods. And our multimodal approach outperformed unimodal methods. Grad-CAM identified potential brain biomarkers consistent with gene analysis and prior research. CONCLUSIONS: Our study demonstrates the effectiveness of deep learning with graph attention networks, surpassing previous SZ diagnostic methods. Multimodal MRI's superiority over unimodal MRI confirms our initial hypothesis. Identifying potential brain biomarkers alongside gene biomarkers holds promise for advancing objective SZ diagnosis and research in SZ.

The efficacy of low frequency repetitive transcial magnetic stimulation for treating auditory verbal hallucinations in schizophrenia: Insights from functional gradient analyses.

Background: Auditory Verbal Hallucinations (AVH) constitute a prominent feature of schizophrenia. Although low-frequency repetitive transcranial magnetic stimulation (rTMS) has demonstrated therapeutic benefits in ameliorating AVH, the underlying mechanisms of its efficacy necessitate further elucidation. Objective: This study investigated the cortical gradient characteristics and their associations with clinical responses in schizophrenia patients with AVH, mediated through 1 Hz rTMS targeting the left temporoparietal junction. Method: Functional gradient metrics were employed to examine the hierarchy patterns of cortical organization, capturing whole-brain functional connectivity profiles in patients and controls. Results: The 1 Hz rTMS treatment effectively ameliorated the positive symptoms in patients, specifically targeting AVH. Initial evaluations revealed expanded global gradient distribution patterns and specific principal gradient variations in certain brain regions in patients at baseline compared to a control cohort. Following treatment, these divergent global and local patterns showed signs of normalizing. Furthermore, there was observed a closer alignment in between-network dispersion among various networks after treatment, including the somatomotor, attention, and limbic networks, indicating a potential harmonization of brain functionality. Conclusion: Low-frequency rTMS induces alternations in principal functional gradient patterns, may serve as imaging markers to elucidate the mechanisms underpinning the therapeutic efficacy of rTMS on AVH in schizophrenia.

Dose adjustment of paroxetine based on CYP2D6 activity score inferred metabolizer status in Chinese Han patients with depressive or anxiety disorders: a prospective study and cross-ethnic meta-analysis.

BACKGROUND: Understanding the impact of CYP2D6 metabolism on paroxetine, a widely used antidepressant, is essential for precision dosing. METHODS: We conducted an 8-week, multi-center, single-drug, 2-week wash period prospective cohort study in 921 Chinese Han patients with depressive or anxiety disorders (ChiCTR2000038462). We performed CYP2D6 genotyping (single nucleotide variant and copy number variant) to derive the CYP2D6 activity score and evaluated paroxetine treatment outcomes including steady-state concentration, treatment efficacy, and adverse reaction. CYP2D6 metabolizer status was categorized into poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultrarapid metabolizers (UMs). The influence of CYP2D6 metabolic phenotype on paroxetine treatment outcomes was examined using multiple regression analysis and cross-ethnic meta-analysis. The therapeutic reference range of paroxetine was estimated by receiver operating characteristic (ROC) analyses. FINDINGS: After adjusting for demographic factors, the steady-state concentrations of paroxetine in PMs, IMs, and UMs were 2.50, 1.12, and 0.39 times that of EMs, with PM and UM effects being statistically significant (multiple linear regression, P = 0.03 and P = 0.04). Sex and ethnicity influenced the comparison between IMs and EMs. Moreover, poor efficacy of paroxetine was associated with UM, and a higher risk of developing adverse reactions was associated with lower CYP2D6 activity score. Lastly, cross-ethnic meta-analysis suggested dose adjustments for PMs, IMs, EMs, and UMs in the East Asian population to be 35%, 40%, 143%, and 241% of the manufacturer's recommended dose, and 62%, 68%, 131%, and 159% in the non-East Asian population. INTERPRETATION: Our findings advocate for precision dosing based on the CYP2D6 metabolic phenotype, with sex and ethnicity being crucial considerations in this approach. FUNDING: National Natural Science Foundation of China; Academy of Medical Sciences Research Unit.

Nanopore sensitization based on a double loop hybridization chain reaction and G-quadruplex.

The widespread implementation of solid-state nanopores faces challenges such as lower resolution and increased electrical noise when compared to biological nanopores. Incorporating specific nucleic acid reactions can enhance resolution. In this study, we've developed a nucleic acid amplifier to enhance the sensitivity of solid-state nanopores, utilizing a G-rich sequence and hybridization chain reaction. This amplifier improves target concentration and volume amplification, showing promise in nanopore sensitivity tests.

The impact of depressive and anxious symptoms on non-suicidal self-injury behavior in adolescents: a network analysis.

PURPOSE: Conceptualizing adolescent NSSI and emotional symptoms as a system of causal elements could provide valuable insights into the development of non-suicidal self-injury (NSSI) in adolescent. This study aimed to explore the intricate relationship between NSSI, depressive symptoms, and anxious symptoms in adolescents, identifying key symptoms to establish a theoretical foundation for targeted and effective interventions addressing NSSI behaviors in this population. METHODS: A total of 412 adolescents with NSSI behaviors were selected from outpatients. Generalized anxious disorder scale (GAD-7) and patient health questionnaire (PHQ-9) were employed to measure anxious symptoms and depressive symptoms, respectively. The adolescent non-suicidal self-injury assessment questionnaire (ANSSIAQ) was used to evaluate NSSI of adolescent. Using network analysis, the NSSI、depressive symptoms and anxious symptoms network were constructed to identify the most central symptoms and the bridge symptoms within the networks. RESULTS: The findings revealed that the NSSI functional nodes "coping with sadness and disappointment" and "relieving stress or anxious" exhibited the strongest correlation, with a regularized partial correlation coefficient was 0.401. The symptoms "having a desire to harm oneself and unable to stop" and the node "depressive symptoms" had the highest strength centrality in the network, and their strength centrality indices were 1.267 and 1.263, respectively. The bridge nodes were "having a desire to harm oneself and unable to stop" and "expressing one's despair and hopelessness", with expected impact indices of 0.389 and 0.396, respectively. CONCLUSION: In adolescents, the network revealed a closer connection between NSSI and depressive symptoms. "The desire to not stop hurting oneself" is not only broadly connected to other nodes but also could activate other nodes to maintain NSSI behavior. In light of these findings, precise targets for pharmacological treatment, psychotherapy, physical therapy, etc., are identified for adolescents with NSSI. Targeting this specific aspect in interventions may contribute to preventing and reducing NSSI behavior in adolescents.

Efficacy of functional magnetic resonance imaging-guided personalized repetitive transcranial magnetic stimulation (fMRI-rTMS) in depressive patients with emotional blunting: study protocol for a randomized controlled trial.

BACKGROUND: Emotional blunting is a symptom that has always been present in depressed patients. Repetitive transcranial magnetic stimulation (rTMS) is a safe and effective supplementary therapy for treating depression. However, the effectiveness and brain imaging processes of functional magnetic resonance imaging-guided personalized rTMS (fMRI-rTMS) in the treatment of depression with emotional blunting have not been observed in randomized controlled trials. METHODS: This study is a randomized, controlled, double-blind, and single-center clinical trial in which 80 eligible depressed patients with emotional blunting will be randomly assigned to two groups: a functional magnetic resonance imaging-guided personalized rTMS (fMRI-rTMS) group and a control group. Individuals in the fMRI-rTMS group (n = 40) will receive high-frequency rTMS (10 Hz, 120% MT). The main target of stimulation will be the area most relevant to the functional connectivity of the right medial prefrontal cortex (mPFC) and amygdala. The control group (n = 40) will receive sham stimulation, with a coil flipped to 90 degrees relative to the vertical scalp. All patients will receive 15 consecutive days of treatment, with each session lasting half an hour per day, followed by 8 weeks of follow-up. The primary outcome is the comparison of Oxford Depression Questionnaire (ODQ) scores between these two groups at different time points. The secondary outcomes include evaluating other clinical scales and assessing the differences in brain imaging changes between the two groups before and after treatment. DISCUSSION: This trial aims to examine the effects of functional magnetic resonance imaging-guided personalized rTMS (fMRI-rTMS) intervention on depressed patients experiencing emotional blunting and to elucidate the potential mechanism behind it. The results will provide new evidence for using fMRI-rTMS in treating depression with emotional blunting in the future. TRIAL REGISTRATION: ClinicalTrials.gov INCT05555940. Registered on 13 September 2022 at http://clinicaltrials.gov .

Low-frequency rTMS induces modifications in cortical structural connectivity - functional connectivity coupling in schizophrenia patients with auditory verbal hallucinations.

Auditory verbal hallucinations (AVH) are distinctive clinical manifestations of schizophrenia. While low-frequency repetitive transcranial magnetic stimulation (rTMS) has demonstrated potential in mitigating AVH, the precise mechanisms by which it operates remain obscure. This study aimed to investigate alternations in structural connectivity and functional connectivity (SC-FC) coupling among schizophrenia patients with AVH prior to and following treatment with 1 Hz rTMS that specifically targets the left temporoparietal junction. Initially, patients exhibited significantly reduced macroscopic whole brain level SC-FC coupling compared to healthy controls. Notably, SC-FC coupling increased significantly across multiple networks, including the somatomotor, dorsal attention, ventral attention, frontoparietal control, and default mode networks, following rTMS treatment. Significant alternations in SC-FC coupling were noted in critical nodes comprising the somatomotor network and the default mode network, such as the precentral gyrus and the ventromedial prefrontal cortex, respectively. The alternations in SC-FC coupling exhibited a correlation with the amelioration of clinical symptom. The results of our study illuminate the intricate relationship between white matter structures and neuronal activity in patients who are receiving low-frequency rTMS. This advances our understanding of the foundational mechanisms underlying rTMS treatment for AVH.

Targeting suicidal ideation in major depressive disorder with MRI-navigated Stanford accelerated intelligent neuromodulation therapy.

High suicide risk represents a serious problem in patients with major depressive disorder (MDD), yet treatment options that could safely and rapidly ameliorate suicidal ideation remain elusive. Here, we tested the feasibility and preliminary efficacy of the Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT) in reducing suicidal ideation in patients with MDD. Thirty-two MDD patients with moderate to severe suicidal ideation participated in the current study. Suicidal ideation and depression symptoms were assessed before and after 5 days of open-label SAINT. The neural pathways supporting rapid-acting antidepressant and suicide prevention effects were identified with dynamic causal modelling based on resting-state functional magnetic resonance imaging. We found that 5 days of SAINT effectively alleviated suicidal ideation in patients with MDD with a high response rate of 65.63%. Moreover, the response rates achieved 78.13% and 90.63% with 2 weeks and 4 weeks after SAINT, respectively. In addition, we found that the suicide prevention effects of SAINT were associated with the effective connectivity involving the insula and hippocampus, while the antidepressant effects were related to connections of the subgenual anterior cingulate cortex (sgACC). These results show that SAINT is a rapid-acting and effective way to reduce suicidal ideation. Our findings further suggest that distinct neural mechanisms may contribute to the rapid-acting effects on the relief of suicidal ideation and depression, respectively.

Active versus sham DLPFC-NAc rTMS for depressed adolescents with anhedonia using resting-state functional magnetic resonance imaging (fMRI): a study protocol for a randomized placebo-controlled trial.

BACKGROUND: Anhedonia, which is defined as the inability to feel pleasure, is considered a core symptom of major depressive disorder (MDD). It can lead to several adverse outcomes in adolescents, including heightened disease severity, resistance to antidepressants, recurrence of MDD, and even suicide. Specifically, patients who suffer from anhedonia may exhibit a limited response to selective serotonin reuptake inhibitors (SSRIs) and cognitive behavioral therapy (CBT). Previous researches have revealed a link between anhedonia and abnormalities within the reward circuitry, making the nucleus accumbens (NAc) a potential target for treatment. However, since the NAc is deep within the brain, repetitive transcranial magnetic stimulation (rTMS) has the potential to modulate this specific region. Recent advances have enabled treatment technology to precisely target the left dorsolateral prefrontal cortex (DLPFC) and modify the functional connectivity (FC) between DLPFC and NAc in adolescent patients with anhedonia. Therefore, we plan to conduct a study to explore the safety and effectiveness of using resting-state functional connectivity magnetic resonance imaging (fcMRI)-guided rTMS to alleviate anhedonia in adolescents diagnosed with MDD. METHODS: The aim of this article is to provide a study protocol for a parallel-group randomized, double-blind, placebo-controlled experiment. The study will involve 88 participants who will be randomly assigned to receive either active rTMS or sham rTMS. The primary object is to measure the percentage change in the severity of anhedonia, using the Snaith-Hamilton Pleasure Scale (SHAPS). The assessment will be conducted from the baseline to 8-week post-treatment period. The secondary outcome includes encompassing fMRI measurements, scores on the 17-item Hamilton Rating Scale for Depression (HAMD-17), the Montgomery Asberg Depression Rating Scale (MADRS), the Chinese Version of Temporal Experience of Pleasure Scale (CV-TEPS), and the Chinese Version of Beck Scale for Suicide Ideation (BSI-CV). The Clinical Global Impression (CGI) scores will also be taken into account, and adverse events will be monitored. These evaluations will be conducted at baseline, as well as at 1, 2, 4, and 8 weeks. DISCUSSION: If the hypothesis of the current study is confirmed, (fcMRI)-guided rTMS could be a powerful tool to alleviate the core symptoms of MDD and provide essential data to explore the mechanism of anhedonia. TRIAL REGISTRATION: ClinicalTrials.gov NCT05544071. Registered on 16 September 2022.

Accelerated transcranial magnetic stimulation for major depressive disorder: A quick path to relief?

Transcranial magnetic stimulation (TMS) is a safe, tolerable, and evidence-based intervention for major depressive disorder (MDD). However, even after decades of research, nearly half of the patients with MDD fail to respond to conventional TMS, with responding slowly and requiring daily attendance at the treatment site for 4-6 weeks. To intensify antidepressant efficacy and shorten treatment duration, accelerated TMS protocols, which involve multiple sessions per day over a few days, have been proposed and evaluated for safety and viability. We reviewed and summarized the current knowledge in accelerated TMS, including stimulation parameters, antidepressant efficacy, anti-suicidal efficacy, safety, and adverse effects. Limitations and suggestions for future directions are also addressed, along with a brief discussion on the application of accelerated TMS during the COVID-19 pandemic. This article is categorized under: Neuroscience > Clinical Neuroscience.

Large-scale effective connectivity analysis reveals the existence of two mutual inhibitory systems in patients with major depression.

It is posited that cognitive and affective dysfunction in patients with major depression disorder (MDD) may be caused by dysfunctional signal propagation in the brain. By leveraging dynamic causal modeling, we investigated large-scale directed signal propagation (effective connectivity) among distributed large-scale brain networks with 43 MDD patients and 56 healthy controls. The results revealed the existence of two mutual inhibitory systems: the anterior default mode network, auditory network, sensorimotor network, salience network and visual networks formed an "emotional" brain, while the posterior default mode network, central executive networks, cerebellum and dorsal attention network formed a "rational brain". These two networks exhibited excitatory intra-system connectivity and inhibitory inter-system connectivity. Patients were characterized by potentiated intra-system connections within the "emotional/sensory brain", as well as over-inhibition of the "rational brain" by the "emotional/sensory brain". The hierarchical architecture of the large-scale effective connectivity networks was then analyzed using a PageRank algorithm which revealed a shift of the controlling role of the "rational brain" to the "emotional/sensory brain" in the patients. These findings inform basic organization of distributed large-scale brain networks and furnish a better characterization of the neural mechanisms of depression, which may facilitate effective treatment.

Lactate: a prospective target for therapeutic intervention in psychiatric disease.

ABSTRACT: Although antipsychotics that act via monoaminergic neurotransmitter modulation have considerable therapeutic effect, they cannot completely relieve clinical symptoms in patients suffering from psychiatric disorders. This may be attributed to the limited range of neurotransmitters that are regulated by psychotropic drugs. Recent findings indicate the need for investigation of psychotropic medications that target less-studied neurotransmitters. Among these candidate neurotransmitters, lactate is developing from being a waste metabolite to a glial-neuronal signaling molecule in recent years. Previous studies have suggested that cerebral lactate levels change considerably in numerous psychiatric illnesses; animal experiments have also shown that the supply of exogenous lactate exerts an antidepressant effect. In this review, we have described how medications targeting newer neurotransmitters offer promise in psychiatric diseases; we have also summarized the advances in the use of lactate (and its corresponding signaling pathways) as a signaling molecule. In addition, we have described the alterations in brain lactate levels in depression, anxiety, bipolar disorder, and schizophrenia and have indicated the challenges that need to be overcome before brain lactate can be used as a therapeutic target in psychopharmacology.

Rich-club reorganization of white matter structural network in schizophrenia patients with auditory verbal hallucinations following 1 Hz rTMS treatment.

The human brain comprises a large-scale structural network of regions and interregional pathways, including a selectively defined set of highly central and interconnected hub regions, often referred to as the "rich club", which may play a pivotal role in the integrative processes of the brain. A quintessential symptom of schizophrenia, auditory verbal hallucinations (AVH) have shown a decrease in severity following low-frequency repetitive transcranial magnetic stimulation (rTMS). However, the underlying mechanism of rTMS in treating AVH remains elusive. This study investigated the effect of low-frequency rTMS on the rich-club organization within the brain in patients diagnosed with schizophrenia who experience AVH using diffusion tensor imaging data. Through by constructing structural connectivity networks, we identified several critical rich hub nodes, which constituted a rich-club subnetwork, predominantly located in the prefrontal cortices. Notably, our findings revealed enhanced connection strength and density within the rich-club subnetwork following rTMS treatment. Furthermore, we found that the decreased connectivity within the subnetwork components, including the rich-club subnetwork, was notably enhanced in patients following rTMS treatment. In particular, the increased connectivity strength of the right median superior frontal gyrus, which functions as a critical local bridge, with the right postcentral gyrus exhibited a significant correlation with improvements in both positive symptoms and AVH. These findings provide valuable insights into the role of rTMS in inducing reorganizational changes within the rich-club structural network in schizophrenia and shed light on potential mechanisms through which rTMS may alleviate AVH.

Alterations in brain connectivity patterns in schizophrenia patients with auditory verbal hallucinations during low frequency repetitive transcranial magnetic stimulation.

OBJECTIVE: Auditory verbal hallucinations (AVH) are a characteristic symptom of schizophrenia. Although low-frequency repetitive transcranial magnetic stimulation (rTMS) has been demonstrated to alleviate the severity of AVH, its exact neurophysiological mechanisms remain unclear. This study aimed to elucidate the alterations in brain connectivity patterns in schizophrenia patients with AVH after low frequency rTMS. Furthermore, the relationship between these alterations and clinical outcomes was examined, thereby identifying potential biomarkers for rTMS treatment efficacy. METHODS: A total of 30 schizophrenia patients with AVH and 33 healthy controls were recruited. The patients received 1 Hz rTMS applied to the left temporoparietal junction region over 15 days. Resting-state functional magnetic resonance imaging scans were conducted for all participants. Subsequently, degree centrality (DC) and seed-based functional connectivity (FC) analyses were employed to identify specific alterations in brain connectivity patterns after rTMS treatment. RESULTS: At baseline, patients exhibited divergent DC patterns in the frontal, occipital, and limbic lobes compared to healthy controls. In addition, prior to treatment, patients demonstrated altered FC from the superior frontal gyrus seeds that linked to the frontal, temporal, and somatosensory regions. Following rTMS treatment, these abnormalities were notably reversed, correlating with improved clinical outcomes. CONCLUSIONS: These findings demonstrate that schizophrenia patients with AVH exhibited atypical interactions within the frontal and temporal lobes. These alterations might be crucial biomarkers for predicting the efficacy of low frequency rTMS.

Habenula Volume and Functional Connectivity Changes Following Laparoscopic Sleeve Gastrectomy for Obesity Treatment.

BACKGROUND: Neuroimaging studies have revealed alterations in habenular (Hb) structure and functional connectivity (FC) in psychiatric conditions. The Hb plays a particularly critical role in regulating negative emotions, which trigger excessive food intake and obesity. However, obesity and weight loss intervention (i.e., laparoscopic sleeve gastrectomy [LSG])-associated changes in Hb structure and FC have not been studied. METHODS: We used voxel-based morphometry analysis to measure changes in gray matter volume (GMV) in the Hb in 56 patients with obesity at pre-LSG and 12 months post-LSG and in 78 normal-weight (NW) control participants. Then, we conducted Hb seed-based resting-state FC (RSFC) to examine obesity-related and LSG-induced alterations in RSFC. Finally, we used mediation analysis to characterize the interrelationships among Hb GMV, RSFC, and behaviors. RESULTS: Compared with NW participants, Hb GMV was smaller in patients at pre-LSG and increased at 12 months post-LSG to levels equivalent to that of NW; in addition, increases in Hb GMV were correlated with reduced body mass index (BMI). Compared with NW participants, pre-LSG patients showed greater RSFCs of the Hb-insula, Hb-precentral gyrus, and Hb-rolandic operculum and weaker RSFCs of the Hb-thalamus, Hb-hypothalamus, and Hb-caudate; LSG normalized these RSFCs. Decreased RSFC of the Hb-insula was correlated with reduced BMI, Yale Food Addiction Scale rating, and emotional eating; reduced hunger levels were correlated with increased RSFCs of the Hb-thalamus and Hb-hypothalamus; and reduced BMI and Yale Food Addiction Scale ratings were correlated with increased RSFCs of the Hb-thalamus and Hb-hypothalamus, respectively. The bidirectional relationships between Hb GMV and RSFC of the Hb-insula contributed to reduced BMI. CONCLUSIONS: These findings indicate that LSG increased Hb GMV and that its related improvement in RSFC of the Hb-insula may mediate long-term benefits of LSG for eating behaviors and weight loss.

Cerebral blood flow changes in schizophrenia patients with auditory verbal hallucinations during low-frequency rTMS treatment.

Auditory verbal hallucinations (AVH) are a prominent symptom of schizophrenia. Low-frequency repetitive transcranial magnetic stimulation (rTMS) has been evidenced to improve the treatment of AVH in schizophrenia. Although abnormalities in resting-state cerebral blood flow (CBF) have been reported in schizophrenia, the perfusion alterations specific to schizophrenia patients with AVH during rTMS require further investigation. In this study, we used arterial spin labeling (ASL) to investigate changes in brain perfusion in schizophrenia patients with AVH, and their associations with clinical improvement following low-frequency rTMS treatment applied to the left temporoparietal junction area. We observed improvements in clinical symptoms (e.g., positive symptoms and AVH) and certain neurocognitive functions (e.g., verbal learning and visual learning) following treatment. Furthermore, at baseline, the patients showed reductions in CBF in regions associated with language, sensory, and cognition compared to controls, primarily located in the prefrontal cortices (e.g., left inferior frontal gyrus and left middle frontal gyrus), occipital lobe (e.g., left calcarine cortex), and cingulate cortex (e.g., bilateral middle cingulate cortex), compared to controls. Conversely, we observed increased CBF in the left inferior temporal gyrus and bilateral putamen in patients relative to controls, regions known to be involved in AVH. However, the hypoperfusion or hyperperfusion patterns did not persist and instead were normalized, and were related to clinical response (e.g., AVH) in patients during low-frequency rTMS treatment. Importantly, the changes in brain perfusion were related to clinical response (e.g., AVH) in patients. Our findings suggest that low-frequency rTMS can regulate brain perfusion involving critical circuits by its remote effect in schizophrenia, and may play an important mechanistic role in the treatment of AVH.

rTMS ameliorates depressive-like behaviors and regulates the gut microbiome and medium- and long-chain fatty acids in mice exposed to chronic unpredictable mild stress.

INTRODUCTION: Repetitive transcranial magnetic stimulation (rTMS) is a clinically useful therapy for depression. However, the effects of rTMS on the metabolism of fatty acids (FAs) and the composition of gut microbiota in depression are not well established. METHODS: Mice received rTMS (15 Hz, 1.26 T) for seven consecutive days after exposure to chronic unpredictable mild stress (CUMS). The subsequent depressive-like behaviors, the composition of gut microbiota of stool samples, as well as medium- and long-chain fatty acids (MLCFAs) in the plasma, prefrontal cortex (PFC), and hippocampus (HPC) were evaluated. RESULTS: CUMS induced remarkable changes in gut microbiotas and fatty acids, specifically in community diversity of gut microbiotas and PUFAs in the brain. 15 Hz rTMS treatment alleviates depressive-like behaviors and partially normalized CUMS induced alterations of microbiotas and MLCFAs, especially the abundance of Cyanobacteria, Actinobacteriota, and levels of polyunsaturated fatty acids (PUFAs) in the hippocampus and PFC. CONCLUSION: These findings revealed that the modulation of gut microbiotas and PUFAs metabolism might partly contribute to the antidepressant effect of rTMS.

A phase 3, multicenter, double-blind, randomized, placebo-controlled clinical trial to verify the efficacy and safety of ansofaxine (LY03005) for major depressive disorder.

Major depressive disorder (MDD) is the most prevalent form of depression and is becoming a great challenge for public health and medical practice. Although first-line antidepressants offer therapeutic benefits, about 35% of depressed patients are not adequately treated, creating a substantial unmet medical need. A multicenter, double-blind, randomized, placebo-controlled phase 3 clinical trial was conducted in patients with MDD in China to assess the efficacy and safety of ansofaxine (LY03005), a potential triple reuptake inhibitor of serotonin, norepinephrine, and dopamine. Eligible 588 MDD patients were included and randomly assigned (1:1:1) to 8-week treatment with ansofaxine 80 mg/day(n = 187), ansofaxine 160 mg/day(n = 186), or placebo(n = 185). The primary efficacy endpoint was the Montgomery-Åsberg Depression Rating Scale (MADRS) total score change from baseline to the end of the study. Safety indexes included adverse events, vital signs, physical examination, laboratory tests, 12-lead electrocardiogram (ECG), and evaluation of suicide tendency and sexual function. Significant differences were found in mean changes in MADRS total score at week 8 in the two ansofaxine groups (80 mg, -20.0; 160 mg, -19.9) vs. placebo (-14.6; p < 0.0001). All doses of ansofaxine were generally well-tolerated. Treatment-emergent adverse events (TEAEs) were reported by 137 (74.46%) patients in ansofaxine 80 mg group, 144 (78.26%) patients in ansofaxine 160 mg and 125 (67.93%) patients in the placebo group. The incidence of treatment-related adverse events (TRAEs) was 59.2% (109 patients), 65.22% (120 patients) in the 80, 160 mg ansofaxine groups, and 45.11% (83 patients) in the placebo group. The initial results of this trial indicate that ansofaxine at both the 80 mg/day and 160 mg/day was effective and safe in adult patients with MDD. ClinicalTrials.gov Identifier: NCT04853407.

Increased thalamic gray matter volume induced by repetitive transcranial magnetic stimulation treatment in patients with major depressive disorder.

Purpose: Repetitive transcranial magnetic stimulation (rTMS) is an effective therapy in improving depressive symptoms in MDD patients, but the intrinsic mechanism is still unclear. In this study, we investigated the influence of rTMS on brain gray matter volume for alleviating depressive symptoms in MDD patients using structural magnetic resonance imaging (sMRI) data. Methods: Patients with first episode, unmedicated patients with MDD (n = 26), and healthy controls (n = 31) were selected for this study. Depressive symptoms were assessed before and after treatment by using the HAMD-17 score. High-frequency rTMS treatment was conducted in patients with MDD over 15 days. The rTMS treatment target is located at the F3 point of the left dorsolateral prefrontal cortex. Structural magnetic resonance imaging (sMRI) data were collected before and after treatment to compare the changes in brain gray matter volume. Results: Before treatment, patients with MDD had significantly reduced gray matter volumes in the right fusiform gyrus, left and right inferior frontal gyrus (triangular part), left inferior frontal gyrus (orbital part), left parahippocampal gyrus, left thalamus, right precuneus, right calcarine fissure, and right median cingulate gyrus compared with healthy controls (P < 0.05). After rTMS treatment, significant growth in gray matter volume of the bilateral thalamus was observed in depressed patients (P < 0.05). Conclusion: Bilateral thalamic gray matter volumes were enlarged in the thalamus of MDD patients after rTMS treatment and may be the underlying neural mechanism for the treatment of rTMS on depression.