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1.
Neurodevelopmental effects of childhood malnutrition: A neuroimaging perspective.
Galler, JR, Bringas-Vega, ML, Tang, Q, Rabinowitz, AG, Musa, KI, Chai, WJ, Omar, H, Abdul Rahman, MR, Abd Hamid, AI, Abdullah, JM, et al
NeuroImage. 2021;:117828
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Abstract
Approximately one in five children worldwide suffers from childhood malnutrition and its complications, including increased susceptibility to inflammation and infectious diseases. Due to improved early interventions, most of these children now survive early malnutrition, even in low-resource settings (LRS). However, many continue to exhibit neurodevelopmental deficits, including low IQ, poor school performance, and behavioral problems over their lifetimes. Most studies have relied on neuropsychological tests, school performance, and mental health and behavioral measures. Few studies, in contrast, have assessed brain structure and function, and to date, these have mainly relied on low-cost techniques, including electroencephalography (EEG) and evoked potentials (ERP). The use of more advanced methods of neuroimaging, including magnetic resonance imaging (MRI) and functional near-infrared spectroscopy (fNIRS), has been limited by cost factors and lack of availability of these technologies in developing countries, where malnutrition is nearly ubiquitous. This report summarizes the current state of knowledge and evidence gaps regarding childhood malnutrition and the study of its impact on neurodevelopment. It may help to inform the development of new strategies to improve the identification, classification, and treatment of neurodevelopmental disabilities in underserved populations at the highest risk for childhood malnutrition.
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Is microvascular dysfunction a systemic disorder with common biomarkers found in the heart, brain, and kidneys? - A scoping review.
Nowroozpoor, A, Gutterman, D, Safdar, B
Microvascular research. 2021;:104123
Abstract
Although microvascular dysfunction (MVD) has been well characterized in individual organs as different disease entities, clinical evidence is mounting in support of an underlying systemic process. To address this hypothesis, we systematically searched PubMed and Medline for studies in adults published between 2014 and 2019 that measured blood biomarkers of MVD in three vital organs i.e. brain, heart, and the kidney. Of the 9706 unique articles 321 met the criteria, reporting 49 biomarkers of which 16 were common to the three organs. Endothelial dysfunction, inflammation including reactive oxidation, immune activation, and coagulation were the commonly recognized pathways. Triglyceride, C-reactive protein, Cystatin C, homocysteine, uric acid, IL-6, NT-proBNP, thrombomodulin, von Willebrand Factor, and uric acid were increased in MVD of all three organs. In contrast, vitamin D was decreased. Adiponectin, asymmetric dimethylarginine, total cholesterol, high-density and low-density cholesterol were found to be variably increased or decreased in studies. We review the pathways underlying MVD in the three organs and summarize evidence supporting its systemic nature. This scoping review informs clinicians and researchers in the multi-system manifestation of MVD. Future work should focus on longitudinal investigations to evaluate the multi-system involvement of this disease.
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Neonatal Hypoglycemia and Brain Vulnerability.
De Angelis, LC, Brigati, G, Polleri, G, Malova, M, Parodi, A, Minghetti, D, Rossi, A, Massirio, P, Traggiai, C, Maghnie, M, et al
Frontiers in endocrinology. 2021;:634305
Abstract
Neonatal hypoglycemia is a common condition. A transient reduction in blood glucose values is part of a transitional metabolic adaptation following birth, which resolves within the first 48 to 72 h of life. In addition, several factors may interfere with glucose homeostasis, especially in case of limited metabolic stores or increased energy expenditure. Although the effect of mild transient asymptomatic hypoglycemia on brain development remains unclear, a correlation between severe and prolonged hypoglycemia and cerebral damage has been proven. A selective vulnerability of some brain regions to hypoglycemia including the second and the third superficial layers of the cerebral cortex, the dentate gyrus, the subiculum, the CA1 regions in the hippocampus, and the caudate-putamen nuclei has been observed. Several mechanisms contribute to neuronal damage during hypoglycemia. Neuronal depolarization induced by hypoglycemia leads to an elevated release of glutamate and aspartate, thus promoting excitotoxicity, and to an increased release of zinc to the extracellular space, causing the extensive activation of poly ADP-ribose polymerase-1 which promotes neuronal death. In this review we discuss the cerebral glucose homeostasis, the mechanisms of brain injury following neonatal hypoglycemia and the possible treatment strategies to reduce its occurrence.
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Gut Microbiota and Neuroplasticity.
Murciano-Brea, J, Garcia-Montes, M, Geuna, S, Herrera-Rincon, C
Cells. 2021;(8)
Abstract
The accumulating evidence linking bacteria in the gut and neurons in the brain (the microbiota-gut-brain axis) has led to a paradigm shift in the neurosciences. Understanding the neurobiological mechanisms supporting the relevance of actions mediated by the gut microbiota for brain physiology and neuronal functioning is a key research area. In this review, we discuss the literature showing how the microbiota is emerging as a key regulator of the brain's function and behavior, as increasing amounts of evidence on the importance of the bidirectional communication between the intestinal bacteria and the brain have accumulated. Based on recent discoveries, we suggest that the interaction between diet and the gut microbiota, which might ultimately affect the brain, represents an unprecedented stimulus for conducting new research that links food and mood. We also review the limited work in the clinical arena to date, and we propose novel approaches for deciphering the gut microbiota-brain axis and, eventually, for manipulating this relationship to boost mental wellness.
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Full-length isoform transcriptome of the developing human brain provides further insights into autism.
Chau, KK, Zhang, P, Urresti, J, Amar, M, Pramod, AB, Chen, J, Thomas, A, Corominas, R, Lin, GN, Iakoucheva, LM
Cell reports. 2021;(9):109631
Abstract
Alternative splicing plays an important role in brain development, but its global contribution to human neurodevelopmental diseases (NDDs) requires further investigation. Here we examine the relationships between splicing isoform expression in the brain and de novo loss-of-function mutations from individuals with NDDs. We analyze the full-length isoform transcriptome of the developing human brain and observe differentially expressed isoforms and isoform co-expression modules undetectable by gene-level analyses. These isoforms are enriched in loss-of-function mutations and microexons, are co-expressed with a unique set of partners, and have higher prenatal expression. We experimentally test the effect of splice-site mutations and demonstrate exon skipping in five NDD risk genes, including SCN2A, DYRK1A, and BTRC. Our results suggest that the splice site mutation in BTRC reduces translational efficiency, likely affecting Wnt signaling through impaired degradation of β-catenin. We propose that functional effects of mutations should be investigated at the isoform- rather than gene-level resolution.
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Does Dysbiosis Increase the Risk of Developing Schizophrenia? - A Comprehensive Narrative Review.
Novais, F, Capela, J, Machado, S, Murillo-Rodriguez, E, Telles-Correia, D
Current topics in medicinal chemistry. 2021;(11):976-984
Abstract
BACKGROUND There is increasing evidence regarding the influence of the intestinal microbiota on the disease processes of various organs and systems. Dysbiosis, that is, alteration of the composition and function of the microbiota may constitute an important risk factor for the development of mental disorders, namely, schizophrenia. OBJECTIVE This works aims to review current evidence regarding the pathological mechanisms leading from dysbiosis to schizophrenia and in particular the deficit syndrome in schizophrenia. METHODS Scientific articles from PubMed, SCOPUS, EMBASE, and Web of Science Core Collection published between September 2017 and December 2020 were included in this review. RESULTS The commensal intestinal flora plays an important role in neurodevelopment. In the presence of dysbiosis, this maturation gets disturbed, resulting in the modification of brain structures and inflammatory responses at the intestinal, systemic, and Central Nervous System (CNS) levels. These disturbances may be linked to the development of symptoms of the disease. The microbiota exerts its influence on the CNS through several pathways, however, in this paper we focused on the membrane hypothesis and the inflammatory hypothesis. We explored the evidence concerning the use of probiotics, prebiotics, and fecal transplants. CONCLUSION Although there is no consensus regarding the alterations that could constitute a risk factor for schizophrenia, some of the species appear to be more frequently altered, and their relationship with the host is dysregulated in patients at risk and with established schizophrenia, particularly in deficit schizophrenia.
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Gut-brain axis: A matter of concern in neuropsychiatric disorders…!
Naveed, M, Zhou, QG, Xu, C, Taleb, A, Meng, F, Ahmed, B, Zhang, Y, Fukunaga, K, Han, F
Progress in neuro-psychopharmacology & biological psychiatry. 2021;:110051
Abstract
The gut microbiota is composed of a large number of microbes, usually regarded as commensal bacteria. It has become gradually clear that gastrointestinal microbiota affects gut pathophysiology and the central nervous system (CNS) function by modulating the signaling pathways of the microbiota-gut-brain (MGB) axis. This bidirectional MGB axis communication primarily acts through neuroendocrine, neuroimmune, and autonomic nervous systems (ANS) mechanisms. Accumulating evidence reveals that gut microbiota interacts with the host brain, and its modulation may play a critical role in the pathology of neuropsychiatric disorders. Recently, neuroscience research has established the significance of gut microbiota in the development of brain systems that are essential to stress-related behaviors, including depression and anxiety. Application of modulators of the MGB, such as psychobiotics (e.g., probiotics), prebiotics, and specific diets, may be a promising therapeutic approach for neuropsychiatric disorders. The present review article primarily focuses on the relevant features of the disturbances of the MGB axis in the pathophysiology of neuropsychiatric disorders and its potential mechanisms.
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Emerging roles of oxidative stress in brain aging and Alzheimer's disease.
Ionescu-Tucker, A, Cotman, CW
Neurobiology of aging. 2021;:86-95
Abstract
Reactive oxygen species (ROS) are metabolic byproducts that are necessary for physiological function but can be toxic at high levels. Levels of these oxidative stressors increase gradually throughout the lifespan, impairing mitochondrial function and damaging all parts of the body, particularly the central nervous system. Emerging evidence suggests that accumulated oxidative stress may be one of the key mechanisms causing cognitive aging and neurodegenerative diseases such as Alzheimer's disease (AD). Here, we synthesize the current literature on the effect of neuronal oxidative stress on mitochondrial dysfunction, DNA damage and epigenetic changes related to cognitive aging and AD. We further describe how oxidative stress therapeutics such as antioxidants, caloric restriction and physical activity can reduce oxidation and prevent cognitive decline in brain aging and AD. Of the currently available therapeutics, we propose that long term physical activity is the most promising avenue for improving cognitive health by reducing ROS while promoting the low levels required for optimal function.
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Going with the grain: Fiber, cognition, and the microbiota-gut-brain-axis.
Berding, K, Carbia, C, Cryan, JF
Experimental biology and medicine (Maywood, N.J.). 2021;(7):796-811
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Abstract
Healthy dietary intake has been acknowledged for decades as one of the main contributors to health. More recently, the field of nutritional psychiatry has progressed our understanding regarding the importance of nutrition in supporting mental health and cognitive function. Thereby, individual nutrients, including omega-3 fatty acids and polyphenols, have been recognized to be key drivers in this relationship. With the progress in appreciating the influence of dietary fiber on health, increasingly research is focusing on deciphering its role in brain processes. However, while the importance of dietary fiber in gastrointestinal and metabolic health is well established, leading to the development of associated health claims, the evidence is not conclusive enough to support similar claims regarding cognitive function. Albeit the increasing knowledge of the impact of dietary fiber on mental health, only a few human studies have begun to shed light onto the underexplored connection between dietary fiber and cognition. Moreover, the microbiota-gut-brain axis has emerged as a key conduit for the effects of nutrition on the brain, especially fibers, that are acted on by specific bacteria to produce a variety of health-promoting metabolites. These metabolites (including short chain fatty acids) as well as the vagus nerve, the immune system, gut hormones, or the kynurenine pathway have been proposed as underlying mechanisms of the microbiota-brain crosstalk. In this minireview, we summarize the evidence available from human studies on the association between dietary fiber intake and cognitive function. We provide an overview of potential underlying mechanisms and discuss remaining questions that need to be answered in future studies. While this field is moving at a fast pace and holds promise for future important discoveries, especially data from human cohorts are required to further our understanding and drive the development of public health recommendations regarding dietary fiber in brain health.
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Altered functional network activities for behavioral adjustments and Bayesian learning in young men with Internet gaming disorder.
Ma, SS, Li, CR, Zhang, S, Worhunsky, PD, Zhou, N, Zhang, JT, Liu, L, Yao, YW, Fang, XY
Journal of behavioral addictions. 2021;(1):112-122
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Abstract
BACKGROUND AND AIMS Deficits in cognitive control represent a core feature of addiction. Internet Gaming Disorder (IGD) offers an ideal model to study the mechanisms underlying cognitive control deficits in addiction, eliminating the confounding effects of substance use. Studies have reported behavioral and neural deficits in reactive control in IGD, but it remains unclear whether individuals with IGD are compromised in proactive control or behavioral adjustment by learning from the changing contexts. METHODS Here, fMRI data of 21 male young adults with IGD and 21 matched healthy controls (HC) were collected during a stop-signal task. We employed group independent component analysis to investigate group differences in temporally coherent, large-scale functional network activities during post-error slowing, the typical type of behavioral adjustments. We also employed a Bayesian belief model to quantify the trial-by-trial learning of the likelihood of stop signal - P(Stop) - a broader process underlying behavioral adjustment, and identified the alterations in functional network responses to P(Stop). RESULTS The results showed diminished engagement of the fronto-parietal network during post-error slowing, and weaker activity in the ventral attention and anterior default mode network in response to P(Stop) in IGD relative to HC. DISCUSSION AND CONCLUSIONS These results add to the literatures by suggesting deficits in updating and anticipating conflicts as well as in behavioral adjustment according to contextual information in individuals with IGD.