Neurons respond to nutrient deprivation by activating autophagic pathways that promote survival under subsequent metabolic stress. Here, we show that short-term nutrient deprivation or pharmacological inhibition of mTORC1 enhances neuronal resistance to glutamate-induced excitotoxicity in primary cerebellar cultures characterized by a rapid decline in p62/SQSTM1 levels and a decrease in procaspase-3 levels, suggesting a potential mechanism for enhanced cell survival. Importantly, extracellular vesicles (EVs) secreted by the neurons during transient nutrient deprivation protect naïve recipient neurons by activating Akt and reducing excitotoxic cell death, indicating that these vesicles transmit pro-survival signals. Our findings uncover a stress-induced intercellular communication mechanism with therapeutic potential in neuroprotection, ischemic preconditioning, and vesicle-based interventions.

OBJECTIVE:The purpose of the study was to evaluate the usefulness and reliability of the Russian versions of the Global Assessment of Disability Related to Seizures (GADS) and Global Assessment of Severity of Epilepsy (GASE), as Patient-Reported Outcomes Measures (PROMs), among patients with epilepsy (PWE) in the Russian population. Additionally, we aimed to identify predictors of seizure-related disability and epilepsy severity in our patients. METHODS:Data from 186 adult PWE consecutively enrolled in the outpatient clinic of the Moscow Research and Clinical Center for Neuropsychiatry were used to assess the validity of the scales. Clinical and demographic data were collected. Patients completed the GADS and GASE scales and a range of other measures (Neurological Disorders Depression Inventory for Epilepsy, Epilepsy Anxiety Survey Instrument-brief version, Quality of Life in Epilepsy Inventory-31, EpiTrack, Epilepsy Stigma Scale) to assess the psychometric properties of the scales. Multiple linear regression models were developed to identify predictors of patient-reported disability from seizures and epilepsy severity. RESULTS:Both GADS and GASE demonstrated convergent validity, known-groups validity, and construct validity. The most significant predictors of GADS score included the frequency of seizures, achieving 1-year seizure freedom, official disability status, employment status, stigma, and anxiety. The main predictor of GASE scores was self-reported disability due to seizures (GADS), followed by quality of life, frequency of seizures, stigma, and cognitive function. SIGNIFICANCE:The study confirmed the validity and usefulness of the Russian versions of the GADS and GASE scales, which can be used in both clinical and research settings.

Extracellular vesicles (EVs) are a broad category of small vesicles released by cells in the central nervous system (CNS) that facilitate intercellular communication and contribute to various diseases. In neuroscience, one of the most important and well-characterized EV subtypes is exosomes. However, current issues with EV nomenclature make it difficult to draw firm conclusions due to variability in usage across different studies. One solution to overcome this challenge is to use established markers for isolating different types of CNS-derived EVs. This article provides an up-to-date list of potential EV markers, focusing on surface markers. We discuss the role of EVs in CNS diseases and explore each candidate's potential to be used as a specific EV surface marker. We also highlight how non-adherence to EV nomenclature leads to confusion and misuse of EV markers. Additional challenges in EV research, such as isolation methods and the lack of comparative studies between plasma and tissue-derived EVs, are discussed. Providing a list of new possible CNS-derived EV marker candidates can lead to more precise isolation and description of EVs, thereby enhancing our understanding of EV signaling and advancing our knowledge of neurological diseases.

Extracellular vesicles (EVs) are membrane-bound nanoparticles naturally secreted by cells, playing a vital role in intercellular communication and holding significant promise as therapeutic agents. These natural carriers deliver various molecules into cells, including proteins and nucleic acids. There are numerous methods to load and modify EVs, encompassing physical, chemical, and biological approaches. EVs demonstrate the capacity to target specific cells within organs, even requiring blood–tissue transition. The protein corona significantly influences EV availability and cargo delivery, with biomolecules residing both within and conjugated to the EV membrane. Furthermore, embedding EVs within biomaterials such as hydrogels, scaffolds, and nanofibers can enhance their stability, targeting specificity, and therapeutic potential. By addressing cargo loading and cell/tissue-specific targeting, EVs offer a novel therapeutic strategy for various diseases, including cancer, autoimmune disorders, and neurodegenerative diseases. Furthermore, EVs show promise as vaccination tools, delivering messenger RNA and proteins of various pathogens. Advances in EV biology and engineering would provide improved strategies for vesicle targeting, enhanced cargo loading, and safe and effective delivery. The convergence of technological advancements, interdisciplinary collaboration, and an enhanced understanding of EVs promises to revolutionize therapeutic approaches to a wide range of diseases, establishing EV-based treatments as a cornerstone of future medicine.

PURPOSE:Persons with epilepsy (PWE) are at an increased risk for self-injurious behaviors. While suicidal behavior in PWE has been the subject of considerable research, data on nonsuicidal self-injury (NSSI) in PWE remains limited. The aim of this study was to describe the basic characteristics of NSSI in PWE and to identify associated sociodemographic, biographical, psychological, and clinical factors. METHODS:A cross-sectional study assessed 209 consecutive adult PWE with non-psychotic mental disorders using the Self-Injurious Thoughts and Behaviors Interview, Beck Depression Inventory, State-Trait Anxiety Inventory, Brief Reasons for Living Inventory, Modified 36-Item Personality Inventory for DSM-5 and ICD-11 Brief Form Plus-Modified, World Health Organization Quality of Life - 100, as well as a case-report form, to collect relevant for the study data. RESULTS:Lifetime NSSI was reported by 27.7% of PWE, with cutting, carving hitting, picking a wound, biting, and skin scraping being the most common methods. NSSI in PWE was associated with significant features in sociodemographic (born after 1980), biographical (school bullying), clinical (higher levels of depression, anxiety, suicidal ideation and suicide attempts), and psychological profiles (deficits in suicide resilience factors, more pronounced traits of negative affectivity, detachment, antagonism, and psychoticism), and a poorer quality of life. CONCLUSION:This is the first study to report methods and other NSSI-related parameters in PWE. NSSI is associated with numerous negative parameters, some of which are potentially modifiable, and may therefore become a target for therapeutic interventions with potential benefit in terms of reducing suicide risk, which is high in this subpopulation of PWE.

Extracellular vesicles (EVs) are considered to be a promising tool in disease diagnosis. However, the clinical translation of EV-based liquid biopsy faces significant challenges due to the lack of inexpensive, rapid, and high-throughput methods of EV analysis. Bead-based platforms, combined with conventional flow cytometry, allow for the simultaneous capture and immunolabeling of EVs. In this study, we present a new approach based on the label-free isolation of EVs by tannic acid-coated superparamagnetic beads (TASPMB) combined with immunofluorescence detection of EV membrane proteins using flow cytometry. First, we tested the molecular profiling capabilities of the approach using EVs derived from human breast and colorectal cancer cell lines and from plasma of colorectal cancer patients to recognize the tetraspanin protein CD63 and the epithelial cell adhesion molecule (EpCAM). Subsequently, the developed approach was validated to identify proteins on EVs enriched with TASPMB from the conditioned media of SKBR3 and HT29 cell cultures without preliminary purification by a size-exclusion chromatography (SEC) column. The developed approach demonstrates a high capacity for isolating EVs and subsequently profiling of their membrane proteins, with a total assay time of approximately 2 h. The approach presented here can be a promising tool for rapid detection of EV membrane proteins using conventional instruments, such as flow cytometry.

IntroductionSuicide remains a significant public health problem worldwide, particularly in Eastern European countries. Previous studies have shown that nonsuicidal self-injury (NSSI) is one of the most important risk factors for suicide attempts, particularly among people with mental disorders. At the same time, the risk of various dramatic outcomes, including suicide, is likely to vary among different NSSI subtypes. The aim of this study was to evaluate the relationships between NSSI parameters and clinical/psychological variables in Russian patients with non-psychotic mental disorders and suicidal ideation.MethodsThe Inventory of Statements About Self-Injury-1 (ISAS) was translated and adapted in the sample of Russian patients with NSSI. The study sample consisted of 614 consecutively enrolled patients with NSSI and suicidal ideation. The data were clustered based on the method and frequency of NSSI, and the relationships between frequency and method patterns and other NSSI parameters (age at onset of NSSI, experience of physical pain during NSSI, etc.), clinical characteristics (anxiety and depression levels, psychiatric diagnosis), psychological profiles, and quality of life were evaluated.ResultsCluster analysis identified three subtypes of NSSI. Patients with a greater frequency and variety of methods of NSSI attempted suicide more often, were more clinically severe, had significantly higher scores on most pathological personality traits, had less resilience to suicide, and had a lower quality of life.DiscussionOur findings support the need for a high level of clinical attention to people with mental disorders who frequently engage in NSSI using a variety of methods. The significant differences in many of the parameters studied between the other two clusters highlighted the importance of further research into the typologization of NSSI behavior, which could lead to increased certainty in the prognosis of NSSI patients and become the basis for targeted therapy.

Ischemic stroke (IS) is one of the leading causes of long-term disability worldwide. At the same time, there is still no unequivocal understanding of the causes of the varying degrees and speed of recovery of patients after IS. Recovery from IS results from the highly organized interaction of brain structures and cells with other organs and tissues and involves a number of pathophysiological processes occurring both inside and outside the brain. Exosomes are involved in modulating pathophysiological processes after IS by mediating cell-tissue communication, primarily by delivering cargo such as proteins and microRNAs. A comparative quantitative analysis of the protein profiles of serum exosomes of patients examined at different stages after IS was carried out. The expression of proteins associated with immune system functioning and coagulation in the serum exosomes of patients examined 1.5–2 years after IS was significantly higher compared to the parameters of patients examined in the earlier post-stroke period. The results indicate an increased level of immune system activation in the long-term post-stroke period compared to the early post-stroke period and the involvement of exosomes in this process. Further study of the molecular and biochemical parameters of exosomes in the long-term post-stroke period will allow us to assess the risks of negative IS outcomes and find potential targets for their reduction.

In our previous studies, we have found a suppressive effect of a single administration of pentylenetetrazole (PTZ) at a subconvulsive dose on cellular proliferation in the dentate gyrus. In the present work, we show that this decrease in proliferation develops after acute anxiogenic effect of PTZ and is present only in the posterior part of the hippocampus, where a decrease in the number of neuronal NO synthase expressing cells has been also found. These changes were also accompanied by a decrease in the level of nNOS protein in the hippocampus. Taken together, these observations may indicate the possible involvement of nNOS in the suppression of cellular proliferation in the dentate gyrus of the posterior hippocampus during the development of the anxiogenic effect of PTZ.

One of the hottest themes in neurobiology now is small extracellular vesicles (sEVs), particularly their involvement in diagnostics [1]. One distinctive advantage of sEVs usage in this context is permeability of blood-brain barrier to the vesicles [2]. Neuronal sEVs entering the bloodstream can give some evidence of neurodegenerative disease, for example, Alzheimer's [3] well before clinical manifestations. Moreover, content of patients' neuron-derived sEVs may suggest mechanisms of psychiatric diseases [4].

Objective: The aim of the study was to investigate the level of anxiety as well as the attitude toward disease and mitigation strategies in people with non-psychotic mental disorders and healthy controls. Methods: A case-control study (1:4) was conducted during a self-isolation regimen in Moscow. Cases were adult patients with NPMD admitted to the Moscow Research and Clinical Center for Neuropsychiatry. Sex and age-matched controls (individuals who have never sought psychiatric help) were selected from a cohort of 7498 Moscow residents who participated in a large cross-sectional survey delivered via social networks and popular Russian web platforms. Fisher's exact test, Mann-Whitney U test, and General linear modelling were used as statistic methods. Results: In the univariate analysis, patients with NPMD had a lower level of education and were less likely to be married. The level of the trait but not state anxiety was higher in people with NPMD. People with mental disorders were significantly more often concerned about the negative impact of the COVID-19 pandemic on their lives, were more likely to be confident that they would contract the coronavirus and their disease would be severe, showed suboptimal adherence to mitigation strategies, were dissatisfied with the amount of information they received about the COVID-19 disease, and were more concerned about becoming a victim of domestic violence. Marital status, education, use of information resources, dissatisfaction with information about COVID-19, use of public transport, paying attention to the need of others and domestic violence assessment remained significant in the general linear model. All the factors included in the multivariate model accounted for 36.4% of the variance. Conclusion: People with NPMD have a higher level of trait anxiety and are prompted to develop a constellation of maladaptive beliefs toward a pandemic. These beliefs, along with the lack of reliable information on coronavirus infection, can lead to misunderstanding and disregard of sanitary and self-isolation recommendations. Educational programs and vaccination campaigns should be sensitive to these features of people with NPMD.

—Extracellular vesicles (EVs) are a new and actively developing area of modern experimental and theoretical biology, which attracts researchers primarily by the possibility of using EVs as diagnostic biomarkers and therapeutic agents. Currently, the greatest amount of data has been accumulated on small extracellular vesicles (sEVs)—exosomes, vesicles of endosomal origin, and ectosomes (previously known as microvesicles), which are the product of direct budding from the plasma membrane. In this review, we address the major steps in the biogenesis of exosomes and ectosomes, the major processes of intracellular membrane trafficking, and signaling involving sEVs. The role of the sEVs in the physiology and pathophysiology of the nervous system is also discussed, as well as many promising aspects of the study of sEVs biology.

BACKGROUND:Fibromyalgia (FM) is a chronic pain syndrome associated with significant distress and numerous unpleasant consequences. Mental health problems in people with FM have been reported in many studies. People with mental disorders are thought to be at higher risk of FM than the general population, but the prevalence has not been established. OBJECTIVE:We aimed to investigate the prevalence of FM in a representative sample of inpatients with non-psychotic mental disorders. Additionally, we aimed to assess the psychometric properties of the Fibromyalgia Rapid Screening Tool (FiRST) in the Russian-speaking population of people with mental disorders. METHODS:Consecutive inpatients admitted to the Moscow Research and Clinical Center for Neuropsychiatry for treatment of non-psychotic mental disorders were evaluated for FM by a neurologist and completed the FiRST, Beck Depression Inventory (BDI), and State and Trait Anxiety Inventory (STAI). RESULTS:Of the 1168 patients evaluated 9.0% met the diagnostic criteria for FM. FM was associated with being female, having a diagnosis of unipolar depression, and having higher total scores on the BDI and STAI. The psychometric properties of the FiRST were good (McDonald's omega 0.79, corrected item-total correlation greater than 0.45). An optimal cut-off point with the highest Yuden's index (J = 0.75) was >3 (AUC of 0.89). CONCLUSION:FM is a common comorbidity in people with non-psychotic mental disorders, associated with being female, having a diagnosis of unipolar depression, and having more severe anxiety and depression. The FiRST can be used for the FM screening with its cut-off >3 in people with non-psychotic mental disorders. SIGNIFICANCE STATEMENT:It is the first study to determine the prevalence of FM in people with non-psychotic spectrum mental disorders. The study design included a consecutive sample in a real-life setting to avoid bias. In addition, we evaluated the psychometric properties of the FM screening instrument in a population of people with mental disorders and established the cut-off. The specificity of this subpopulation is explained by both the high prevalence of pain symptoms and the overlap of some psychiatric and FM symptoms.

—The aim of the study was to determine the quantitative characteristics of small extracellular vesicles (sEV) in the blood of patients with non-suicidal self-injury (NSSI) and comparison of the concentration and size of sEVs in patients with major depressive disorder (MDD) with and without NSSI, as well as to assess the relationship between the size and concentration of sEVs in the sample with such parameters as the severity of situational and personal anxiety, depression, and suicidal risk. The study included 28 patients (11 m/17 f) with a current episode of major depression and at least five episodes of NSSI in the last 12 months (main group, mean age 28.3 years) and 28 patients with major depression identical in sex and age without NSSI throughout life (comparison group). Patients’ mental status was assessed using the MINI interview, the Beck Depression Inventory II (BDI II), and the Spielberger Anxiety Scale. Isolation of sEVs from blood was carried out using polyethylene glycol (PEG) precipitation and gel filtration. The size and concentration of isolated particles were estimated using dynamic light scattering (DLS) and nanoparticle tracking analysis (NTA). The groups differed significantly in the severity of depression according to the BDI-II questionnaire, the Spielberger Situational Anxiety Scale, and the Spielberger Personality Anxiety Scale. The assessment of suicidal risk, carried out according to the corresponding module of the MINI questionnaire, revealed a significantly larger number of participants with medium and high suicidal risk in the group of patients with NSSI. The sEV fraction was isolated from the blood of the patients of the main group and the comparison group. There were no differences in the concentration or size of sEVs between groups of patients with depression with and without NSSI. In our study, we found no dependence of the concentration and size of sEVs on the severity of depression, situational and personal anxiety, and the severity of suicidal risk. Conclusion: NSSI in individuals with major depressive disorder is associated with a more severe course of the disorder (greater severity of depression, situational and personal anxiety), as well as a higher risk of suicide. Our study did not reveal any differences in the quantitative characteristics of sEV in patients with a depressive episode with and without NSSI. Future studies should focus on investigating the structural differences and functional features of sEVs in NSSI.

Small extracellular vesicles (sEVs) and their role in mental and addictive disorders are extremely promising research areas. Because of their small size, sEVs can pass through the blood–brain barrier. The membrane of sEVs contain proteins that protect them against destruction by the organism’s immune system. Due to these properties, sEVs circulating in the blood can be used as potential biomarkers of processes occurring in the brain. Exposure to psychoactive substances in vitro and in vivo affects sEV biogenesis and significantly alters the amount of sEVs and chemical composition of their cargo. Based on the published reports, sEVs carry numerous potential biomarkers of addictive pathologies, although the diagnostic significance of these markers still has to be evaluated. A large body of evidence indicates that psychoactive substances influence Rab family GTPases, Toll-like receptors, complement system components, and cytokines. In some studies, the effect of psychoactive substances on sEVs was found to be sex-dependent. It has become commonly accepted that sEVs are involved in the regulation of neuroinflammation and interaction between glial cells and neurons, as well as between peripheral cells and cells of the central nervous system. Here, we formulated a hypothesis on the existence of two mechanisms/stages involved in the effect of psychoactive substances on sEVs: the “fast” mechanism that provides neuroplasticity, and the “slow” one, resulting from the impaired biogenesis of sEVs and formation of aberrant vesicles.

Objective: We aimed to evaluate the sociodemographic, clinical, and psychological characteristics associated with psychogenic non-epileptic seizures (PNES) in patients with epilepsy, with particular emphasis on the personality profile assessed from a dimensional perspective. Methods: The cohort study included 77 consecutive inpatients with active epilepsy aged 36-55 years; 52 (67.5%) were female. The presence of PNES was confirmed by video-EEG monitoring. All patients underwent the MiniInternational Neuropsychiatric Interview to diagnose psychiatric disorders. All participants completed the Neurological Disorders Depression Inventory in Epilepsy, the Epilepsy Anxiety Survey Instrument - brief version, and the Personality Inventory for DSM-5 and ICD-11 Brief Form Plus Modified. Chi-square and Fisher's exact tests were used to compare categorical variables, and the Brunner-Munzel test was used for quantitative variables. Results: Twenty-four patients (31.2%) had both epilepsy and PNES. There were no significant differences in social, demographic or clinical characteristics, psychiatric diagnoses or depression severity. Compared to patients with epilepsy alone, patients with epilepsy and PNES had higher anxiety scores and more pronounced maladaptive personality traits such as disinhibition and psychoticism. Significance: The main novelty of our study is that using the recently proposed dimensional approach to personality disorders and an appropriate instrument we assessed all personality domains listed in two of the most widely used classifications of mental disorders (DSM-5 and ICD-11) in PWE with and without PNES. To our knowledge, this is the first study to demonstrate the association of the maladaptive traits of psychoticism and disinhibition with the development of PNES in PWE.

IntroductionThe prevalence of major depressive disorder (MDD) increased during the COVID-19 pandemic. Data on suicidality in these patients during the pandemic period remain scarce. The aim of the study was to determine the prevalence and variables associated with serious suicide risk in Russian inpatients with MDD during the COVID-19 pandemic.MethodsA cross-sectional cohort study with consecutive sampling was conducted from January 1, 2021 to December 31, 2021. All patients completed the Mini International Neuropsychiatric Interview (M.I.N.I.) (including the suicidality module), the Beck Depression Inventory, and the State-Trait Anxiety Inventory, and underwent a semi-structured interview to collect relevant demographic and clinical data. Effect sizes for all independent variables and covariates were calculated using partial eta-squared (ηp2).ResultsOf the 6757 patients with non-psychotic mental disorders assessed, 1605 (23.7%) had MDD confirmed by the M.I.N.I., of whom 17.8% were at serious risk for suicide according to the M.I.N.I. suicidality module. Factors independently associated with serious suicide risk in Russian inpatients with MDD during the pandemic were younger age (ηp2 = 0.021), greater severity of depression (0.038), higher state anxiety (0.003), and nonsuicidal self-injury (NSSI) (0.066). The same variables, except for state anxiety, were independently associated with suicide risk in the subgroup of MDD patients previously infected with SARS-CoV2.ConclusionIn the COVID-19 pandemic, the proportion of patients with MDD at serious risk of suicide was similar to pre-pandemic data. No associations were found between suicidality in patients with MDD and COVID-related factors. Younger age, greater severity of depression, and especially NSSI were the most significant risk factors for suicide in patients with MDD during the COVID-19 pandemic.

Two periods of autophagy activation with a different significance for the development of resistance were demonstrated in the model of neuronal resistance to the toxic glutamate challenge (trophic factor deprivation). The autophagy inhibitor 3-methyladenine (3-MA) at a concentration of 1.25 mM significantly suppressed resistance development but only if applied immediately after deprivation of trophic factors. Inhibition of autophagy with 3-MA during deprivation did not affect resistance production. In addition, activation of autophagy caused a decrease in caspase-3 activity, although the mechanism of this process remains unclear. We hypothesize that development of resistance in neurons is mediated by a decrease in caspase-3 activity caused by autophagy activation.

OBJECTIVE:In Eastern European countries, suicide rate are among the highest in the world and suicide attempts are among the most important risk factors. The aim of this study is to identify factors associated with suicide attempt (SA) in non-psychotic patients with suicidal ideation (SI). METHODS:Among 6204 consecutive adult patients (residents of Moscow) with non-psychotic mental disorders (NPMD), 361 individuals aged 18-77 years (median 24 years) were enrolled in the study after screening for lifetime SI with the Self-Injurious Thoughts and Behaviors Interview (SITBI). All participants were assessed for sociodemographic variables, psychiatric diagnosis, family history of mental disorders, history of abuse, sexual behavior, psychiatric treatments, suicide plan, SA, and nonsuicidal self-injury (NSSI). Results of multivariable analyses (MV) are presented as odds ratios (OR) with 95% confidence intervals (CI). RESULTS:166 patients (46%) reported lifetime SA. In MV, variables associated with SA included smoking (OR 2.1; 95% CI 1.2-3.7), having made a suicide plan (OR 3.4; 95% CI 2.0-5.7), and scars covered by tattoos (OR 5.2; 95% CI 1.5-17.9). History of law violation (OR 2.0; 95% 1.0-4.2) was of borderline significance. CONCLUSIONS:Transition from SI to SA in patients with NPMD was associated with smoking, suicide planning, history of law violation and presence of tattoos covering scars.