Brain Disorders Research Articles

Psychoneuroimmunology of Mood Disorders.

Recent research has shed light on the intricate relationship between mood disorders, such as major depressive disorder (MDD) and bipolar disorder (BD), and inflammation. This chapter explores the complex interplay involving immune and metabolic dysfunction in the pathophysiology of these disorders, emphasizing their association with autoimmunity/inflammatory conditions, chronic low-grade systemic inflammation, T cell overactivation, and immunosenescence. This perspective underscores the notion that MDD and BD are not solely brain disorders, highlighting their nature as multi-system conditions.

Long-term exposure to ambient benzene and brain disorders among urban adults

Long-term exposure to ambient benzene and brain disorders among urban adults

Pathophysiological role of high mobility group box-1 signaling in neurodegenerative diseases.

Nucleocytoplasmic translocation of HMGB1 (high mobility group box-1) plays a significant role in disease progression. Several methods contribute to the translocation of HMGB1 from the nucleus to the cytoplasm, including inflammasome activation, TNF-α signaling, CRM1-mediated transport, reactive oxygen species (ROS), JAK/STAT pathway, RIP3-mediated p53 involvement, XPO-1-mediated transport, and calcium-dependent mechanisms. Due to its diverse functions at various subcellular locations, HMGB1 has been identified as a crucial factor in several Central Nervous System (CNS) disorders, including Huntington's disease (HD), Parkinson's disease (PD), and Alzheimer's disease (AD). HMGB1 displays a wide array of roles in the extracellular environment as it interacts with several receptors, including CXCR4, TLR2, TLR4, TLR8, and RAGE, by engaging in these connections, HMGB1 can effectively regulate subsequent signaling pathways, hence exerting an impact on the progression of brain disorders through neuroinflammation. Therefore, focusing on treating neuroinflammation could offer a common therapeutic strategy for several disorders. The objective of the current literature is to demonstrate the pathological role of HMGB1 in various neurological disorders. This review also offers insights into numerous therapeutic targets that promise to advance multiple treatments intended to alleviate brain illnesses.

SMPD4-mediated sphingolipid metabolism regulates brain and primary cilia development.

Genetic variants in multiple sphingolipid biosynthesis genes cause human brain disorders. A recent study looked at people from 12 unrelated families with variants in the gene SMPD4, a neutral sphingomyelinase that metabolizes sphingomyelin into ceramide at an early stage of the biosynthesis pathway. These individuals have severe developmental brain malformations, including microcephaly and cerebellar hypoplasia. The disease mechanism of SMPD4 was not known and so we pursued a new mouse model. We hypothesized that the role of SMPD4 in producing ceramide is important for making primary cilia, a crucial organelle mediating cellular signaling. We found that the mouse model has cerebellar hypoplasia due to failure of Purkinje cell development. Human induced pluripotent stem cells lacking SMPD4 exhibit neural progenitor cell death and have shortened primary cilia, which is rescued by adding exogenous ceramide. SMPD4 production of ceramide is crucial for human brain development.

Chronic implantable flexible serpentine probe reveals impaired spatial coding of place cells in epilepsy

Abstract Developing minimally invasive and reliable electrode probes for neural signal recording is crucial for advancing neuroscience and treating major brain disorders. Flexible neural probes offer superior long-term recording capabilities over traditional rigid probes. This study introduces a parylene-based serpentine electrode probe for stable, long-term neural monitoring. Inspired by the flexibility and morphology of snakes, the probe's serpentine design ensures stable anchorage within the brain tissue during subject movement. The probe features a hydrophilic surface and is combined with a biodegradable silk fibroin-PEG coating, significantly enhancing biocompatibility and mitigating inflammatory responses. In vivo experiments demonstrate that these probes maintain stable, high-quality neural recordings for over eight months. The probes are also used to investigate the neural bases of epilepsy-induced cognitive deficits. By analyzing place cell dynamics in mice pre- and post-epileptic events, we identified the correlation between impaired spatial encoding and the observed cognitive deficits in epileptic mice. This study highlights the potential of our flexible probes in neurological research and medical applications.

Therapeutic potential of stem cell-derived extracellular vesicles in neurodegenerative diseases associated with cognitive decline.

In the central nervous system, cell-to-cell interaction is essential for brain plasticity and repair, and its alteration is critically involved in the development of neurodegenerative diseases. Neural stem cells are a plentiful source of biological signals promoting neuroplasticity and the maintenance of cognitive functions. Extracellular vesicles (EVs) represent an additional strategy for cells to release signals in the surrounding cellular environment or to exchange information among both neighboring and distant cells. In the last years, rising attention has been devoted to the ability of stem cell (SC)-derived EVs to counteract inflammatory and degenerative brain disorders taking advantage of their immunomodulatory capacities and regenerative potential. Here, we review the role of adult neurogenesis impairment in the cognitive decline associated with neurodegenerative diseases and describe the beneficial effects of SC-derived EVs on brain plasticity and repair also discussing the advantages of SC-derived EV administration versus SC transplantation in the treatment of neurodegenerative disorders.

Temporal dynamics of neurovascular unit changes following blood-brain barrier opening in the putamen of non-human primates.

Low-intensity focused ultrasound (LIFU) combined with intravenously circulating microbubbles has recently emerged as a novel approach for increasing delivery through the blood-brain barrier (BBB). This technique safely and transiently enables therapeutic agents to overcome the BBB, which typically poses a significant obstacle for treatment of brain disorders. However, the full impact of LIFU on the entire neurovascular unit (NVU), as well as the mechanisms and factors involved in restoring BBB integrity still require further elucidation. We conducted immunohistochemical analyses of the putamen in non-human primates to monitor changes over time [immediately post-treatment (3 h) and at 7- and 30-days post-BBB opening] in vascular, glial, and immune cells. Additionally, we examined the dynamic interactions among these elements and their role in the restorative process at the BBB level. A mild inflammatory response primarily involving microglia, astrocytes, and T- and B-lymphocytes was observed in the treated putamen acutely after BBB opening. These cells, recruited in response to the vascular changes, stimulate upregulation of PDGFRβ, a pericyte-specific marker, and VEGF-A, a pro-angiogenic factor. This was associated with vascular sprouting by 7 days post-BBB opening. Importantly, no notable long-term alterations were observed in the NVU 30 days post-BBB opening. These results offer further evidence regarding the efficacy and safety of LIFU in achieving BBB opening in the primate brain, indicating that nearly all changes in the NVU revert to baseline within 30 days post-treatment. This also suggests that angiogenesis may play an important role in restoring vascular integrity after BBB opening.

Investigations of Acute Ischemic Stroke Detection Techniques from CT Images Using Machine Learning Approaches

Stroke is a kind of cerebrovascular accident (CVA) that primarily affects individuals over the age of 50, while it can afflict people of all ages. Stroke patients suffer from a chronic condition that leaves them physically unable till their death. To identify the onset of this illness, numerous studies have been carried out. Common signs of a stroke include stiffness, a shift in posture, and tremors in the arms and legs. Functional and emotional mediation are linked to a significant area of the brain. The symptoms of many brain disorders are similar in the early stages because of disruptions to dopamine and other regulating mechanisms. This is a crucial step in how stroke lesions develop. The CAD system is the most efficient method for identifying a stroke. By speeding up the analysis of the required aberration, the CAD system improves the process of illness diagnosis. The goal of the proposed study is to create a compact system that can lessen processing errors, false positive rates, and complexity—three major problems with the current system. The proposed study uses a machine learning model to interpret and classify a CT brain image that shows an Acute Ischaemic Stroke (AIS) lesion. To distinguish between normal and AIS stroke lesions, the pre-processed image is segmented and classed using a Random Forest classifier. Performance criteria like Peak signal ratio, average gradient, accuracy, specificity, sensitivity, and dice index are used to evaluate the experimental output of the proposed work. The suggested model has a straightforward processing structure and the highest efficiency.

TMET-31. OXIDATIVE STRESS INDUCED PROTEIN AGGREGATION VIA GGCT PRODUCED PYROGLUTAMIC ACID IN DRUG RESISTANT GLIOBLASTOMA

Abstract Drug resistance is a major barrier to cancer therapies and remains poorly understood. Recently, non-mutational mechanisms of drug resistance have been proposed where a more plastic metabolic response can play a major role. Here, we show that upon drug resistance, glioblastoma (GBM) cells have increased oxidative stress, mitochondria function, and protein aggregation. Gamma (y)-glutamylcyclotranserase (GGCT), an enzyme in the y-glutamyl cycle for glutathione production, located on chromosome 7 which is commonly amplified in GBM is also increased upon resistance. We further observe that the byproduct of GGCT – pyroglutamic acid – can bind aggregating proteins and that genetic and pharmacological inhibition of GGCT prevents protein aggregation. Finally, we found increased protein aggregation, GGCT expression, and pyroglutamic acid staining in recurrent GBM patient samples, as well as adjacent normal brain. These findings suggest a new pathway for protein aggregation within drug resistant brain cancer that should be further studied in other brain disorders.

Adeno-Associated Viral Vectors in the Treatment of Epilepsy

Epilepsy is a brain disorder characterized by a persistent predisposition to epileptic seizures. With various etiologies of epilepsy, a significant proportion of patients develop pharmacoresistance to antiepileptic drugs, which necessitates the search for new therapeutic methods, in particular, using gene therapy. This review discusses the use of adeno-associated viral (AAV) vectors in gene therapy for epilepsy, emphasizing their advantages, such as high efficiency of neuronal tissue transduction and low immunogenicity/cytotoxicity. AAV vectors provide the possibility of personalized therapy due to the diversity of serotypes and genomic constructs, which allows for increasing the specificity and effectiveness of treatment. Promising orientations include the modulation of the expression of neuropeptides, ion channels, transcription, and neurotrophic factors, as well as the use of antisense oligonucleotides to regulate seizure activity, which can reduce the severity of epileptic disorders. This review summarizes the current advances in the use of AAV vectors for the treatment of epilepsy of various etiologies, demonstrating the significant potential of AAV vectors for the development of personalized and more effective approaches to reducing seizure activity and improving patient prognosis.

Role of inflammasomes and neuroinflammation in epilepsy.

Epilepsy is a brain disorder characterized by recurrent seizures, which are brief episodes of abnormal electrical activity in the brain and involuntary movement that can lead to physical injury and loss of consciousness. Seizures are canonically accompanied by increased inflammatory cytokine production that promotes neuroinflammation, brain pathology, and seizure propagation. Understanding the source of pro-inflammatory cytokines which promote seizure pathogenesis could be a gateway to precision epilepsy drug design. This review discusses the inflammasome in epilepsy including its role in seizure propagation and negative impacts on brain health. The inflammasome is a multiprotein complex that coordinates IL-1β and IL-18 production in response to tissue damage, cellular stress, and infection. Clinical evidence for inflammasome signaling in epileptogenesis is reviewed followed by a discussion of emerging strategies to modulate inflammasome activity in epilepsy.

Enhanced Fuzzy Score-Based Decision Support System for Early Stroke Prediction

According to the Global Health Observatory (GHO), stroke ranks second worldwide in causing dementia, right after Alzheimer's disease. The mortality rate linked to dementia resulting from stroke is high because symptoms are often recognized late, and stroke can be misinterpreted as other brain disorders. Early detection and diagnosis of stroke is crucial. Therefore, increasing awareness of stroke symptoms and implementing preventive measures becomes imperative. Prompt intervention by healthcare professionals can improve outcomes and reduce long-term complications of stroke. The research introduces an innovative approach for early stroke prediction using a fuzzy scoring-based Decision Support System. This approach encompasses three main modules: Mind-map based Data Modeling, Fuzzy scoring computing, and ML-based Decision System. By incorporating fuzzy logic, the approach extracts valuable knowledge from imprecise and uncertain data. Combining the fuzzy stroke risk model with a machine learning-based decision support system aims to enhance stroke prediction accuracy and improve preventive measures and patient outcomes. The approach's effectiveness was validated using real clinical data and tested with various machine learning classifiers, including K-Nearest Neighbour (KNN), Logistic Regression (LR), Decision Tree (DT), Artificial Neural Network (ANN), and Support Vector Machine (SVM). The results showed a strong correlation between stroke cases and computed risk-scoring values. In comparison to predictions without fuzzy scoring and other related works, the stroke risk prediction using the proposed approach demonstrated higher accuracy, making it a promising method for early stroke detection and prevention.

The Two Faces of HDAC3: Neuroinflammation in Disease and Neuroprotection in Recovery.

Histone deacetylase 3 (HDAC3) is a critical regulator of gene expression, influencing a variety of cellular processes in the central nervous system. As such, dysfunction of this enzyme may serve as a key driver in the pathophysiology of various neuropsychiatric disorders and neurodegenerative diseases. HDAC3 plays a crucial role in regulating neuroinflammation, and is now widely recognized as a major contributor to neurological conditions, as well as in promoting neuroprotective recovery following brain injury, hemorrhage and stroke. Emerging evidence suggests that pharmacological inhibition of HDAC3 can mitigate behavioral and neuroimmune deficits in various brain diseases and disorders, offering a promising therapeutic strategy. Understanding HDAC3 in the healthy brain lays the necessary foundation to define and resolve its dysfunction in a disease state. This review explores the mechanisms of HDAC3 in various cell types and its involvement in disease pathology, emphasizing the potential of HDAC3 inhibition to address neuroimmune, gene expression and behavioral deficits in a range of neurodegenerative and neuropsychiatric conditions.

Data analytics for research on complex brain disorders

There exist many research tools for complex brain disorders both proprietary and open source. Those tools are mostly focused on specific use cases and don’t offer a holistic view of the research and diagnostic processes. The MES-CoBraD platform offers a holistic tool that participates in all the phases of the process from planning to execution. In it researchers can create workflows of the diagnostic and research procedures. The Data Analytics module provides the functionality described in these workflows, mainly the analytical functions. The tools are integrated with the rest of the platform in a seamless manner. They are capable of analyzing different categories of data including imaging data, electroencephalogram (EEG)/polysomnography (PSG), medical device data, and consumer technology data. In this paper we present a summary of how the MES-CoBraD platform operates, the role of the data analytics in it, the actual functions implemented and integrated in the Data Analytics module and a number of use cases which show how each specific function can be used during the research and clinical procedures.

SARS-CoV-2 and HSV-1 Induce Amyloid Aggregation in Human CSF Resulting in Drastic Soluble Protein Depletion.

The corona virus (SARS-CoV-2) pandemic and the resulting long-term neurological complications in patients, known as long COVID, have renewed interest in the correlation between viral infections and neurodegenerative brain disorders. While many viruses can reach the central nervous system (CNS) causing acute or chronic infections (such as herpes simplex virus 1, HSV-1), the lack of a clear mechanistic link between viruses and protein aggregation into amyloids, a characteristic of several neurodegenerative diseases, has rendered such a connection elusive. Recently, we showed that viruses can induce aggregation of purified amyloidogenic proteins via the direct physicochemical mechanism of heterogeneous nucleation (HEN). In the current study, we show that the incubation of HSV-1 and SARS-CoV-2 with human cerebrospinal fluid (CSF) leads to the amyloid aggregation of several proteins known to be involved in neurodegenerative diseases, such as APLP1 (amyloid β precursor like protein 1), ApoE, clusterin, α2-macroglobulin, PGK-1 (phosphoglycerate kinase 1), ceruloplasmin, nucleolin, 14-3-3, transthyretin, and vitronectin. Importantly, UV-inactivation of SARS-CoV-2 does not affect its ability to induce amyloid aggregation, as amyloid formation is dependent on viral surface catalysis via HEN and not its ability to replicate. Additionally, viral amyloid induction led to a dramatic drop in the soluble protein concentration in the CSF. Our results show that viruses can physically induce amyloid aggregation of proteins in human CSF and result in soluble protein depletion, thus providing a potential mechanism that may account for the association between persistent and latent/reactivating brain infections and neurodegenerative diseases.

Neural Stem Cell Therapy for Alzheimer’s Disease: A-State-of-the-Art Review

Alzheimer’s disease (AD) is a brain disorder that is more prevalent in developed nations and remains one of most intractable conditions so far. It is characterized by a gradual onset, a prolonged progression, and an unclear pathophysiology. At the present time, there are no effective treatments available for the disease. However, human neural stem cells (hNSCs) have the capacity to substitute lost neurons in a functional manner, strengthen synaptic networks that have been compromised, and repair the damaged brain. Due to the unavailability of restorative therapeutics, there is a significant global burden on the economy. When it comes to the treatment of neurodegenerative diseases, NSCs provide a potentially game-changing approach to treating Alzheimer’s disease. Through the delivery of trophic factors that promote the viability and regeneration of lost neurons in experimental animals suffering from neurodegenerative disorders, these treatments have the potential to facilitate beneficial recuperation. Positive restorative outcomes may be achieved in a variety of ways, including the replacement of lost cells, the combining of cells, the secretion of neurotrophic factors, the formation of endogenous stem cells, and transdifferentiation. Conversely, there are obstacles that need to be overcome before NSC-based treatments can be used in clinical settings. This review article discusses current developments in the use of neural stem cells (NSCs) for the treatment of Alzheimer’s disease (AD). In addition, we highlight the difficulties and opportunities that are involved with the use of neural stem cell transplant treatment for Alzheimer’s disease.

Probiotic Formulation for Patients With Bipolar or Schizophrenia Spectrum Disorder: A Double-Blind, Randomized Placebo-Controlled Trial.

Probiotic augmentation offers a promising treatment for bipolar disorder (BD) and schizophrenia spectrum disorder (SSD). By targeting microbiome deviations, they may improve both gut and brain health. In this double-blind, randomized, placebo-controlled trial with the multi-strain probiotic formulation Ecologic BARRIER, we aimed to improve psychiatric and cognitive symptoms, intestinal permeability, and gastrointestinal symptoms in patients with BD or SSD. A total of 131 patients were randomized 1:1 to receive either the probiotic supplement (n = 67) or a placebo (n = 64) for 3 months, in addition to treatment-as-usual. The primary outcomes were symptom severity assessed by the Brief Psychiatric Rating Scale and cognitive functioning by the Brief Assessment of Cognition in Schizophrenia. No significant effect of probiotics was observed on psychiatric symptoms, but borderline significant improvement was observed in the cognition category of verbal memory (Linear Mixed Model (LMM)0.33; adjusted P = .059). Probiotics beneficially affected markers of intestinal permeability and inflammation, including zonulin (LMMserum = -18.40; adjusted P = .002; LMMfecal = -10.47; adjusted P = .014) and alpha-1 antitrypsin (LMM 9.26; adjusted P = .025). Indigestion complaints significantly decreased in male participants in the probiotics group (LMM = -0.70; adjusted P = .010). Adverse events were similar between groups. Our study observed significant advantages of probiotics for gut health in BD and SSD, with excellent safety and tolerability. A borderline effect on verbal memory was also indicated. These results underscore the need for further research into microbiome-targeted interventions for patients with complex brain disorders.

Simultaneous assessment of cerebral glucose and oxygen metabolism and perfusion in rats using interleaved deuterium (2H) and oxygen-17 (17O) MRS.

Cerebral glucose and oxygen metabolism and blood perfusion play key roles in neuroenergetics and oxidative phosphorylation to produce adenosine triphosphate (ATP) energy molecules in supporting cellular activity and brain function. Their impairments have been linked to numerous brain disorders. This study aimed to develop an in vivo magnetic resonance spectroscopy (MRS) method capable of simultaneously assessing and quantifying the major cerebral metabolic rates of glucose (CMRGlc) and oxygen (CMRO2) consumption, lactate formation (CMRLac), and tricarboxylic acid (TCA) cycle (VTCA); cerebral blood flow (CBF); and oxygen extraction fraction (OEF) via a single dynamic MRS measurement using an interleaved deuterium (2H) and oxygen-17 (17O) MRS approach. We introduced a single-loop multifrequency radio-frequency (RF) surface coil that can be used to acquire proton (1H) magnetic resonance imaging (MRI) or interleaved low-γ X-nuclei 2H and 17O MRS. By combining this RF coil with a modified MRS pulse sequence, 17O-isotope-labeled oxygen gas inhalation, and intravenous 2H-isotope-labeled glucose administration, we demonstrate for the first time the feasibility of simultaneously and quantitatively measuring six important physiological parameters, CMRGlc, CMRO2, CMRLac, VTCA, CBF, and OEF, in rat brains at 16.4T. The interleaved 2H-17O MRS technique should be readily adapted to image and study cerebral energy metabolism and perfusion in healthy and diseased brains.

Evaluation of allosteric NMDA receptor modulation by GluN2A-selective antagonists using pharmacological equilibrium modeling.

NMDA-type ionotropic glutamate receptors are critically involved in excitatory neurotransmission and their dysfunction is implicated in many brain disorders. Allosteric modulators with selectivity for specific NMDA receptor subtypes are therefore attractive as therapeutic agents, and sustained drug discovery efforts have resulted in a wide range of new allosteric modulators. However, evaluation of allosteric NMDA receptor modulators is limited by the lack of operational ligand-receptor models to describe modulator binding dissociation constants (KB) and effects on agonist binding affinity (α) and efficacy (β). Here, we describe a pharmacological equilibrium model that encapsulates activation and modulation of NMDA receptors, and we apply this model to afford deeper understanding of GluN2A-selective negative allosteric modulators (NAMs), TCN-201, MPX-004, and MPX-007. We exploit slow NAM unbinding to examine receptors at hemi-equilibrium when fully occupied by agonists and modulators to demonstrate that TCN-201 display weaker binding and negative modulation of glycine binding affinity (KB = 42 nM, α = 0.0032) compared to MPX-004 (KB = 9.3 nM, α = 0.0018) and MPX-007 (KB = 1.1 nM, α = 0.00053). MPX-004 increases agonist efficacy (β = 1.19), whereas TCN-201 (β = 0.76) and MPX-007 (β = 0.82) reduce agonist efficacy. These values describing allosteric modulation of diheteromeric GluN1/2A receptors with two modulator binding sites are unchanged in triheteromeric GluN1/2A/2B receptors with a single binding site. This evaluation of NMDA receptor modulation reveals differences between ligand analogs that shape their utility as pharmacological tool compounds and facilitates the design of new modulators with therapeutic potential. Significance Statement Detailed understanding of allosteric NMDA receptor modulation requires pharmacological methods to quantify modulator binding affinity and the strengths of modulation of agonist binding and efficacy. We describe a generic ligand-receptor model for allosteric NMDA receptor modulation and use this model for the characterization of GluN2A-selective NAMs. The model enables quantitative evaluation of a broad range of NMDA receptor modulators and provides opportunities to optimize these modulators by embellishing the interpretation of their structure-activity relationships.

An interview with Professor Benjamin Becker: understanding our brain and mental disorders requires collaboration across all disciplines

Abstract From July 20th to 22nd, 2024, the ISMRM Endorsed Workshop on MR for Psychiatry was held in Chengdu City, China. This prestigious event attracted numerous academic elites worldwide, and Professor Benjamin Becker from the University of Hong Kong was invited. On the morning of July 20, during the “Advances in MR Technology” session, Professor Becker delivered an engaging lecture entitled “Novel approaches to precision MRI-imaging of human emotion”. His presentation was met with great enthusiasm and sparked lively discussions among the participants. Following the conference, the Psychoradiology journal interviewed Professor Benjamin Becker. In the interview, Benjamin emphasized the significant role of interdisciplinary collaboration, spanning various fields including psychology, neuroscience, clinical medicine, biomedical engineering, and computer science. Professor Becker firmly believed that such collaboration was crucial for a deeper understanding of the brain and psychiatric disorders. Additionally, he highly valued the importance of international cooperation, especially in addressing global mental health issues and challenges related to psychiatric disorders.