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Previous studies in small samples have identified inconsistent cortical abnormalities in major depressive disorder (MDD). Despite genetic influences on MDD and the brain, it is unclear how genetic risk for MDD is translated into spatially patterned cortical vulnerability. Here, we initially examined voxel-wise differences in cortical function and structure using the largest multi-modal MRI data from 1660 MDD patients and 1341 controls. Combined with the Allen Human Brain Atlas, we then adopted transcription-neuroimaging spatial correlation and the newly developed ensemble-based gene category enrichment analysis to identify gene categories with expression related to cortical changes in MDD. Results showed that patients had relatively circumscribed impairments in local functional properties and broadly distributed disruptions in global functional connectivity, consistently characterized by hyper-function in associative areas and hypo-function in primary regions. Moreover, the local functional alterations were correlated with genes enriched for biological functions related to MDD in general (e.g., endoplasmic reticulum stress, mitogen-activated protein kinase, histone acetylation, and DNA methylation); and the global functional connectivity changes were associated with not only MDD-general, but also brain-relevant genes (e.g., neuron, synapse, axon, glial cell, and neurotransmitters). Our findings may provide important insights into the transcriptomic signatures of regional cortical vulnerability to MDD.
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Transtorno Depressivo Maior , Transcriptoma , Humanos , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/fisiopatologia , Feminino , Masculino , Adulto , Córtex Cerebral/fisiopatologia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/metabolismo , Pessoa de Meia-Idade , Imageamento por Ressonância Magnética , Perfilação da Expressão GênicaRESUMO
Brain glycogen, which is distinct from muscle glycogen and liver glycogen, has become a crucial node linking metabolism, epigenetics, and autophagy. Recent studies have suggested that brain glycogen governs multiple neurobehavioral processes, such as memory formation and consolidation. However, the changes in brain glycogen levels in mental diseases and the associations of these changes with the disease prognosis are unknown. Here, we review the psychological functions of brain glycogen and the different characteristics of astrocytic glycogen and neuronal glycogen. In addition, we summarize the alterations in brain glycogen levels in depression, schizophrenia and sleep disorders, highlighting that brain glycogen functions as an important metabolite responsible for the development of mental diseases. In summary, brain glycogen is a key to understanding the pathology of mental diseases and deserves more attention in future research.
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INTRODUCTION: Post-traumatic stress disorder (PTSD) is a prevalent and severe psychiatric disorder. Repetitive transcranial magnetic stimulation (rTMS) targeting the dorsolateral prefrontal cortex provides limited relief for symptoms of PTSD. This study will be conducted to validate the efficacy of MRI-guided rTMS in targeting the sites most closely associated with the amygdala for patients with PTSD. We hypothesise that the intervention will improve clinical symptoms by decreasing amygdala activity in patients. METHODS AND ANALYSIS: A randomised, double-blind, sham-controlled trial will be conducted. Forty-eight eligible patients with PTSD will be randomly assigned to receive either active or sham MRI-guided rTMS for 10 consecutive days after the initial MRI scans. MRI scans will be recollected at the end of the intervention. Clinical assessments will be performed at baseline, treatment day 5, treatment day 10, and 2 weeks, 4 weeks, 8 weeks after completion of the intervention to monitor changes in clinical symptoms. The primary assessment outcome is the change in PTSD symptoms between baseline and treatment day 10, as measured by the PTSD Checklist for DSM-5. Repeated measures analysis of variance will be performed using statistical software SPSS V.26.0. The significance level will be set at 0.05. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the Ethics Committee of Xijing Hospital in Xi'an, China (KY20222176-X-1), and the trial has been registered on ClinicalTrials.gov. The findings of this trial will be disseminated at academic conferences or published in peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER: NCT05544110.
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Tonsila do Cerebelo , Imageamento por Ressonância Magnética , Ensaios Clínicos Controlados Aleatórios como Assunto , Transtornos de Estresse Pós-Traumáticos , Estimulação Magnética Transcraniana , Humanos , Transtornos de Estresse Pós-Traumáticos/terapia , Transtornos de Estresse Pós-Traumáticos/diagnóstico por imagem , Estimulação Magnética Transcraniana/métodos , Imageamento por Ressonância Magnética/métodos , Método Duplo-Cego , Tonsila do Cerebelo/diagnóstico por imagem , Adulto , Masculino , Pessoa de Meia-Idade , Feminino , Resultado do Tratamento , Adulto JovemRESUMO
Glycophagy has evolved from an alternative glycogen degradation pathway into a multifaceted pivot to regulate cellular metabolic hemostasis in peripheral tissues. However, the pattern of glycophagy in the brain and its potential therapeutic impact on ischemic stroke remain unknown. Here, we observed that the dysfunction of astrocytic glycophagy was caused by the downregulation of the GABA type A receptor-associated protein like 1 (GABARAPL1) during reperfusion in ischemic stroke patients and mice. PI3K-Akt pathway activation is involved in driving GABARAPL1 downregulation during cerebral reperfusion. Moreover, glycophagy dysfunction-induced glucosamine deficiency suppresses the nuclear translocation of specificity protein 1 and TATA binding protein, the transcription factors for GABARAPL1, by decreasing their O-GlcNAcylation levels, and accordingly feedback inhibits GABARAPL1 in astrocytes during reperfusion. Restoring astrocytic glycophagy by overexpressing GABARAPL1 decreases DNA damage and oxidative injury in astrocytes and improves the survival of surrounding neurons during reperfusion. In addition, a hypocaloric diet in the acute phase after cerebral reperfusion can enhance astrocytic glycophagic flux and accelerate neurological recovery. In summary, glycophagy in the brain links autophagy, metabolism, and epigenetics together, and glycophagy dysfunction exacerbates reperfusion injury after ischemic stroke.
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Astrócitos , AVC Isquêmico , Traumatismo por Reperfusão , Astrócitos/metabolismo , Astrócitos/patologia , Animais , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Camundongos , AVC Isquêmico/metabolismo , AVC Isquêmico/patologia , Humanos , Masculino , Glicogênio/metabolismo , Modelos Animais de Doenças , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Transdução de Sinais , AutofagiaRESUMO
To elucidate the brain-wide information interactions that vary and contribute to individual differences in schizophrenia (SCZ), an information-resolved method is employed to construct individual synergistic and redundant interaction matrices based on regional pairwise BOLD time-series from 538 SCZ and 540 normal controls (NC). This analysis reveals a stable pattern of regionally-specific synergy dysfunction in SCZ. Furthermore, a hierarchical Bayesian model is applied to deconstruct the patterns of whole-brain synergy dysfunction into three latent factors that explain symptom heterogeneity in SCZ. Factor 1 exhibits a significant positive correlation with Positive and Negative Syndrome Scale (PANSS) positive scores, while factor 3 demonstrates significant negative correlations with PANSS negative and general scores. By integrating the neuroimaging data with normative gene expression information, this study identifies that each of these three factors corresponded to a subset of the SCZ risk gene set. Finally, by combining data from NeuroSynth and open molecular imaging sources, along with a spatially heterogeneous mean-field model, this study delineates three SCZ synergy factors corresponding to distinct symptom profiles and implicating unique cognitive, neurodynamic, and neurobiological mechanisms.
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BACKGROUND: Depression accounts for a high proportion of neuropsychiatric disorders and is associated with abnormal states of neurons in specific brain regions. Microglia play a pivotal role in the inflammatory state during depression development; however, the exact mechanism underlying chronic mood states remains unknown. Thus, the present study aimed to determine whether microRNAs (miRNAs) alleviate stress-induced depression-like behavior in mice by regulating the expression levels of their target genes, explore the role of neuroinflammation induced by microglial activation in the pathogenesis and progression of depression, and determine whether the role of the miR-29a-5p/transmembrane protein 33 (TMEM33) axis. METHODS: In this study, chronic unpredictable mild stress (CUMS) mouse depression model, various behavioral tests, western blotting, dual-luciferase reporter assay, enzyme-linked immunosorbent assay, real-time quantitative reverse transcription PCR, immunofluorescence and lentivirus-mediated gene transfer were used. RESULTS: After exposure to the CUMS paradigm, miR-29a-5p was significantly down-regulated. This downregulation subsequently promoted the polarization of microglia M1 by upregulating the expression of TMEM33, resulting in enhanced inflammatory chemokines affecting neurons. Conversely, the upregulation of miR-29a-5p within the prefrontal cortex (PFC) suppressed TMEM33 expression, facilitated microglia M2-polarization, and ameliorated depressive-like behavior. LIMITATIONS: Only rodent models of depression were used, and human samples were not included. CONCLUSIONS: The results of this study suggest that miR-29a-5p deficits within the PFC mediate microglial anomalies and contribute to depressive-like behaviors. miR-29a-5p and TMEM33 may, therefore, serve as potential therapeutic targets for the treatment of depression.
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Depressão , Modelos Animais de Doenças , Proteínas de Membrana , MicroRNAs , Microglia , Córtex Pré-Frontal , Estresse Psicológico , Animais , Masculino , Camundongos , Comportamento Animal/fisiologia , Depressão/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Microglia/metabolismo , MicroRNAs/genética , Córtex Pré-Frontal/metabolismo , Estresse Psicológico/complicações , Estresse Psicológico/metabolismoRESUMO
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.
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Transtornos de Ansiedade , Citocromo P-450 CYP2D6 , Paroxetina , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos de Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/genética , China , Citocromo P-450 CYP2D6/genética , Citocromo P-450 CYP2D6/metabolismo , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/genética , População do Leste Asiático , Genótipo , Paroxetina/administração & dosagem , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Resultado do TratamentoRESUMO
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.
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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.
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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.
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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 NSSIãdepressive 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.
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Comportamento Autodestrutivo , Humanos , Adolescente , Comportamento Autodestrutivo/psicologia , Afeto , Inquéritos e Questionários , Ansiedade , EmoçõesRESUMO
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.
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Esquizofrenia , Humanos , Esquizofrenia/complicações , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/terapia , Estimulação Magnética Transcraniana/métodos , Imageamento por Ressonância Magnética , Alucinações/diagnóstico por imagem , Alucinações/etiologia , Alucinações/terapia , EncéfaloRESUMO
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 .
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Depressão , Estimulação Magnética Transcraniana , Humanos , Encéfalo/diagnóstico por imagem , Método Duplo-Cego , Imageamento por Ressonância Magnética , Córtex Pré-Frontal/diagnóstico por imagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Estimulação Magnética Transcraniana/métodos , Resultado do Tratamento , Depressão/terapiaRESUMO
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.
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Transtorno Depressivo Maior , Estimulação Magnética Transcraniana , Humanos , Adolescente , Estimulação Magnética Transcraniana/efeitos adversos , Estimulação Magnética Transcraniana/métodos , Córtex Pré-Frontal Dorsolateral , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/terapia , Anedonia , Imageamento por Ressonância Magnética , Córtex Pré-Frontal/diagnóstico por imagem , Resultado do Tratamento , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
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.
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Transtorno Depressivo Maior , Humanos , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/terapia , Ideação Suicida , Hipocampo , Imageamento por Ressonância Magnética , Antidepressivos/uso terapêuticoRESUMO
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.
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Transtorno Depressivo Maior , Humanos , Transtorno Depressivo Maior/terapia , Transtorno Depressivo Maior/etiologia , Estimulação Magnética Transcraniana/efeitos adversos , Estimulação Magnética Transcraniana/métodos , Pandemias , Resultado do Tratamento , AntidepressivosRESUMO
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.
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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.
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Transtorno Depressivo Maior , Humanos , Transtorno Depressivo Maior/diagnóstico por imagem , Depressão , Vias Neurais/diagnóstico por imagem , Encéfalo , Mapeamento Encefálico , Imageamento por Ressonância Magnética/métodosRESUMO
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.
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Esquizofrenia , Substância Branca , Humanos , Estimulação Magnética Transcraniana/métodos , Esquizofrenia/complicações , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/terapia , Substância Branca/diagnóstico por imagem , Imagem de Tensor de Difusão , Alucinações/diagnóstico por imagem , Alucinações/etiologia , Alucinações/terapiaRESUMO
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.