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\"In 1934 Wilder Penfield's vision of an establishment dedicated to the relief of sickness and pain and the study of neurology lead to the creation of the Montreal Neurological Institute. Setting the standard for neurological research and care for patients disabled by neurological illnesses, Penfield's institute became a beacon of light in a largely unexplored field of medicine. The Wounded Brain Healed describes the pioneering research that took place during the MNI's first fifty years. During the institute's golden age, Penfield and his colleagues designed the EEG test for the study of epileptic patients, discovered some of the causes of epilepsy, and developed new treatments that have since been adopted worldwide. Additionally, they delineated the sensory and motor representation in the cerebral cortex and localized the major areas of the brain related to speech. The institute also boasts the discoveries of two types of memory--one serving immediate recall, the other long term--as well as the discovery of the localization of short-term memory to the inner structures of the temporal lobe. Physicians and scientists who trained at the MNI went on to establish renowned neurology and neurosurgery departments throughout Canada, the United States, Europe, Asia, and Latin America. Recounting the story of one of Canada's greatest contributions to international medical science through archival research, personal interviews, photographs, illustrations, and paintings, The Wounded Brain Healed provides fascinating insight into the institution that had a global and lasting impact.\"-- Provided by publisher.

Respiratory viruses infect the human upper respiratory tract, mostly causing mild diseases. However, in vulnerable populations, such as newborns, infants, the elderly and immune-compromised individuals, these opportunistic pathogens can also affect the lower respiratory tract, causing a more severe disease (e.g., pneumonia). Respiratory viruses can also exacerbate asthma and lead to various types of respiratory distress syndromes. Furthermore, as they can adapt fast and cross the species barrier, some of these pathogens, like influenza A and SARS-CoV, have occasionally caused epidemics or pandemics, and were associated with more serious clinical diseases and even mortality. For a few decades now, data reported in the scientific literature has also demonstrated that several respiratory viruses have neuroinvasive capacities, since they can spread from the respiratory tract to the central nervous system (CNS). Viruses infecting human CNS cells could then cause different types of encephalopathy, including encephalitis, and long-term neurological diseases. Like other well-recognized neuroinvasive human viruses, respiratory viruses may damage the CNS as a result of misdirected host immune responses that could be associated with autoimmunity in susceptible individuals (virus-induced neuro-immunopathology) and/or viral replication, which directly causes damage to CNS cells (virus-induced neuropathology). The etiological agent of several neurological disorders remains unidentified. Opportunistic human respiratory pathogens could be associated with the triggering or the exacerbation of these disorders whose etiology remains poorly understood. Herein, we present a global portrait of some of the most prevalent or emerging human respiratory viruses that have been associated with possible pathogenic processes in CNS infection, with a special emphasis on human coronaviruses.

Genome-wide association studies have discovered hundreds of loci associated with complex brain disorders, but it remains unclear in which cell types these loci are active. Here we integrate genome-wide association study results with single-cell transcriptomic data from the entire mouse nervous system to systematically identify cell types underlying brain complex traits. We show that psychiatric disorders are predominantly associated with projecting excitatory and inhibitory neurons. Neurological diseases were associated with different cell types, which is consistent with other lines of evidence. Notably, Parkinson’s disease was genetically associated not only with cholinergic and monoaminergic neurons (which include dopaminergic neurons) but also with enteric neurons and oligodendrocytes. Using post-mortem brain transcriptomic data, we confirmed alterations in these cells, even at the earliest stages of disease progression. Our study provides an important framework for understanding the cellular basis of complex brain maladies, and reveals an unexpected role of oligodendrocytes in Parkinson’s disease. Integration of GWAS and single-cell transcriptomic data from the entire nervous system systematically identifies cell types underlying brain complex traits and provides insights into the etiology of Parkinson’s disease.

Bisphenol A (BPA) is an endocrine-disrupting chemical (EDC) and one of the most produced synthetic compounds worldwide. BPA can be found in epoxy resins and polycarbonate plastics, which are frequently used in food storage and baby bottles. However, BPA can bind mainly to estrogen receptors, interfering with various neurologic functions, its use is a topic of significant concern. Nonetheless, the neurotoxicity of BPA has not been fully understood despite numerous investigations on its disruptive effects. Therefore, this review aims to highlight the most recent studies on the implications of BPA on the neurologic system. Our findings suggest that BPA exposure impairs various structural and molecular brain changes, promoting oxidative stress, changing expression levels of several crucial genes and proteins, destructive effects on neurotransmitters, excitotoxicity and neuroinflammation, damaged blood–brain barrier function, neuronal damage, apoptosis effects, disruption of intracellular Ca2+ homeostasis, increase in reactive oxygen species, promoted apoptosis and intracellular lactate dehydrogenase release, a decrease of axon length, microglial DNA damage, astrogliosis, and significantly reduced myelination. Moreover, BPA exposure increases the risk of developing neurologic diseases, including neurovascular (e.g. stroke) and neurodegenerative (e.g. Alzheimer’s and Parkinson’s) diseases. Furthermore, epidemiological studies showed that the adverse effects of BPA on neurodevelopment in children contributed to the emergence of serious neurological diseases like attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), depression, emotional problems, anxiety, and cognitive disorders. In summary, BPA exposure compromises human health, promoting the development and progression of neurologic disorders. More research is required to fully understand how BPA-induced neurotoxicity affects human health.

Ginseng has been used in China as a superior medicinal material for thousands of years that can nourish the five internal organs, calm the mind and benefit wisdom. Due to its anti-inflammatory, antioxidant and neuroprotective activities, one of the active components of ginseng, ginsenoside Rg1, has been extensively investigated in the remedy of brain disorders, especially dementia and depression. In this review, we summarized the research progress on the action mechanisms of Rg1 ameliorating depression-like behaviors, including inhibition of hyperfunction of hypothalamic-pituitary-adrenal (HPA) axis, regulation of synaptic plasticity and gut flora. Rg1 may alleviate Alzheimer’s disease in the early phase, as well as in the middle-late phases through repairing dendrite, axon and microglia- and astrocyte-related inflammations. We also proposed that Rg1 could regulate memory state (the imbalance of working and aversive memory) caused by distinct stimuli. These laboratory studies would further the clinical trials on Rg1. From the prospective of drug development, we discussed the limitations of the present investigations and proposed our ideas to increase permeability and bioavailability of Rg1. Taken together, Rg1 has the potential to treat neuropsychiatric disorders, but a future in-depth investigation of the mechanisms is still required. In addition, drug development will benefit from the clinical trials in one specific neuropsychiatric disorder.

Background Rare and severe neurological disorders in childhood not only heavily affect the life perspective of the patients, but also their caregivers and families. The aim of this study was to investigate the impact of such diseases on the family, especially on the quality of life and life perspectives of parents, but also on the families’ everyday life, based on the model of two diseases which have been well described in recent years with respect to symptoms and course: metachromatic leukodystrophy (MLD) and pontocerebellar hypoplasia type 2 (PCH2). PCH2 is a primary severe developmental disorder, while children with MLD initially develop normally and then progressively deteriorate. Methods Using a semi-standardized questionnaire, 43 families with children suffering from MLD (n = 30) or PCH2 (n = 19) reported data on the severity of the illness/symptoms, on family support and the care situation, as well as on the circumstances of non-affected siblings and the parents’ work situation. In addition, the quality of life of parents and general family functioning was assessed using the PedsQL™ Family Impact Module [23]. Results for the latter were compared to published data from families with children without any chronic condition using student’s t-tests for independent samples. Potential factors influencing the PedsQL™ scores were analyzed using Spearman’s rank correlation. Results Parents of children with MLD and PCH2 reported significantly lower health-related quality of life (HRQOL) compared to parents of healthy children ( P  < 0.001). Mothers showed significantly poorer HRQOL ( P  < 0.05) and were significantly more dissatisfied with their professional development ( P  < 0.05) than fathers, and this was seen in relation to their child's disease. Neither the form of disease (‘primary’ symptomatic PCH2 or ‘secondary’ symptomatic MLD), nor the severity of the child’s illness (in terms of gross motor and speech function) had a specific impact on HRQOL in families. However, the time from diagnosis and advanced symptoms in the terminal disease stage were experienced as especially distressing. Conclusions This study illustrates that MLD and PCH2 affect mothers in particular, but also the entire family. This underlines the need for personalized care and counselling of parents and families, especially following diagnosis and during the end stage in a child with a severe, rare chronic neurological disorder.

Studies suggest that gut dysbiosis occurs in autoimmune neurological diseases, but a comprehensive synthesis of the evidence is lacking. Our aim was to systematically review and meta-analyze the correlation between the gut microbiota and autoimmune neurological disorders to inform clinical diagnosis and therapeutic intervention. We searched the databases of PubMed, Embase, Web of Science, and the Cochrane Library until 1 March 2024 for research on the correlation between gut microbiota and autoimmune neurological disorders. A total of 62 studies provided data and were included in the analysis ( n  = 3,126 patients, n  = 2,843 healthy individuals). Among the included studies, 42 studies provided data on α-diversity. Regarding α-diversity, except for Chao1, which showed a consistent small decrease (SMD = −0.26, 95% CI = −0.45 to −0.07, p < 0.01), other indices demonstrated no significant changes. While most studies reported significant differences in β-diversity, consistent differences were only observed in neuromyelitis optica spectrum disorders. A decrease in short-chain fatty acid (SCFA)-producing bacteria, including Faecalibacterium and Roseburia , was observed in individuals with autoimmune encephalitis, neuromyelitis optica spectrum disorders, myasthenia gravis, and multiple sclerosis. Conversely, an increase in pathogenic or opportunistic pathogens, including Streptococcus and Escherichia-Shigella , was observed in these patients. Subgroup analyses assessed the confounding effects of geography and immunotherapy use. These findings suggest that disturbances of the gut flora are associated with autoimmune neurological diseases, primarily manifesting as non-specific and shared microbial alterations, including a reduction in SCFA-producing bacteria and an increase in pathogenic or opportunistic pathogens.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42023410215.

Background The elucidation of pathomechanisms leading to the manifestation of rare (genetically caused) neurological diseases including neuromuscular diseases (NMD) represents an important step toward the understanding of the genesis of the respective disease and might help to define starting points for (new) therapeutic intervention concepts. However, these “discovery studies” are often limited by the availability of human biomaterial. Moreover, given that results of next-generation-sequencing approaches frequently result in the identification of ambiguous variants, testing of their pathogenicity is crucial but also depending on patient-derived material. Methods Human skin fibroblasts were used to generate a spectral library using pH8-fractionation of followed by nano LC-MS/MS. Afterwards, Allgrove-patient derived fibroblasts were subjected to a data independent acquisition approach. In addition, proteomic signature of an enriched nuclear protein fraction was studied. Proteomic findings were confirmed by immunofluorescence in a muscle biopsy derived from the same patient and cellular lipid homeostasis in the cause of Allgrove syndrome was analysed by fluorescence (BODIPY-staining) and coherent anti-Stokes Raman scattering (CARS) microscopy. Results To systematically address the question if human skin fibroblasts might serve as valuable biomaterial for (molecular) studies of NMD, we generated a protein library cataloguing 8280 proteins including a variety of such linked to genetic forms of motoneuron diseases, congenital myasthenic syndromes, neuropathies and muscle disorders. In silico-based pathway analyses revealed expression of a diversity of proteins involved in muscle contraction and such decisive for neuronal function and maintenance suggesting the suitability of human skin fibroblasts to study the etiology of NMD. Based on these findings, next we aimed to further demonstrate the suitability of this in vitro model to study NMD by a use case: the proteomic signature of fibroblasts derived from an Allgrove-patient was studied. Dysregulation of paradigmatic proteins could be confirmed in muscle biopsy of the patient and protein-functions could be linked to neurological symptoms known for this disease. Moreover, proteomic investigation of nuclear protein composition allowed the identification of protein-dysregulations according with structural perturbations observed in the muscle biopsy. BODIPY-staining on fibroblasts and CARS microscopy on muscle biopsy suggest altered lipid storage as part of the underlying disease etiology. Conclusions Our combined data reveal that human fibroblasts may serve as an in vitro system to study the molecular etiology of rare neurological diseases exemplified on Allgrove syndrome in an unbiased fashion.

Cerebral organoids are three‐dimensional (3D) aggregates with a more advanced composition, maturation, and architecture. It has emerged as a novel and sophisticated model system for studying neurodevelopment and neurological disorders, in comparison to conventional two‐dimensional (2D) cell cultures. However, due to the extraordinarily complex nature of brain development, current cerebral organoids are not as functional and mature as brains. The development of cerebral organoids requires a culture system with sufficient developmental patterning factors, essential cell components, and vasculature. In this review, the critical factors and events that contribute to the development of cerebral organoids are focused on. The advanced design, fabrication techniques, and technologies are also discussed to enhance the application potential of cerebral organoid technology. Cerebral organoids are derived from pluripotent stem cells (PSCs) using bioactive factors and a suitable microenvironment. These organoids have been extensively employed in the development of brain disease mechanisms, models, and treatments. The development and clinical translation of cerebral organoids will be facilitated by novel design, cutting‐edge fabrication techniques, and advanced technologies.

Enterovirus 71 (EV-A71) is one of the major causative agents of hand, foot, and mouth disease. EV-A71 infection is sometimes associated with severe neurological diseases such as acute encephalitis, acute flaccid paralysis, and cardiopulmonary failure. Therefore, EV-A71 is a serious public health concern. Scavenger receptor class B, member 2 (SCARB2) is a type III transmembrane protein that belongs to the CD36 family and is a major receptor for EV-A71. SCARB2 supports attachment and internalization of the virus and initiates conformational changes that lead to uncoating of viral RNA in the cytoplasm. The three-dimensional structure of the virus-receptor complex was elucidated by cryo-electron microscopy. Two α-helices in the head domain of SCARB2 bind to the G-H loop of VP1 and the E-F loop of VP2 capsid proteins of EV-A71. Uncoating takes place in a SCARB2- and low pH-dependent manner. In addition to SCARB2, other molecules support cell surface binding of EV-A71. Heparan sulfate proteoglycans, P-selectin glycoprotein ligand-1, sialylated glycan, annexin II, vimentin, fibronectin, and prohibitin enhance viral infection by retaining the virus on the cell surface. These molecules are known as “attachment receptors” because they cannot initiate uncoating. In vivo, SCARB2 expression was observed in EV-A71 antigen-positive neurons and epithelial cells in the crypts of the palatine tonsils in patients that died of EV-A71 infection. Adult mice are not susceptible to infection by EV-A71, but transgenic mice that express human SCARB2 become susceptible to EV-A71 infection and develop neurological diseases similar to those observed in humans. Attachment receptors may also be involved in EV-A71 infection in vivo. Although heparan sulfate proteoglycans are expressed by many cultured cell lines and enhance infection by a subset of EV-A71 strains, they are not expressed by cells that express SCARB2 at high levels in vivo. Thus, heparan sulfate-positive cells merely adsorb the virus and do not contribute to replication or dissemination of the virus in vivo. In addition to these attachment receptors, cyclophilin A and human tryptophanyl aminoacyl-tRNA synthetase act as an uncoating regulator and an entry mediator that can confer susceptibility to non-susceptibile cells in the absence of SCARB2, respectively. The roles of attachment receptors and other molecules in EV-A71 pathogenesis remain to be elucidated.