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Current Opinion in Neurobiology Oct 2021Redundancy is a ubiquitous property of the nervous system. This means that vastly different configurations of cellular and synaptic components can enable the same neural... (Review)
Review
Redundancy is a ubiquitous property of the nervous system. This means that vastly different configurations of cellular and synaptic components can enable the same neural circuit functions. However, until recently, very little brain disorder research has considered the implications of this characteristic when designing experiments or interpreting data. Here, we first summarise the evidence for redundancy in healthy brains, explaining redundancy and three related sub-concepts: sloppiness, dependencies and multiple solutions. We then lay out key implications for brain disorder research, covering recent examples of redundancy effects in experimental studies on psychiatric disorders. Finally, we give predictions for future experiments based on these concepts.
Topics: Brain; Brain Diseases; Humans; Mental Disorders
PubMed: 34416675
DOI: 10.1016/j.conb.2021.07.008 -
Experimental & Molecular Medicine Jun 2016Mutations occur during cell division in all somatic lineages. Because neurogenesis persists throughout human life, somatic mutations in the brain arise during... (Review)
Review
Mutations occur during cell division in all somatic lineages. Because neurogenesis persists throughout human life, somatic mutations in the brain arise during development and accumulate with the aging process. The human brain consists of 100 billion neurons that form an extraordinarily intricate network of connections to achieve higher level cognitive functions. Due to this network architecture, perturbed neuronal functions are rarely restricted to a focal area; instead, they are often spread via the neuronal network to affect other connected areas. Although somatic diversity is an evident feature of the brain, the extent to which somatic mutations affect the neuronal structure and function and their contribution to neurological disorders associated with disrupted brain connectivity remain largely unexplored. Notably, recent reports indicate that brain somatic mutations can indeed play a critical role that leads to the structural and functional abnormalities of the brain observed in several neurodevelopmental disorders. Here, I review the extent and significance of brain somatic mutations and provide my perspective regarding these mutations as potential molecular lesions underlying relatively common conditions with disrupted brain connectivity. Moreover, I discuss emerging technical platforms that will facilitate the detection of low-frequency somatic mutations and validate the biological functions of the identified mutations in the context of brain connectivity.
Topics: Alzheimer Disease; Animals; Autistic Disorder; Brain; Brain Diseases; Depressive Disorder, Major; Epilepsy; Gene Frequency; Humans; Mutation; Nerve Net; Neurogenesis; Neurons
PubMed: 27282107
DOI: 10.1038/emm.2016.53 -
Genome Apr 2021The gut-brain axis (GBA) is a biochemical link that connects the central nervous system (CNS) and enteric nervous system (ENS). Clinical and experimental evidence... (Review)
Review
The gut-brain axis (GBA) is a biochemical link that connects the central nervous system (CNS) and enteric nervous system (ENS). Clinical and experimental evidence suggests gut microbiota as a key regulator of the GBA. Microbes living in the gut not only interact locally with intestinal cells and the ENS but have also been found to modulate the CNS through neuroendocrine and metabolic pathways. Studies have also explored the involvement of gut microbiota dysbiosis in depression, anxiety, autism, stroke, and pathophysiology of other neurodegenerative diseases. Recent reports suggest that microbe-derived metabolites can influence host metabolism by acting as epigenetic regulators. Butyrate, an intestinal bacterial metabolite, is a known histone deacetylase inhibitor that has shown to improve learning and memory in animal models. Due to high disease variability amongst the population, a multi-omics approach that utilizes artificial intelligence and machine learning to analyze and integrate omics data is necessary to better understand the role of the GBA in pathogenesis of neurological disorders, to generate predictive models, and to develop precise and personalized therapeutics. This review examines our current understanding of epigenetic regulation of the GBA and proposes a framework to integrate multi-omics data for prediction, prevention, and development of precision health approaches to treat brain disorders.
Topics: Animals; Artificial Intelligence; Bacteria; Brain; Brain Diseases; Data Analysis; Dysbiosis; Epigenesis, Genetic; Fatty Acids, Volatile; Gastrointestinal Microbiome; Humans; Machine Learning
PubMed: 33031715
DOI: 10.1139/gen-2020-0136 -
BMJ Case Reports Apr 2013A 48-year-old man presented with long-standing symptoms of major depression in the absence of markedly abnormal neurological findings or structural brain alterations....
A 48-year-old man presented with long-standing symptoms of major depression in the absence of markedly abnormal neurological findings or structural brain alterations. Antidepressive treatment, including medication and psychotherapy, had not led to significant improvement. The EEG, cerebrospinal fluid (CSF) analysis, fluorodeoxyglucose-positron emission tomography and neuropsychological testing showed pathological findings. An epileptic state provided further evidence for an organic encephalopathy. Extensively elevated thyroid-antibodies in the serum and CSF, as well as the rapid and sustained recovery after intravenous treatment with prednisolone, pointed to the diagnosis of a primarily psychiatric manifestation of a steroid responsive encephalopathy associated with autoimmune thyroiditis (SREAT).
Topics: Brain Diseases; Depressive Disorder, Major; Diagnosis, Differential; Electroencephalography; Encephalitis; Glucocorticoids; Hashimoto Disease; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Neuropsychological Tests; Positron-Emission Tomography; Prednisolone
PubMed: 23605832
DOI: 10.1136/bcr-2013-009101 -
Neuroscience Bulletin Apr 2019Investigating the pathophysiological mechanisms underlying brain disorders is a priority if novel therapeutic strategies are to be developed. In vivo studies of animal... (Review)
Review
Investigating the pathophysiological mechanisms underlying brain disorders is a priority if novel therapeutic strategies are to be developed. In vivo studies of animal models and in vitro studies of cell lines/primary cell cultures may provide useful tools to study certain aspects of brain disorders. However, discrepancies among these studies or unsuccessful translation from animal/cell studies to human/clinical studies often occur, because these models generally represent only some symptoms of a neuropsychiatric disorder rather than the complete disorder. Human brain slice cultures from postmortem tissue or resected tissue from operations have shown that, in vitro, neurons and glia can stay alive for long periods of time, while their morphological and physiological characteristics, and their ability to respond to experimental manipulations are maintained. Human brain slices can thus provide a close representation of neuronal networks in vivo, be a valuable tool for investigation of the basis of neuropsychiatric disorders, and provide a platform for the evaluation of novel pharmacological treatments of human brain diseases. A brain bank needs to provide the necessary infrastructure to bring together donors, hospitals, and researchers who want to investigate human brain slices in cultures of clinically and neuropathologically well-documented material.
Topics: Brain; Brain Diseases; Humans; Tissue Culture Techniques
PubMed: 30604279
DOI: 10.1007/s12264-018-0328-1 -
Journal of Nuclear Medicine : Official... Apr 2001Structural and functional images of the brain play an important role as powerful adjuncts in the management of an increasing number of neurologic and psychiatric... (Review)
Review
Structural and functional images of the brain play an important role as powerful adjuncts in the management of an increasing number of neurologic and psychiatric diseases. Brain SPECT, in particular, with perfusion agents or with neuroreceptor imaging radiopharmaceuticals, is rapidly becoming a clinical tool in many places. For many neurologic and psychiatric conditions, this imaging modality has been used in diagnosis, prognosis assessment, evaluation of response to therapy, risk stratification, detection of benign or malignant viable tissue, and choice of medical or surgical therapy. The importance of this technique in nuclear medicine today should not be overlooked, particularly in cerebrovascular diseases, dementias, epilepsy, head injury, malignant brain tumors, movement disorders, obsessive-compulsive disorder, Gilles de la Tourette's syndrome, schizophrenia, depression, panic disorder, and drug abuse.
Topics: Brain; Brain Diseases; Brain Injuries; Cerebrovascular Disorders; Dementia; Epilepsy; Humans; Mental Disorders; Tomography, Emission-Computed, Single-Photon
PubMed: 11337551
DOI: No ID Found -
Cold Spring Harbor Perspectives in... Nov 2015Common somatic conditions are bound to occur by chance in individuals with neurological disorders as prevalent as epilepsy, but when biological links underlying the... (Review)
Review
Common somatic conditions are bound to occur by chance in individuals with neurological disorders as prevalent as epilepsy, but when biological links underlying the comorbidity can be uncovered, the relationship may provide clues into the origin and mechanisms of both. The expanding list of monogenic epilepsies and their associated clinical features offer a remarkable opportunity to mine the epilepsy genome for coordinate neurodevelopmental phenotypes and examine their pathogenic mechanisms. Defined single-gene-linked epilepsy syndromes identified to date include all of the most frequently cited comorbidities, such as cognitive disorders, autism, migraine, mood disorders, late-onset dementia, and even premature lethality. Gene-linked comorbidities may be aggravated by, or independent of, seizure history. Mutations in these genes establish clear biological links between abnormal neuronal synchronization and a variety of neurobehavioral disorders, and critically substantiate the definition of epilepsy as a complex spectrum disorder. Mapping the neural circuitry of epilepsy comorbidities and understanding their single-gene risk should substantially clarify this challenging aspect of clinical epilepsy management.
Topics: Alzheimer Disease; Autistic Disorder; Brain Diseases; Cognition Disorders; Comorbidity; Depression; Epilepsy; Genes; Genetic Predisposition to Disease; Humans
PubMed: 26525453
DOI: 10.1101/cshperspect.a022756 -
Neuroscience and Biobehavioral Reviews Dec 2013It has been widely accepted that the younger the age and/or immaturity of the organism, the greater the brain plasticity, the young age plasticity privilege. This paper... (Review)
Review
It has been widely accepted that the younger the age and/or immaturity of the organism, the greater the brain plasticity, the young age plasticity privilege. This paper examines the relation of a young age to plasticity, reviewing human pediatric brain disorders, as well as selected animal models, human developmental and adult brain disorder studies. As well, we review developmental and childhood acquired disorders that involve a failure of regulatory homeostasis. Our core arguments are as follows:
Topics: Aging; Brain Diseases; Child; Homeostasis; Humans; Neuronal Plasticity
PubMed: 24096190
DOI: 10.1016/j.neubiorev.2013.09.010 -
Journal of Neurology, Neurosurgery, and... Jun 1973This is the second reported case, known to the authors, of complete, but selective, limbic lobe destruction in previously normally functioning central nervous systems....
This is the second reported case, known to the authors, of complete, but selective, limbic lobe destruction in previously normally functioning central nervous systems. Both cases had an amnestic syndrome, whose characteristics were essentially similar to amnestic syndromes previously documented with less complete limbic destruction, with one difference-confabulation remained a prominent feature in the chronic stages of the memory disorder. Our patient exhibited a behavioural syndrome similar to that reported by Klüver and Bucy in monkeys with bilateral anterior temporal lobectomies. Klüver-Bucy like syndromes in man have usually been reported with surgical lesions, usually in patients with pre-existent brain disorder. Our case illustrates that the syndrome can be produced by necrotizing encephalitic lesions. We suggest that the combination of the above two syndromes is essentially a `limbic dementia'.
Topics: Adult; Amnesia; Brain Diseases; Dementia; Electroencephalography; Female; Gyrus Cinguli; Hippocampus; Hodgkin Disease; Humans; Limbic System; Thalamus; Verbal Behavior
PubMed: 4714104
DOI: 10.1136/jnnp.36.3.421 -
Neurologia Medico-chirurgica 2015The use of electrical stimulation to treat pain in human disease dates back to ancient Rome or Greece. Modern deep brain stimulation (DBS) was initially applied for pain... (Review)
Review
The use of electrical stimulation to treat pain in human disease dates back to ancient Rome or Greece. Modern deep brain stimulation (DBS) was initially applied for pain treatment in the 1960s, and was later used to treat movement disorders in the 1990s. After recognition of DBS as a therapy for central nervous system (CNS) circuit disorders, DBS use showed drastic increase in terms of adaptability to disease and the patient's population. More than 100,000 patients have received DBS therapy worldwide. The established indications for DBS are Parkinson's disease, tremor, and dystonia, whereas global indications of DBS expanded to other neuronal diseases or disorders such as neuropathic pain, epilepsy, and tinnitus. DBS is also experimentally used to manage cognitive disorders and psychiatric diseases such as major depression, obsessive-compulsive disorder (OCD), Tourette's syndrome, and eating disorders. The importance of ethics and conflicts surrounding the regulation and freedom of choice associated with the application of DBS therapy for new diseases or disorders is increasing. These debates are centered on the use of DBS to treat new diseases and disorders as well as its potential to enhance ability in normal healthy individuals. Here we present three issues that need to be addressed in the future: (1) elucidation of the mechanisms of DBS, (2) development of new DBS methods, and (3) miniaturization of the DBS system. With the use of DBS, functional neurosurgery entered into the new era that man can manage and control the brain circuit to treat intractable neuronal diseases and disorders.
Topics: Animals; Brain Diseases; Decision Making; Deep Brain Stimulation; Epilepsy; Humans; Neurosurgical Procedures
PubMed: 25925757
DOI: 10.2176/nmc.ra.2014-0394