Connectional-style-guided contextual representation learning for brain disease diagnosis.

Structural magnetic resonance imaging (sMRI) has shown great clinical value and has been widely used in deep learning (DL) based computer-aided brain disease diagnosis. Previous DL-based approaches focused on local shapes and textures in brain sMRI that may be significant only within a particular domain. The learned representations are likely to contain spurious information and have poor generalization ability in other diseases and datasets. To facilitate capturing meaningful and robust features, it is necessary to first comprehensively understand the intrinsic pattern of the brain that is not restricted within a single data/task domain. Considering that the brain is a complex connectome of interlinked neurons, the connectional properties in the brain have strong biological significance, which is shared across multiple domains and covers most pathological information. In this work, we propose a connectional style contextual representation learning model (CS-CRL) to capture the intrinsic pattern of the brain, used for multiple brain disease diagnosis. Specifically, it has a vision transformer (ViT) encoder and leverages mask reconstruction as the proxy task and Gram matrices to guide the representation of connectional information. It facilitates the capture of global context and the aggregation of features with biological plausibility. The results indicate that CS-CRL achieves superior accuracy in multiple brain disease diagnosis tasks across six datasets and three diseases and outperforms state-of-the-art models. Furthermore, we demonstrate that CS-CRL captures more brain-network-like properties, and better aggregates features, is easier to optimize, and is more robust to noise, which explains its superiority in theory.

A no-fault risk compensation approach for radiation risks incurred in space travel.

In this paper we recommend an appropriate compensation approach should be established for fatality and disabilities that may occur due to space radiation exposures of government or industry workers. A brief review of compensation approaches for nuclear energy and nuclear weapons development workers in the United States and other countries is described. We then summarize issues in the application of probability of causation calculation and provide examples of probability of causation (PC) calculations for missions to the International Space Station and Earth's moon or for Mars exploration. The main focus of this paper follows with a recommendation of a no-fault approach to compensation with the creation of appropriate insurance policies funded by employers to cover all disabilities or fatality, without requiring proof of causation or restriction to conditions that imply causation. Importantly we propose that the compensation described should be managed by recourse to private insurers.

Ketogenic therapy towards precision medicine for brain diseases.

Precision nutrition and nutrigenomics are emerging in the development of therapies for multiple diseases. The ketogenic diet (KD) is the most widely used clinical diet, providing high fat, low carbohydrate, and adequate protein. KD produces ketones and alters the metabolism of patients. Growing evidence suggests that KD has therapeutic effects in a wide range of neuronal diseases including epilepsy, neurodegeneration, cancer, and metabolic disorders. Although KD is considered to be a low-side-effect diet treatment, its therapeutic mechanism has not yet been fully elucidated. Also, its induced keto-response among different populations has not been elucidated. Understanding the ketone metabolism in health and disease is critical for the development of KD-associated therapeutics and synergistic therapy under any physiological background. Here, we review the current advances and known heterogeneity of the KD response and discuss the prospects for KD therapy from a precision nutrition perspective.

Ribosome Profiling and Mass Spectrometry Reveal Widespread Mitochondrial Translation Defects in a Striatal Cell Model of Huntington Disease.

Huntington disease (HD) is caused by an expanded polyglutamine mutation in huntingtin (mHTT) that promotes prominent atrophy in the striatum and subsequent psychiatric, cognitive deficits, and choreiform movements. Multiple lines of evidence point to an association between HD and aberrant striatal mitochondrial functions; however, the present knowledge about whether (or how) mitochondrial mRNA translation is differentially regulated in HD remains unclear. We found that protein synthesis is diminished in HD mitochondria compared to healthy control striatal cell models. We utilized ribosome profiling (Ribo-Seq) to analyze detailed snapshots of ribosome occupancy of the mitochondrial mRNA transcripts in control and HD striatal cell models. The Ribo-Seq data revealed almost unaltered ribosome occupancy on the nuclear-encoded mitochondrial transcripts involved in oxidative phosphorylation (SDHA, Ndufv1, Timm23, Tomm5, Mrps22) in HD cells. By contrast, ribosome occupancy was dramatically increased for mitochondrially encoded oxidative phosphorylation mRNAs (mt-Nd1, mt-Nd2, mt-Nd4, mt-Nd4l, mt-Nd5, mt-Nd6, mt-Co1, mt-Cytb, and mt-ATP8). We also applied tandem mass tag-based mass spectrometry identification of mitochondrial proteins to derive correlations between ribosome occupancy and actual mature mitochondrial protein products. We found many mitochondrial transcripts with comparable or higher ribosome occupancy, but diminished mitochondrial protein products, in HD. Thus, our study provides the first evidence of a widespread dichotomous effect on ribosome occupancy and protein abundance of mitochondria-related genes in HD.

Constructing hierarchical attentive functional brain networks for early AD diagnosis.

Analyzing functional brain networks (FBN) with deep learning has demonstrated great potential for brain disorder diagnosis. The conventional construction of FBN is typically conducted at a single scale with a predefined brain region atlas. However, numerous studies have identified that the structure and function of the brain are hierarchically organized in nature. This urges the need of representing FBN in a hierarchical manner for more effective analysis of the complementary diagnostic insights at different scales. To this end, this paper proposes to build hierarchical FBNs adaptively within the Transformer framework. Specifically, a sparse attention-based node-merging module is designed to work alongside the conventional network feature extraction modules in each layer. The proposed module generates coarser nodes for further FBN construction and analysis by combining fine-grained nodes. By stacking multiple such layers, a hierarchical representation of FBN can be adaptively learned in an end-to-end manner. The hierarchical structure can not only integrate the complementary information from multiscale FBN for joint analysis, but also reduce the model complexity due to decreasing node sizes. Moreover, this paper argues that the nodes defined by the existing atlases are not necessarily the optimal starting level to build FBN hierarchy and exploring finer nodes may further enrich the FBN representation. In this regard, each predefined node in an atlas is split into multiple sub-nodes, overcoming the scale limitation of the existing atlases. Extensive experiments conducted on various data sets consistently demonstrate the superior performance of the proposed method over the competing methods.

Transcranial photobiomodulation for brain diseases: review of animal and human studies including mechanisms and emerging trends.

The brain diseases account for 30% of all known diseases. Pharmacological treatment is hampered by the blood-brain barrier, limiting drug delivery to the central nervous system (CNS). Transcranial photobiomodulation (tPBM) is a promising technology for treating brain diseases, due to its effectiveness, non-invasiveness, and affordability. tPBM has been widely used in pre-clinical experiments and clinical trials for treating brain diseases, such as stroke and Alzheimer's disease. This review provides a comprehensive overview of tPBM. We summarize emerging trends and new discoveries in tPBM based on over one hundred references published in the past 20 years. We discuss the advantages and disadvantages of tPBM and highlight successful experimental and clinical protocols for treating various brain diseases. A better understanding of tPBM mechanisms, the development of guidelines for clinical practice, and the study of dose-dependent and personal effects hold great promise for progress in treating brain diseases.

Validating a minipig model of reversible cerebral demyelination using human diagnostic modalities and electron microscopy.

BACKGROUND: Inflammatory demyelinating diseases of the central nervous system, such as multiple sclerosis, are significant sources of morbidity in young adults despite therapeutic advances. Current murine models of remyelination have limited applicability due to the low white matter content of their brains, which restricts the spatial resolution of diagnostic imaging. Large animal models might be more suitable but pose significant technological, ethical and logistical challenges. METHODS: We induced targeted cerebral demyelinating lesions by serially repeated injections of lysophosphatidylcholine in the minipig brain. Lesions were amenable to follow-up using the same clinical imaging modalities (3T magnetic resonance imaging, 11C-PIB positron emission tomography) and standard histopathology protocols as for human diagnostics (myelin, glia and neuronal cell markers), as well as electron microscopy (EM), to compare against biopsy data from two patients. FINDINGS: We demonstrate controlled, clinically unapparent, reversible and multimodally trackable brain white matter demyelination in a large animal model. De-/remyelination dynamics were slower than reported for rodent models and paralleled by a degree of secondary axonal pathology. Regression modelling of ultrastructural parameters (g-ratio, axon thickness) predicted EM features of cerebral de- and remyelination in human data. INTERPRETATION: We validated our minipig model of demyelinating brain diseases by employing human diagnostic tools and comparing it with biopsy data from patients with cerebral demyelination. FUNDING: This work was supported by the DFG under Germany's Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy, ID 390857198) and TRR 274/1 2020, 408885537 (projects B03 and Z01).

Understanding immune microenvironment alterations in the brain to improve the diagnosis and treatment of diverse brain diseases.

Abnormal inflammatory states in the brain are associated with a variety of brain diseases. The dynamic changes in the number and function of immune cells in cerebrospinal fluid (CSF) are advantageous for the early prediction and diagnosis of immune diseases affecting the brain. The aggregated factors and cells in inflamed CSF may represent candidate targets for therapy. The physiological barriers in the brain, such as the blood‒brain barrier (BBB), establish a stable environment for the distribution of resident immune cells. However, the underlying mechanism by which peripheral immune cells migrate into the brain and their role in maintaining immune homeostasis in CSF are still unclear. To advance our understanding of the causal link between brain diseases and immune cell status, we investigated the characteristics of immune cell changes in CSF and the molecular mechanisms involved in common brain diseases. Furthermore, we summarized the diagnostic and treatment methods for brain diseases in which immune cells and related cytokines in CSF are used as targets. Further investigations of the new immune cell subtypes and their contributions to the development of brain diseases are needed to improve diagnostic specificity and therapy.

Diphenyl Diselenide Attenuates Mitochondrial Damage During Initial Hypoxia and Enhances Resistance to Recurrent Hypoxia.

Hypoxia plays a significant role in the development of various cerebral diseases, many of which are associated with the potential risk of recurrence due to mitochondrial damage. Conventional drug treatments are not always effective for hypoxia-related brain diseases, necessitating the exploration of alternative compounds. In this study, we investigated the potential of diphenyl diselenide [(PhSe)2] to ameliorate locomotor impairments and mitigate brain mitochondrial dysfunction in zebrafish subjected to hypoxia. Additionally, we explored whether these improvements could confer resistance to recurrent hypoxia. Through a screening process, an appropriate dose of (PhSe)2 was determined, and animals exposed to hypoxia received a single intraperitoneal injection of 100 mg/kg of the compound or vehicle. After 1 h from the injection, evaluations were conducted on locomotor deficits, (PhSe)2 content, mitochondrial electron transport system, and mitochondrial viability in the brain. The animals were subsequently exposed to recurrent hypoxia to assess the latency time to hypoxia symptoms. The findings revealed that (PhSe)2 effectively crossed the blood-brain barrier, attenuated locomotor deficits induced by hypoxia, and improved brain mitochondrial respiration by modulating complex III. Furthermore, it enhanced mitochondrial viability in the telencephalon, contributing to greater resistance to recurrent hypoxia. These results demonstrate the beneficial effects of (PhSe)2 on both hypoxia and recurrent hypoxia, with cerebral mitochondria being a critical target of its action. Considering the involvement of brain hypoxia in numerous pathologies, (PhSe)2 should be further tested to determine its effectiveness as a potential treatment for hypoxia-related brain diseases.

Stable, neuron-specific gene expression in the mouse brain.

Gene delivery to, and expression in, the mouse brain is important for understanding gene functions in brain development and disease, or testing gene therapies. Here, we describe an approach to express a transgene in the mouse brain in a cell-type-specific manner. We use stereotaxic injection of a transgene-expressing adeno-associated virus into the mouse brain via the intracerebroventricular route. We demonstrate stable and sustained expression of the transgene in neurons of adult mouse brain, using a reporter gene driven by a neuron-specific promoter. This approach represents a rapid, simple, and cost-effective method for global gene expression in the mouse brain, in a cell-type-specific manner, without major surgical interventions. The described method represents a helpful resource for genetically engineering mice to express a therapeutic gene, for gene therapy studies, or to deliver genetic material for genome editing and developing knockout animal models.

The Landscape of Biomimetic Nanovesicles in Brain Diseases.

Brain diseases, such as brain tumors, neurodegenerative diseases, cerebrovascular diseases, and brain injuries, are caused by various pathophysiological changes, which pose a serious health threat. Brain disorders are often difficult to treat due to the presence of the blood-brain barrier (BBB). Biomimetic nanovesicles (BNVs), including endogenous extracellular vesicles (EVs) derived from various cells and artificial nanovesicles, possess the ability to penetrate the BBB and thus can be utilized for drug delivery to the brain. BNVs, especially endogenous EVs, are widely distributed in body fluids and usually carry various disease-related signal molecules such as proteins, RNA, and DNA, and may also be analyzed to understand the etiology and pathogenesis of brain diseases. This review covers the exhaustive classification and characterization of BNVs and pathophysiological roles involved in various brain diseases, and emphatically focuses on nanotechnology-integrated BNVs for brain disease theranostics, including various diagnosis strategies and precise therapeutic regulations (e.g., immunity regulation, disordered protein clearance, anti-neuroinflammation, neuroregeneration, angiogenesis, and the gut-brain axis regulation). The remaining challenges and future perspectives regarding the nanotechnology-integrated BNVs for the diagnosis and treatment of brain diseases are also discussed and outlined.

Are postnatal traumatic events an underestimated cause of porencephalic lesions in dogs and cats?

Introduction: Porencephaly is defined as a fluid-filled cavity of variable size in the brain cortex. It is regarded as a congenital condition and is typically considered a developmental or an encephaloclastic defect. Our hypothesis is that postnatal traumatic events in the first few months of life may represent a cause of canine and feline porencephaly that is more common than generally suspected. The aims of this study were to retrospectively investigate porencephaly in a large population of dogs and cats, detect MRI features that might be useful to differentiate postnatal acquired traumatic forms from congenital/perinatal porencephaly, and define the prevalence of seizure activity in porencephalic patients. Materials and methods: This is a double-center, descriptive, retrospective case series. Databases were searched for cases within a 17-year time span that involve dogs and cats with an MRI-based diagnosis of cerebral cavitary lesions. Animals were included if a complete signalment and an exhaustive MRI of the brain were available. Besides the porencephalic lesions, MRIs of the head were reviewed to detect concomitant musculoskeletal abnormalities. Results: Thirty-two cases involving nine cats and twenty-three dogs were selected. Of all the cases, 21.9% were aged six years or older at the time of diagnosis. All patients in which the neuroanatomical localization was available showed clinical signs of a prosencephalic disorder. Epileptic seizures were observed in 71.8% of cases. A single porencephalic cavity was found in 78.1% of cases. The most affected cerebral lobe was the parietal lobe (n = 20). The defects involved both the grey and white matter in 78.1% of cases. Twenty cases showed concomitant musculoskeletal abnormalities overlying the porencephalic cavities. Fourteen of twenty cases showed evidence of fractures, of which thirteen showed depression of the calvarium and twelve masticatory muscle abnormalities. Of these, seven of fourteen had a history consistent with a head trauma in the first period of life. Conclusion: The recognition of skull fractures and muscular abnormalities closely associated with the porencephalic cavity may support a diagnosis of a postnatal traumatic origin of porencephaly. Therefore, this study highlights the importance of evaluating musculoskeletal structures in the MRIs of the heads of porencephalic cases.

How has the brain disease model of addiction contributed to tobacco control?

Our paper evaluates the extent to which the brain disease model of addiction (BDMA) has contributed to reducing the prevalence of tobacco smoking and  tobacco-related harm over the past 20 years. We discuss the ways in which genetic and neuroscience research on nicotine addiction have contributed to our understanding of tobacco smoking. We then examine the extent to which the BDMA has produced more effective treatments to assist smoking cessation. We also assess the degree to which the BDMA has contributed to the tobacco control policies that have produced substantial reductions in tobacco-related morbidity and mortality in the two decades since the model was first proposed by Alan Leshner. We also assess whether the BDMA has reduced the stigmatisation of people who smoke tobacco.

Site-oriented conjugation of poly(2-methacryloyloxyethyl phosphorylcholine) for enhanced brain delivery of antibody.

Antibody therapeutics are limited in treating brain diseases due to poor blood-brain barrier (BBB) penetration. We have discovered that poly 2-methacryloyloxyethyl phosphorylcholine (PMPC), a biocompatible polymer, effectively facilitates BBB penetration via receptor-mediated transcytosis and have developed a PMPC-shell-based platform for brain delivery of therapeutic antibodies, termed nanocapsule. Yet, the platform results in functional loss of antibodies due to epitope masking by the PMPC polymer network, which necessitates the incorporation of a targeting moiety and degradable crosslinker to enable on-site antibody release. In this study, we developed a novel platform based on site-oriented conjugation of PMPC to the antibody, allowing it to maintain key functionalities of the original antibody. With an optimized PMPC chain length, the PMPC-antibody conjugate exhibited enhanced brain delivery while retaining epitope recognition, cellular internalization, and antibody-dependent cellular phagocytic activity. This simple formula incorporates only the antibody and PMPC without requiring additional components, thereby addressing the issues of the nanocapsule platform and paving the way for PMPC-based brain delivery strategies for antibodies.

Mitochondria and Brain Disease: A Comprehensive Review of Pathological Mechanisms and Therapeutic Opportunities.

Mitochondria play a vital role in maintaining cellular energy homeostasis, regulating apoptosis, and controlling redox signaling. Dysfunction of mitochondria has been implicated in the pathogenesis of various brain diseases, including neurodegenerative disorders, stroke, and psychiatric illnesses. This review paper provides a comprehensive overview of the intricate relationship between mitochondria and brain disease, focusing on the underlying pathological mechanisms and exploring potential therapeutic opportunities. The review covers key topics such as mitochondrial DNA mutations, impaired oxidative phosphorylation, mitochondrial dynamics, calcium dysregulation, and reactive oxygen species generation in the context of brain disease. Additionally, it discusses emerging strategies targeting mitochondrial dysfunction, including mitochondrial protective agents, metabolic modulators, and gene therapy approaches. By critically analysing the existing literature and recent advancements, this review aims to enhance our understanding of the multifaceted role of mitochondria in brain disease and shed light on novel therapeutic interventions.

Update on Nonhuman Primate Models of Brain Disease and Related Research Tools.

The aging of the population is an increasingly serious issue, and many age-related illnesses are on the rise. These illnesses pose a serious threat to the health and safety of elderly individuals and create a serious economic and social burden. Despite substantial research into the pathogenesis of these diseases, their etiology and pathogenesis remain unclear. In recent decades, rodent models have been used in attempts to elucidate these disorders, but such models fail to simulate the full range of symptoms. Nonhuman primates (NHPs) are the most ideal neuroscientific models for studying the human brain and are more functionally similar to humans because of their high genetic similarities and phenotypic characteristics in comparison with humans. Here, we review the literature examining typical NHP brain disease models, focusing on NHP models of common diseases such as dementia, Parkinson's disease, and epilepsy. We also explore the application of electroencephalography (EEG), magnetic resonance imaging (MRI), and optogenetic study methods on NHPs and neural circuits associated with cognitive impairment.

Global trends and hotspots in research on acupuncture for stroke: a bibliometric and visualization analysis.

Acupuncture has been widely used in stroke and post-stroke rehabilitation (PSR), but there is no literature on the bibliometric analysis of acupuncture for stroke. This study aimed to characterize the global publications and analyze the trends of acupuncture for stroke in the past 40 years. We identified 1157 publications from the Web of Science Core Collection. The number of publications grew slowly in the first three decades from 1980 until it started to grow after 2010, with significant growth in 2011-2012 and 2019-2020. China, the USA, and South Korea are the top three countries in this field, and China has formed good internal cooperative relations. Early studies focused on the clinical efficacy of acupuncture for stroke. In the last five years, more emphasis has been placed on the effectiveness of acupuncture in treating sequelae and complications, combined with neuroimaging studies to explore the mechanisms of brain injury repair and neurological recovery. Acupuncture for stroke has a vast research potential, and researchers from different countries/regions and organizations still need to remove academic barriers to enhance communication and collaboration.