Differences in Relative Levels of 88 microRNAs in Various Regions of the Normal Adult Human Brain.

PubMed

Filatova, Elena V; Alieva, Anelya; Shadrina, Maria I; Slominsky, Petr A

2017-08-16

Since the discovery of microRNAs (miRNAs) in the 1990s, our knowledge about their biology has grown considerably. The increasing number of studies addressing the role of miRNAs in development and in various diseases emphasizes the need for a comprehensive catalogue of accurate sequence, expression and conservation information regarding the large number of miRNAs proposed recently in all organs and tissues. The objective of this study was to provide data on the levels of miRNA expression in 15 tissues of the normal human brain. We conducted an analysis of the relative levels of 88 of the most abundantly expressed and best characterized miRNA derived postmortem from well-characterized samples of various regions of the brains from five normal individuals. The cluster analysis revealed some differences in the relative levels of these miRNAs among the brain regions studied. Such diversity can be explained by different functioning of these brain regions. We hope that the data from the current study are a resource that will be useful to our colleagues in this exciting field, as more hypotheses will be generated and tested with regard to small noncoding RNA in the human brain in healthy and disease states. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Common Genetic Variant in VIT Is Associated with Human Brain Asymmetry.

PubMed

Tadayon, Sayed H; Vaziri-Pashkam, Maryam; Kahali, Pegah; Ansari Dezfouli, Mitra; Abbassian, Abdolhossein

2016-01-01

Brain asymmetry varies across individuals. However, genetic factors contributing to this normal variation are largely unknown. Here we studied variation of cortical surface area asymmetry in a large sample of subjects. We performed principal component analysis (PCA) to capture correlated asymmetry variation across cortical regions. We found that caudal and rostral anterior cingulate together account for a substantial part of asymmetry variation among individuals. To find SNPs associated with this subset of brain asymmetry variation we performed a genome-wide association study followed by replication in an independent cohort. We identified one SNP (rs11691187) that had genome-wide significant association (P Combined = 2.40e-08). The rs11691187 is in the first intron of VIT. In a follow-up analysis, we found that VIT gene expression is associated with brain asymmetry in six donors of the Allen Human Brain Atlas. Based on these findings we suggest that VIT contributes to normal brain asymmetry variation. Our results can shed light on disorders associated with altered brain asymmetry.

Uniform distributions of glucose oxidation and oxygen extraction in gray matter of normal human brain: No evidence of regional differences of aerobic glycolysis.

PubMed

Hyder, Fahmeed; Herman, Peter; Bailey, Christopher J; Møller, Arne; Globinsky, Ronen; Fulbright, Robert K; Rothman, Douglas L; Gjedde, Albert

2016-05-01

Regionally variable rates of aerobic glycolysis in brain networks identified by resting-state functional magnetic resonance imaging (R-fMRI) imply regionally variable adenosine triphosphate (ATP) regeneration. When regional glucose utilization is not matched to oxygen delivery, affected regions have correspondingly variable rates of ATP and lactate production. We tested the extent to which aerobic glycolysis and oxidative phosphorylation power R-fMRI networks by measuring quantitative differences between the oxygen to glucose index (OGI) and the oxygen extraction fraction (OEF) as measured by positron emission tomography (PET) in normal human brain (resting awake, eyes closed). Regionally uniform and correlated OEF and OGI estimates prevailed, with network values that matched the gray matter means, regardless of size, location, and origin. The spatial agreement between oxygen delivery (OEF≈0.4) and glucose oxidation (OGI ≈ 5.3) suggests that no specific regions have preferentially high aerobic glycolysis and low oxidative phosphorylation rates, with globally optimal maximum ATP turnover rates (VATP ≈ 9.4 µmol/g/min), in good agreement with (31)P and (13)C magnetic resonance spectroscopy measurements. These results imply that the intrinsic network activity in healthy human brain powers the entire gray matter with ubiquitously high rates of glucose oxidation. Reports of departures from normal brain-wide homogeny of oxygen extraction fraction and oxygen to glucose index may be due to normalization artefacts from relative PET measurements. © The Author(s) 2016.

Reexpression of a developmentally regulated antigen in Down syndrome and Alzheimer disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wolozin, B.; Scicutella, A.; Davies, P.

1988-08-01

ALZ-50 is a monoclonal antibody that recognizes a protein of apparent molecular mass 68 kilodaltons (A68). The protein is present in the brains of patients with Alzheimer disease but is not detectable in normal adult brain tissue. The authors report that ALZ-50-reactive neurons are found in normal fetal and neonatal human brain and in brain tissue from neonatal individuals with Down syndrome. Reactive neurons decrease sharply in number after age 2 and reappear in older individuals with Down syndrome and in patients with Alzheimer disease.

Age-related apparent diffusion coefficient changes in the normal brain.

PubMed

Watanabe, Memi; Sakai, Osamu; Ozonoff, Al; Kussman, Steven; Jara, Hernán

2013-02-01

To measure the mean diffusional age-related changes of the brain over the full human life span by using diffusion-weighted spin-echo single-shot echo-planar magnetic resonance (MR) imaging and sequential whole-brain apparent diffusion coefficient (ADC) histogram analysis and, secondarily, to build mathematical models of these normal age-related changes throughout human life. After obtaining institutional review board approval, a HIPAA-compliant retrospective search was conducted for brain MR imaging studies performed in 2007 for various clinical indications. Informed consent was waived. The brain data of 414 healthy subjects (189 males and 225 females; mean age, 33.7 years; age range, 2 days to 89.3 years) were obtained with diffusion-weighted spin-echo single-shot echo-planar MR imaging. ADC histograms of the whole brain were generated. ADC peak values, histogram widths, and intracranial volumes were plotted against age, and model parameters were estimated by using nonlinear regression. Four different stages were identified for aging changes in ADC peak values, as characterized by specific mathematical terms: There were age-associated exponential decays for the maturation period and the development period, a constant term for adulthood, and a linear increase for the senescence period. The age dependency of ADC peak value was simulated by using four-term six-coefficient function, including biexponential and linear terms. This model fit the data very closely (R(2) = 0.91). Brain diffusivity as a whole demonstrated age-related changes through four distinct periods of life. These results could contribute to establishing an ADC baseline of the normal brain, covering the full human life span.

The potential application of a transcriptionally regulated oncolytic herpes simplex virus for human cancer therapy

PubMed Central

Miao, L; Fraefel, C; Sia, K C; Newman, J P; Mohamed-Bashir, S A; Ng, W H; Lam, P Y P

2014-01-01

Background: Emerging studies have shown the potential benefit of arming oncolytic viruses with therapeutic genes. However, most of these therapeutic genes are placed under the regulation of ubiquitous viral promoters. Our goal is to generate a safer yet potent oncolytic herpes simplex virus type-1 (HSV-1) for cancer therapy. Methods: Using bacterial artificial chromosome (BAC) recombineering, a cell cycle-regulatable luciferase transgene cassette was replaced with the infected cell protein 6 (ICP6) coding region (encoded for UL39 or large subunit of ribonucleotide reductase) of the HSV-1 genome. These recombinant viruses, YE-PC8, were further tested for its proliferation-dependent luciferase gene expression. Results: The ability of YE-PC8 to confer proliferation-dependent transgene expression was demonstrated by injecting similar amount of viruses into the tumour-bearing region of the brain and the contralateral normal brain parenchyma of the same mouse. The results showed enhanced levels of luciferase activities in the tumour region but not in the normal brain parenchyma. Similar findings were observed in YE-PC8-infected short-term human brain patient-derived glioma cells compared with normal human astrocytes. intratumoural injection of YE-PC8 viruses resulted in 77% and 80% of tumour regression in human glioma and human hepatocellular carcinoma xenografts, respectively. Conclusion: YE-PC8 viruses confer tumour selectivity in proliferating cells and may be developed further as a feasible approach to treat human cancers. PMID:24196790

Global differential expression of genes located in the Down Syndrome Critical Region in normal human brain

PubMed Central

Montoya, Julio Cesar; Fajardo, Dianora; Peña, Angela; Sánchez, Adalberto; Domínguez, Martha C; Satizábal, José María

2014-01-01

Background: The information of gene expression obtained from databases, have made possible the extraction and analysis of data related with several molecular processes involving not only in brain homeostasis but its disruption in some neuropathologies; principally in Down syndrome and the Alzheimer disease. Objective: To correlate the levels of transcription of 19 genes located in the Down Syndrome Critical Region (DSCR) with their expression in several substructures of normal human brain. Methods: There were obtained expression profiles of 19 DSCR genes in 42 brain substructures, from gene expression values available at the database of the human brain of the Brain Atlas of the Allen Institute for Brain Sciences", (http://human.brain-map.org/). The co-expression patterns of DSCR genes in brain were calculated by using multivariate statistical methods. Results: Highest levels of gene expression were registered at caudate nucleus, nucleus accumbens and putamen among central areas of cerebral cortex. Increased expression levels of RCAN1 that encode by a protein involved in signal transduction process of the CNS were recorded for PCP4 that participates in the binding to calmodulin and TTC3; a protein that is associated with differentiation of neurons. That previously identified brain structures play a crucial role in the learning process, in different class of memory and in motor skills. Conclusion: The precise regulation of DSCR gene expression is crucial to maintain the brain homeostasis, especially in those areas with high levels of gene expression associated with a remarkable process of learning and cognition. PMID:25767303

Accumulation of methylsulfonylmethane in the human brain: identification by multinuclear magnetic resonance spectroscopy.

PubMed

Lin, A; Nguy, C H; Shic, F; Ross, B D

2001-09-15

Methylsulfonylmethane (MSM) is a widely available 'alternative' medicine. In vivo magnetic resonance spectroscopy (MRS) was used to detect and quantify MSM in the brains of four patients with memory loss and in three normal volunteers all of who had ingested MSM at the recommended doses of 1-3 g daily. MSM was detected in all subjects at concentrations of 0.42-3.40 mmole/kg brain and was equally distributed between gray and white matter. MSM was undetectable in drug-naïve normal subjects (N=25), patients screened for 'toxic exposure' (N=50) or patients examined with 1H MRS for the diagnosis of probable Alzheimer Disease (N=520) between 1991 and 2001. No adverse clinical or neurochemical effects were observed. Appearance of MSM in significant concentrations in the human brain indicates ready transfer across the intact blood-brain barrier, of a compound with no known medical benefits.

A Four-Dimensional Probabilistic Atlas of the Human Brain

PubMed Central

Mazziotta, John; Toga, Arthur; Evans, Alan; Fox, Peter; Lancaster, Jack; Zilles, Karl; Woods, Roger; Paus, Tomas; Simpson, Gregory; Pike, Bruce; Holmes, Colin; Collins, Louis; Thompson, Paul; MacDonald, David; Iacoboni, Marco; Schormann, Thorsten; Amunts, Katrin; Palomero-Gallagher, Nicola; Geyer, Stefan; Parsons, Larry; Narr, Katherine; Kabani, Noor; Le Goualher, Georges; Feidler, Jordan; Smith, Kenneth; Boomsma, Dorret; Pol, Hilleke Hulshoff; Cannon, Tyrone; Kawashima, Ryuta; Mazoyer, Bernard

2001-01-01

The authors describe the development of a four-dimensional atlas and reference system that includes both macroscopic and microscopic information on structure and function of the human brain in persons between the ages of 18 and 90 years. Given the presumed large but previously unquantified degree of structural and functional variance among normal persons in the human population, the basis for this atlas and reference system is probabilistic. Through the efforts of the International Consortium for Brain Mapping (ICBM), 7,000 subjects will be included in the initial phase of database and atlas development. For each subject, detailed demographic, clinical, behavioral, and imaging information is being collected. In addition, 5,800 subjects will contribute DNA for the purpose of determining genotype– phenotype–behavioral correlations. The process of developing the strategies, algorithms, data collection methods, validation approaches, database structures, and distribution of results is described in this report. Examples of applications of the approach are described for the normal brain in both adults and children as well as in patients with schizophrenia. This project should provide new insights into the relationship between microscopic and macroscopic structure and function in the human brain and should have important implications in basic neuroscience, clinical diagnostics, and cerebral disorders. PMID:11522763

EEG mapping and low-resolution brain electromagnetic tomography (LORETA) in diagnosis and therapy of psychiatric disorders: evidence for a key-lock principle.

PubMed

Saletu, Bernd; Anderer, Peter; Saletu-Zyhlarz, Gerda M; Pascual-Marqui, Roberto D

2005-04-01

Different psychiatric disorders, such as schizophrenia with predominantly positive and negative symptomatology, major depression, generalized anxiety disorder, agoraphobia, obsessive-compulsive disorder, multi-infarct dementia, senile dementia of the Alzheimer type and alcohol dependence, show EEG maps that differ statistically both from each other and from normal controls. Representative drugs of the main psychopharmacological classes, such as sedative and non-sedative neuroleptics and antidepressants, tranquilizers, hypnotics, psychostimulants and cognition-enhancing drugs, induce significant and typical changes to normal human brain function, which in many variables are opposite to the above-mentioned differences between psychiatric patients and normal controls. Thus, by considering these differences between psychotropic drugs and placebo in normal subjects, as well as between mental disorder patients and normal controls, it may be possible to choose the optimum drug for a specific patient according to a key-lock principle, since the drug should normalize the deviant brain function. This is supported by 3-dimensional low-resolution brain electromagnetic tomography (LORETA), which identifies regions within the brain that are affected by psychiatric disorders and psychopharmacological substances.

Red-backed vole brain promotes highly efficient in vitro amplification of abnormal prion protein from macaque and human brains infected with variant Creutzfeldt-Jakob disease agent.

USGS Publications Warehouse

Nemecek, Julie; Nag, Nabanita; Carlson, Christina M.; Schneider, Jay R.; Heisey, Dennis M.; Johnson, Christopher J.; Asher, David M.; Gregori, Luisa

2013-01-01

Rapid antemortem tests to detect individuals with transmissible spongiform encephalopathies (TSE) would contribute to public health. We investigated a technique known as protein misfolding cyclic amplification (PMCA) to amplify abnormal prion protein (PrPTSE) from highly diluted variant Creutzfeldt-Jakob disease (vCJD)-infected human and macaque brain homogenates, seeking to improve the rapid detection of PrPTSE in tissues and blood. Macaque vCJD PrPTSE did not amplify using normal macaque brain homogenate as substrate (intraspecies PMCA). Next, we tested interspecies PMCA with normal brain homogenate of the southern red-backed vole (RBV), a close relative of the bank vole, seeded with macaque vCJD PrPTSE. The RBV has a natural polymorphism at residue 170 of the PrP-encoding gene (N/N, S/S, and S/N). We investigated the effect of this polymorphism on amplification of human and macaque vCJD PrPTSE. Meadow vole brain (170N/N PrP genotype) was also included in the panel of substrates tested. Both humans and macaques have the same 170S/S PrP genotype. Macaque PrPTSE was best amplified with RBV 170S/S brain, although 170N/N and 170S/N were also competent substrates, while meadow vole brain was a poor substrate. In contrast, human PrPTSE demonstrated a striking narrow selectivity for PMCA substrate and was successfully amplified only with RBV 170S/S brain. These observations suggest that macaque PrPTSE was more permissive than human PrPTSE in selecting the competent RBV substrate. RBV 170S/S brain was used to assess the sensitivity of PMCA with PrPTSE from brains of humans and macaques with vCJD. PrPTSE signals were reproducibly detected by Western blot in dilutions through 10-12 of vCJD-infected 10% brain homogenates. This is the first report showing PrPTSE from vCJD-infected human and macaque brains efficiently amplified with RBV brain as the substrate. Based on our estimates, PMCA showed a sensitivity that might be sufficient to detect PrPTSE in vCJD-infected human and macaque blood.

Tau Processing by Mural Cells in Traumatic Brain Injury and Alzheimer’s Disease

DTIC Science & Technology

2017-10-01

Cerebrovessels were treated with recombinant human tau (5ng/ml) for 1 hour at 37oC and total tau uptake was assessed in the lysates via ELISA . We observed a...to 5ng/ml recombinant human tau (rhtau-441) for 1 hour at 37oC. Lysates were analyzed for total tau content by ELISA and normalized to total protein...and 6 months post-last injury). Brain vessels were analyzed for PDGFRβ and α-SMC-actin content by ELISA and normalized to total protein using the

Molecular networks and the evolution of human cognitive specializations.

PubMed

Fontenot, Miles; Konopka, Genevieve

2014-12-01

Inroads into elucidating the origins of human cognitive specializations have taken many forms, including genetic, genomic, anatomical, and behavioral assays that typically compare humans to non-human primates. While the integration of all of these approaches is essential for ultimately understanding human cognition, here, we review the usefulness of coexpression network analysis for specifically addressing this question. An increasing number of studies have incorporated coexpression networks into brain expression studies comparing species, disease versus control tissue, brain regions, or developmental time periods. A clearer picture has emerged of the key genes driving brain evolution, as well as the developmental and regional contributions of gene expression patterns important for normal brain development and those misregulated in cognitive diseases. Copyright © 2014 Elsevier Ltd. All rights reserved.

Development of a High Angular Resolution Diffusion Imaging Human Brain Template

PubMed Central

Varentsova, Anna; Zhang, Shengwei; Arfanakis, Konstantinos

2014-01-01

Brain diffusion templates contain rich information about the microstructure of the brain, and are used as references in spatial normalization or in the development of brain atlases. The accuracy of diffusion templates constructed based on the diffusion tensor (DT) model is limited in regions with complex neuronal micro-architecture. High angular resolution diffusion imaging (HARDI) overcomes limitations of the DT model and is capable of resolving intravoxel heterogeneity. However, when HARDI is combined with multiple-shot sequences to minimize image artifacts, the scan time becomes inappropriate for human brain imaging. In this work, an artifact-free HARDI template of the human brain was developed from low angular resolution multiple-shot diffusion data. The resulting HARDI template was produced in ICBM-152 space based on Turboprop diffusion data, was shown to resolve complex neuronal micro-architecture in regions with intravoxel heterogeneity, and contained fiber orientation information consistent with known human brain anatomy. PMID:24440528

Gene expression profiles in anatomically and functionally distinct regions of the normal aged human brain

PubMed Central

Liang, Winnie S.; Dunckley, Travis; Beach, Thomas G.; Grover, Andrew; Mastroeni, Diego; Walker, Douglas G.; Caselli, Richard J.; Kukull, Walter A.; McKeel, Daniel; Morris, John C.; Hulette, Christine; Schmechel, Donald; Alexander, Gene E.; Reiman, Eric M.; Rogers, Joseph; Stephan, Dietrich A.

2008-01-01

In this article, we have characterized and compared gene expression profiles from laser capture microdissected neurons in six functionally and anatomically distinct regions from clinically and histopathologically normal aged human brains. These regions, which are also known to be differentially vulnerable to the histopathological and metabolic features of Alzheimer’s disease (AD), include the entorhinal cortex and hippocampus (limbic and paralimbic areas vulnerable to early neurofibrillary tangle pathology in AD), posterior cingulate cortex (a paralimbic area vulnerable to early metabolic abnormalities in AD), temporal and prefrontal cortex (unimodal and heteromodal sensory association areas vulnerable to early neuritic plaque pathology in AD), and primary visual cortex (a primary sensory area relatively spared in early AD). These neuronal profiles will provide valuable reference information for future studies of the brain, in normal aging, AD and other neurological and psychiatric disorders. PMID:17077275

Brain Entropy Mapping Using fMRI

PubMed Central

Wang, Ze; Li, Yin; Childress, Anna Rose; Detre, John A.

2014-01-01

Entropy is an important trait for life as well as the human brain. Characterizing brain entropy (BEN) may provide an informative tool to assess brain states and brain functions. Yet little is known about the distribution and regional organization of BEN in normal brain. The purpose of this study was to examine the whole brain entropy patterns using a large cohort of normal subjects. A series of experiments were first performed to validate an approximate entropy measure regarding its sensitivity, specificity, and reliability using synthetic data and fMRI data. Resting state fMRI data from a large cohort of normal subjects (n = 1049) from multi-sites were then used to derive a 3-dimensional BEN map, showing a sharp low-high entropy contrast between the neocortex and the rest of brain. The spatial heterogeneity of resting BEN was further studied using a data-driven clustering method, and the entire brain was found to be organized into 7 hierarchical regional BEN networks that are consistent with known structural and functional brain parcellations. These findings suggest BEN mapping as a physiologically and functionally meaningful measure for studying brain functions. PMID:24657999

Non-invasive intraoperative optical coherence tomography of the resection cavity during surgery of intrinsic brain tumors

NASA Astrophysics Data System (ADS)

Giese, A.; Böhringer, H. J.; Leppert, J.; Kantelhardt, S. R.; Lankenau, E.; Koch, P.; Birngruber, R.; Hüttmann, G.

2006-02-01

Optical coherence tomography (OCT) is a non-invasive imaging technique with a micrometer resolution. It allows non-contact / non-invasive analysis of central nervous system tissues with a penetration depth of 1-3,5 mm reaching a spatial resolution of approximately 4-15 μm. We have adapted spectral-domain OCT (SD-OCT) and time-domain OCT (TD-OCT) for intraoperative detection of residual tumor during brain tumor surgery. Human brain tumor tissue and areas of the resection cavity were analyzed during the resection of gliomas using this new technology. The site of analysis was registered using a neuronavigation system and biopsies were taken and submitted to routine histology. We have used post image acquisition processing to compensate for movements of the brain and to realign A-scan images for calculation of a light attenuation factor. OCT imaging of normal cortex and white matter showed a typical light attenuation profile. Tumor tissue depending on the cellularity of the specimen showed a loss of the normal light attenuation profile resulting in altered light attenuation coefficients compared to normal brain. Based on this parameter and the microstructure of the tumor tissue, which was entirely absent in normal tissue, OCT analysis allowed the discrimination of normal brain tissue, invaded brain, solid tumor tissue, and necrosis. Following macroscopically complete resections OCT analysis of the resection cavity displayed the typical microstructure and light attenuation profile of tumor tissue in some specimens, which in routine histology contained microscopic residual tumor tissue. We have demonstrated that this technology may be applied to the intraoperative detection of residual tumor during resection of human gliomas.

Intrathecal enzyme replacement therapy reduces lysosomal storage in the brain and meninges of the canine model of MPS I.

PubMed

Kakkis, E; McEntee, M; Vogler, C; Le, S; Levy, B; Belichenko, P; Mobley, W; Dickson, P; Hanson, S; Passage, M

2004-01-01

Enzyme replacement therapy (ERT) has been developed for several lysosomal storage disorders, including mucopolysaccharidosis I (MPS I), and is effective at reducing lysosomal storage in many tissues and in ameliorating clinical disease. However, intravenous ERT does not adequately treat storage disease in the central nervous system (CNS), presumably due to effects of the blood-brain barrier on enzyme distribution. To circumvent this barrier, we studied whether intrathecal (IT) recombinant human alpha-L-iduronidase (rhIDU) could penetrate and treat the brain and meninges. An initial dose-response study showed that doses of 0.46-4.14 mg of IT rhIDU successfully penetrated the brain of normal dogs and reached tissue levels 5.6 to 18.9-fold normal overall and 2.7 to 5.9-fold normal in deep brain sections lacking CSF contact. To assess the efficacy and safety in treating lysosomal storage disease, four weekly doses of approximately 1 mg of IT rhIDU were administered to MPS I-affected dogs resulting in a mean 23- and 300-fold normal levels of iduronidase in total brain and meninges, respectively. Quantitative glycosaminoglycan (GAG) analysis showed that the IT treatment reduced mean total brain GAG to normal levels and achieved a 57% reduction in meningeal GAG levels accompanied by histologic improvement in lysosomal storage in all cell types. The dogs did develop a dose-dependent immune response against the recombinant human protein and a meningeal lymphocytic/plasmacytic infiltrate. The IT route of ERT administration may be an effective way to treat the CNS disease in MPS I and could be applicable to other lysosomal storage disorders.

Engineering the Brain: Ethical Issues and the Introduction of Neural Devices.

PubMed

Klein, Eran; Brown, Tim; Sample, Matthew; Truitt, Anjali R; Goering, Sara

2015-01-01

Neural devices now under development stand to interact with and alter the human brain in ways that may challenge standard notions of identity, normality, authority, responsibility, privacy and justice.

The Myth of the Normal, Average Human Brain—The ICBM Experience: (1) Subject Screening and Eligibility

PubMed Central

Mazziotta, John C.; Woods, Roger; Iacoboni, Marco; Sicotte, Nancy; Yaden, Kami; Tran, Mary; Bean, Courtney; Kaplan, Jonas; Toga, Arthur W.

2009-01-01

In the course of developing an atlas and reference system for the normal human brain throughout the human age span from structural and functional brain imaging data, the International Consortium for Brain Mapping (ICBM) developed a set of “normal” criteria for subject inclusion and the associated exclusion criteria. The approach was to minimize inclusion of subjects with any medical disorders that could affect brain structure or function. In the past two years, a group of 1,685 potential subjects responded to solicitation advertisements at one of the consortium sites (UCLA). Subjects were screened by a detailed telephone interview and then had an in-person history and physical examination. Of those who responded to the advertisement and considered themselves to be normal, only 31.6% (532 subjects) passed the telephone screening process. Of the 348 individuals who submitted to in-person history and physical examinations, only 51.7% passed these screening procedures. Thus, only 10.7% of those individuals who responded to the original advertisement qualified for imaging. The most frequent cause for exclusion in the second phase of subject screening was high blood pressure followed by abnormal signs on neurological examination. It is concluded that the majority of individuals who consider themselves normal by self-report are found not to be so by detailed historical interviews about underlying medical conditions and by thorough medical and neurological examinations. Recommendations are made with regard to the inclusion of subjects in brain imaging studies and the criteria used to select them. PMID:18775497

Human brain metastatic stroma attracts breast cancer cells via chemokines CXCL16 and CXCL12.

PubMed

Chung, Brile; Esmaeili, Ali A; Gopalakrishna-Pillai, Sailesh; Murad, John P; Andersen, Emily S; Kumar Reddy, Naveen; Srinivasan, Gayathri; Armstrong, Brian; Chu, Caleb; Kim, Young; Tong, Tommy; Waisman, James; Yim, John H; Badie, Behnam; Lee, Peter P

2017-01-01

The tumor microenvironment is composed of heterogeneous populations of cells, including cancer, immune, and stromal cells. Progression of tumor growth and initiation of metastasis is critically dependent on the reciprocal interactions between cancer cells and stroma. Through RNA-Seq and protein analyses, we found that cancer-associated fibroblasts derived from human breast cancer brain metastasis express significantly higher levels of chemokines CXCL12 and CXCL16 than fibroblasts from primary breast tumors or normal breast. To further understand the interplay between cancer cells and cancer-associated fibroblasts from each site, we developed three-dimensional organoids composed of patient-derived primary or brain metastasis cancer cells with matching cancer-associated fibroblasts. Three-dimensional CAF aggregates generated from brain metastasis promote migration of cancer cells more effectively than cancer-associated fibroblast aggregates derived from primary tumor or normal breast stromal cells. Treatment with a CXCR4 antagonist and/or CXCL16 neutralizing antibody, alone or in combination, significantly inhibited migration of cancer cells to brain metastatic cancer-associated fibroblast aggregates. These results demonstrate that human brain metastasis cancer-associated fibroblasts potently attract breast cancer cells via chemokines CXCL12 and CXCL16, and blocking CXCR6-CXCL16/CXCR4-CXCL12 receptor-ligand interactions may be an effective therapy for preventing breast cancer brain metastasis.

A brain imaging repository of normal structural MRI across the life course: Brain Images of Normal Subjects (BRAINS).

PubMed

Job, Dominic E; Dickie, David Alexander; Rodriguez, David; Robson, Andrew; Danso, Sammy; Pernet, Cyril; Bastin, Mark E; Boardman, James P; Murray, Alison D; Ahearn, Trevor; Waiter, Gordon D; Staff, Roger T; Deary, Ian J; Shenkin, Susan D; Wardlaw, Joanna M

2017-01-01

The Brain Images of Normal Subjects (BRAINS) Imagebank (http://www.brainsimagebank.ac.uk) is an integrated repository project hosted by the University of Edinburgh and sponsored by the Scottish Imaging Network: A Platform for Scientific Excellence (SINAPSE) collaborators. BRAINS provide sharing and archiving of detailed normal human brain imaging and relevant phenotypic data already collected in studies of healthy volunteers across the life-course. It particularly focusses on the extremes of age (currently older age, and in future perinatal) where variability is largest, and which are under-represented in existing databanks. BRAINS is a living imagebank where new data will be added when available. Currently BRAINS contains data from 808 healthy volunteers, from 15 to 81years of age, from 7 projects in 3 centres. Additional completed and ongoing studies of normal individuals from 1st to 10th decades are in preparation and will be included as they become available. BRAINS holds several MRI structural sequences, including T1, T2, T2* and fluid attenuated inversion recovery (FLAIR), available in DICOM (http://dicom.nema.org/); in future Diffusion Tensor Imaging (DTI) will be added where available. Images are linked to a wide range of 'textual data', such as age, medical history, physiological measures (e.g. blood pressure), medication use, cognitive ability, and perinatal information for pre/post-natal subjects. The imagebank can be searched to include or exclude ranges of these variables to create better estimates of 'what is normal' at different ages. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

In vitro 3D regeneration-like growth of human patient brain tissue.

PubMed

Tang-Schomer, M D; Wu, W B; Kaplan, D L; Bookland, M J

2018-05-01

In vitro culture of primary neurons is widely adapted with embryonic but not mature brain tissue. Here, we extended a previously developed bioengineered three-dimensional (3D) embryonic brain tissue model to resected normal patient brain tissue in an attempt to regenerate human neurons in vitro. Single cells and small sized (diameter < 100 μm) spheroids from dissociated brain tissue were seeded into 3D silk fibroin-based scaffolds, with or without collagen or Matrigel, and compared with two-dimensional cultures and scaffold-free suspension cultures. Changes of cell phenotypes (neuronal, astroglial, neural progenitor, and neuroepithelial) were quantified with flow cytometry and analyzed with a new method of statistical analysis specifically designed for percentage comparison. Compared with a complete lack of viable cells in conventional neuronal cell culture condition, supplements of vascular endothelial growth factor-containing pro-endothelial cell condition led to regenerative growth of neurons and astroglial cells from "normal" human brain tissue of epilepsy surgical patients. This process involved delayed expansion of Nestin+ neural progenitor cells, emergence of TUJ1+ immature neurons, and Vimentin+ neuroepithelium-like cell sheet formation in prolonged cultures (14 weeks). Micro-tissue spheroids, but not single cells, supported the brain tissue growth, suggesting importance of preserving native cell-cell interactions. The presence of 3D scaffold, but not hydrogel, allowed for Vimentin+ cell expansion, indicating a different growth mechanism than pluripotent cell-based brain organoid formation. The slow and delayed process implied an origin of quiescent neural precursors in the neocortex tissue. Further optimization of the 3D tissue model with primary human brain cells could provide personalized brain disease models. Copyright © 2018 John Wiley & Sons, Ltd.

High-Speed and Scalable Whole-Brain Imaging in Rodents and Primates.

PubMed

Seiriki, Kaoru; Kasai, Atsushi; Hashimoto, Takeshi; Schulze, Wiebke; Niu, Misaki; Yamaguchi, Shun; Nakazawa, Takanobu; Inoue, Ken-Ichi; Uezono, Shiori; Takada, Masahiko; Naka, Yuichiro; Igarashi, Hisato; Tanuma, Masato; Waschek, James A; Ago, Yukio; Tanaka, Kenji F; Hayata-Takano, Atsuko; Nagayasu, Kazuki; Shintani, Norihito; Hashimoto, Ryota; Kunii, Yasuto; Hino, Mizuki; Matsumoto, Junya; Yabe, Hirooki; Nagai, Takeharu; Fujita, Katsumasa; Matsuda, Toshio; Takuma, Kazuhiro; Baba, Akemichi; Hashimoto, Hitoshi

2017-06-21

Subcellular resolution imaging of the whole brain and subsequent image analysis are prerequisites for understanding anatomical and functional brain networks. Here, we have developed a very high-speed serial-sectioning imaging system named FAST (block-face serial microscopy tomography), which acquires high-resolution images of a whole mouse brain in a speed range comparable to that of light-sheet fluorescence microscopy. FAST enables complete visualization of the brain at a resolution sufficient to resolve all cells and their subcellular structures. FAST renders unbiased quantitative group comparisons of normal and disease model brain cells for the whole brain at a high spatial resolution. Furthermore, FAST is highly scalable to non-human primate brains and human postmortem brain tissues, and can visualize neuronal projections in a whole adult marmoset brain. Thus, FAST provides new opportunities for global approaches that will allow for a better understanding of brain systems in multiple animal models and in human diseases. Copyright © 2017 Elsevier Inc. All rights reserved.

Network Analysis: Applications for the Developing Brain

PubMed Central

Chu-Shore, Catherine J.; Kramer, Mark A.; Bianchi, Matt T.; Caviness, Verne S.; Cash, Sydney S.

2011-01-01

Development of the human brain follows a complex trajectory of age-specific anatomical and physiological changes. The application of network analysis provides an illuminating perspective on the dynamic interregional and global properties of this intricate and complex system. Here, we provide a critical synopsis of methods of network analysis with a focus on developing brain networks. After discussing basic concepts and approaches to network analysis, we explore the primary events of anatomical cortical development from gestation through adolescence. Upon this framework, we describe early work revealing the evolution of age-specific functional brain networks in normal neurodevelopment. Finally, we review how these relationships can be altered in disease and perhaps even rectified with treatment. While this method of description and inquiry remains in early form, there is already substantial evidence that the application of network models and analysis to understanding normal and abnormal human neural development holds tremendous promise for future discovery. PMID:21303762

Linking brain imaging and genomics in the study of Alzheimer's disease and aging.

PubMed

Reiman, Eric M

2007-02-01

My colleagues and I have been using positron emission tomography (PET) and magnetic resonance imaging (MRI) to detect and track the brain changes associated with Alzheimer's disease (AD) and normal brain aging in cognitively normal persons with two copies, one copy, and no copies of the apolipoprotein E (APOE) epsilon4 allele, a common AD susceptibility gene. In this review article, I consider how brain imaging techniques could be used to evaluate putative AD prevention therapies in cognitively normal APOE epsilon4 carriers and putative age-modifying therapies in cognitively normal APOE epsilon4 noncarriers, how they could help investigate the individual and aggregate effects of putative AD risk modifiers, and how they could help guide the investigation of a molecular mechanism associated with AD vulnerability and normal neurological aging. I suggest how high-resolution genome-wide genetic and transcriptomic studies could further help in the scientific understanding of AD, aging, and other common and genetically complex phenotypes, such as variation in normal human memory performance, and in the discovery and evaluation of promising treatments for these phenotypes. Finally, I illustrate the push-pull relationship between brain imaging, genomics research, and other neuroscientific research in the study of AD and aging.

Early parental care is important for hippocampal maturation: evidence from brain morphology in humans.

PubMed

Rao, Hengyi; Betancourt, Laura; Giannetta, Joan M; Brodsky, Nancy L; Korczykowski, Marc; Avants, Brian B; Gee, James C; Wang, Jiongjiong; Hurt, Hallam; Detre, John A; Farah, Martha J

2010-01-01

The effects of early life experience on later brain structure and function have been studied extensively in animals, yet the relationship between childhood experience and normal brain development in humans remains largely unknown. Using a unique longitudinal data set including ecologically valid in-home measures of early experience during childhood (at age 4 and 8 years) and high-resolution structural brain imaging during adolescence (mean age 14 years), we examined the effects on later brain morphology of two dimensions of early experience: parental nurturance and environmental stimulation. Parental nurturance at age 4 predicts the volume of the left hippocampus in adolescence, with better nurturance associated with smaller hippocampal volume. In contrast, environmental stimulation did not correlate with hippocampal volume. Moreover, the association between hippocampal volume and parental nurturance disappears at age 8, supporting the existence of a sensitive developmental period for brain maturation. These findings indicate that variation in normal childhood experience is associated with differences in brain morphology, and hippocampal volume is specifically associated with early parental nurturance. Our results provide neuroimaging evidence supporting the important role of warm parental care during early childhood for brain maturation.

Glymphatic MRI in idiopathic normal pressure hydrocephalus.

PubMed

Ringstad, Geir; Vatnehol, Svein Are Sirirud; Eide, Per Kristian

2017-10-01

The glymphatic system has in previous studies been shown as fundamental to clearance of waste metabolites from the brain interstitial space, and is proposed to be instrumental in normal ageing and brain pathology such as Alzheimer's disease and brain trauma. Assessment of glymphatic function using magnetic resonance imaging with intrathecal contrast agent as a cerebrospinal fluid tracer has so far been limited to rodents. We aimed to image cerebrospinal fluid flow characteristics and glymphatic function in humans, and applied the methodology in a prospective study of 15 idiopathic normal pressure hydrocephalus patients (mean age 71.3 ± 8.1 years, three female and 12 male) and eight reference subjects (mean age 41.1 + 13.0 years, six female and two male) with suspected cerebrospinal fluid leakage (seven) and intracranial cyst (one). The imaging protocol included T1-weighted magnetic resonance imaging with equal sequence parameters before and at multiple time points through 24 h after intrathecal injection of the contrast agent gadobutrol at the lumbar level. All study subjects were kept in the supine position between examinations during the first day. Gadobutrol enhancement was measured at all imaging time points from regions of interest placed at predefined locations in brain parenchyma, the subarachnoid and intraventricular space, and inside the sagittal sinus. Parameters demonstrating gadobutrol enhancement and clearance in different locations were compared between idiopathic normal pressure hydrocephalus and reference subjects. A characteristic flow pattern in idiopathic normal hydrocephalus was ventricular reflux of gadobutrol from the subarachnoid space followed by transependymal gadobutrol migration. At the brain surfaces, gadobutrol propagated antegradely along large leptomeningeal arteries in all study subjects, and preceded glymphatic enhancement in adjacent brain tissue, indicating a pivotal role of intracranial pulsations for glymphatic function. In idiopathic normal pressure hydrocephalus, we found delayed enhancement (P < 0.05) and decreased clearance of gadobutrol (P < 0.05) at the Sylvian fissure. Parenchymal (glymphatic) enhancement peaked overnight in both study groups, possibly indicating a crucial role of sleep, and was larger in normal pressure hydrocephalus patients (P < 0.05 at inferior frontal gyrus). We interpret decreased gadobutrol clearance from the subarachnoid space, along with persisting enhancement in brain parenchyma, as signs of reduced glymphatic clearance in idiopathic normal hydrocephalus, and hypothesize that reduced glymphatic function is instrumental for dementia in this disease. The study shows promise for glymphatic magnetic resonance imaging as a method to assess human brain metabolic function and renders a potential for contrast enhanced brain extravascular space imaging. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.

Detecting activity-evoked pH changes in human brain

PubMed Central

Magnotta, Vincent A.; Heo, Hye-Young; Dlouhy, Brian J.; Dahdaleh, Nader S.; Follmer, Robin L.; Thedens, Daniel R.; Welsh, Michael J.; Wemmie, John A.

2012-01-01

Localized pH changes have been suggested to occur in the brain during normal function. However, the existence of such pH changes has also been questioned. Lack of methods for noninvasively measuring pH with high spatial and temporal resolution has limited insight into this issue. Here we report that a magnetic resonance imaging (MRI) strategy, T1 relaxation in the rotating frame (T1ρ), is sufficiently sensitive to detect widespread pH changes in the mouse and human brain evoked by systemically manipulating carbon dioxide or bicarbonate. Moreover, T1ρ detected a localized acidosis in the human visual cortex induced by a flashing checkerboard. Lactate measurements and pH-sensitive 31P spectroscopy at the same site also identified a localized acidosis. Consistent with the established role for pH in blood flow recruitment, T1ρ correlated with blood oxygenation level-dependent contrast commonly used in functional MRI. However, T1ρ was not directly sensitive to blood oxygen content. These observations indicate that localized pH fluctuations occur in the human brain during normal function. Furthermore, they suggest a unique functional imaging strategy based on pH that is independent of traditional functional MRI contrast mechanisms. PMID:22566645

Development of a high angular resolution diffusion imaging human brain template.

PubMed

Varentsova, Anna; Zhang, Shengwei; Arfanakis, Konstantinos

2014-05-01

Brain diffusion templates contain rich information about the microstructure of the brain, and are used as references in spatial normalization or in the development of brain atlases. The accuracy of diffusion templates constructed based on the diffusion tensor (DT) model is limited in regions with complex neuronal micro-architecture. High angular resolution diffusion imaging (HARDI) overcomes limitations of the DT model and is capable of resolving intravoxel heterogeneity. However, when HARDI is combined with multiple-shot sequences to minimize image artifacts, the scan time becomes inappropriate for human brain imaging. In this work, an artifact-free HARDI template of the human brain was developed from low angular resolution multiple-shot diffusion data. The resulting HARDI template was produced in ICBM-152 space based on Turboprop diffusion data, was shown to resolve complex neuronal micro-architecture in regions with intravoxel heterogeneity, and contained fiber orientation information consistent with known human brain anatomy. Copyright © 2014 Elsevier Inc. All rights reserved.

Transcallosal transfer of information and functional asymmetry of the human brain.

PubMed

Nowicka, Anna; Tacikowski, Pawel

2011-01-01

The corpus callosum is the largest commissure in the brain and acts as a "bridge" of nerve fibres connecting the two cerebral hemispheres. It plays a crucial role in interhemispheric integration and is responsible for normal communication and cooperation between the two hemispheres. Evolutionary pressures guiding brain size are accompanied by reduced interhemispheric and enhanced intrahemispheric connectivity. Some lines of evidence suggest that the speed of transcallosal conduction is limited in large brains (e.g., in humans), thus favouring intrahemispheric processing and brain lateralisation. Patterns of directional symmetry/asymmetry of transcallosal transfer time may be related to the degree of brain lateralisation. Neural network modelling and electrophysiological studies on interhemispheric transmission provide data supporting this supposition.

Brain tissues volume measurements from 2D MRI using parametric approach

NASA Astrophysics Data System (ADS)

L'vov, A. A.; Toropova, O. A.; Litovka, Yu. V.

2018-04-01

The purpose of the paper is to propose a fully automated method of volume assessment of structures within human brain. Our statistical approach uses maximum interdependency principle for decision making process of measurements consistency and unequal observations. Detecting outliers performed using maximum normalized residual test. We propose a statistical model which utilizes knowledge of tissues distribution in human brain and applies partial data restoration for precision improvement. The approach proposes completed computationally efficient and independent from segmentation algorithm used in the application.

EEG topography and tomography (LORETA) in the classification and evaluation of the pharmacodynamics of psychotropic drugs.

PubMed

Saletu, Bernd; Anderer, Peter; Saletu-Zyhlarz, Gerda M

2006-04-01

By multi-lead computer-assisted quantitative analyses of human scalp-recorded electroencephalogram (QEEG) in combination with certain statistical procedures (quantitative pharmaco-EEG) and mapping techniques (pharmaco-EEG mapping or topography), it is possible to classify psychotropic substances and objectively evaluate their bioavailability at the target organ, the human brain. Specifically, one may determine at an early stage of drug development whether a drug is effective on the central nervous system (CNS) compared with placebo, what its clinical efficacy will be like, at which dosage it acts, when it acts and the equipotent dosages of different galenic formulations. Pharmaco-EEG maps of neuroleptics, antidepressants, tranquilizers, hypnotics, psychostimulants and nootropics/cognition-enhancing drugs will be described. Methodological problems, as well as the relationships between acute and chronic drug effects, alterations in normal subjects and patients, CNS effects and therapeutic efficacy will be discussed. Imaging of drug effects on the regional brain electrical activity of healthy subjects by means of EEG tomography such as low-resolution electromagnetic tomography (LORETA) has been used for identifying brain areas predominantly involved in psychopharmacological action. This will be shown for the representative drugs of the four main psychopharmacological classes, such as 3 mg haloperidol for neuroleptics, 20 mg citalopram for antidepressants, 2 mg lorazepam for tranquilizers and 20 mg methylphenidate for psychostimulants. LORETA demonstrates that these psychopharmacological classes affect brain structures differently. By considering these differences between psychotropic drugs and placebo in normal subjects, as well as between mental disorder patients and normal controls, it may be possible to choose the optimum drug for a specific patient according to a key-lock principle, since the drug should normalize the deviant brain function. Thus, pharmaco-EEG topography and tomography are valuable methods in human neuropsychopharmacology, clinical psychiatry and neurology.

The biochemical, nanomechanical and chemometric signatures of brain cancer

NASA Astrophysics Data System (ADS)

Abramczyk, Halina; Imiela, Anna

2018-01-01

Raman spectroscopy and imaging combined with AFM topography and mechanical indentation by AFM have been shown to be an effective tool for analysis and discrimination of human brain tumors from normal structures. Raman methods have potential to be applied in clinical practice as they allow for identification of tumor margins during surgery. In this study, we investigate medulloblastoma (grade IV WHO) (n = 5) and the tissue from the negative margins used as normal controls. We compare a high grade medulloblastoma (IV grade), and non-tumor samples from human central nervous system (CNS) tissue. Based on the properties of the Raman vibrational spectra and Raman images we provide a real-time feedback that is label-free method to monitor tumor metabolism that reveals reprogramming of biosynthesis of lipids, and proteins. We have found that the high-grade tumors of central nervous system (medulloblastoma) exhibit enhanced level of β-sheet conformation and down-regulated level of α-helix conformation when comparing against normal tissue. We have shown that the ratio of Raman intensities I2930/I2845 at 2930 and 2845 cm- 1 is a good source of information on the ratio of lipid and protein contents. We have found that the ratio reflects the lipid and protein contents of tumorous brain tissue compared to the non-tumor tissue. Almost all brain tumors have the Raman intensity ratios significantly higher (1.99 ± 0.026) than that found in non-tumor brain tissue, which is 1.456 ± 0.02, and indicates that the relative amount of lipids compared to proteins is significantly higher in the normal brain tissue. Mechanical indentation using AFM on sliced human brain tissues (medulloblastoma, grade IV) revealed that the mechanical properties of this tissue are strongly heterogeneous, between 1.8 and 75.7 kPa, and the mean of 27.16 kPa. The sensitivity and specificity obtained directly from PLSDA and cross validation gives a sensitivity and specificity of 98.5% and 96% and 96.3% and 92% for cross-validation, respectively. The high sensitivity and specificity demonstrates usefulness for a proper decision for a Raman diagnostic test on biochemical alterations monitored by Raman spectroscopy related to brain cancer development.

Small-world human brain networks: Perspectives and challenges.

PubMed

Liao, Xuhong; Vasilakos, Athanasios V; He, Yong

2017-06-01

Modelling the human brain as a complex network has provided a powerful mathematical framework to characterize the structural and functional architectures of the brain. In the past decade, the combination of non-invasive neuroimaging techniques and graph theoretical approaches enable us to map human structural and functional connectivity patterns (i.e., connectome) at the macroscopic level. One of the most influential findings is that human brain networks exhibit prominent small-world organization. Such a network architecture in the human brain facilitates efficient information segregation and integration at low wiring and energy costs, which presumably results from natural selection under the pressure of a cost-efficiency balance. Moreover, the small-world organization undergoes continuous changes during normal development and ageing and exhibits dramatic alterations in neurological and psychiatric disorders. In this review, we survey recent advances regarding the small-world architecture in human brain networks and highlight the potential implications and applications in multidisciplinary fields, including cognitive neuroscience, medicine and engineering. Finally, we highlight several challenging issues and areas for future research in this rapidly growing field. Copyright © 2017 Elsevier Ltd. All rights reserved.

Glymphatic MRI in idiopathic normal pressure hydrocephalus

PubMed Central

Ringstad, Geir; Vatnehol, Svein Are Sirirud; Eide, Per Kristian

2017-01-01

Abstract The glymphatic system has in previous studies been shown as fundamental to clearance of waste metabolites from the brain interstitial space, and is proposed to be instrumental in normal ageing and brain pathology such as Alzheimer’s disease and brain trauma. Assessment of glymphatic function using magnetic resonance imaging with intrathecal contrast agent as a cerebrospinal fluid tracer has so far been limited to rodents. We aimed to image cerebrospinal fluid flow characteristics and glymphatic function in humans, and applied the methodology in a prospective study of 15 idiopathic normal pressure hydrocephalus patients (mean age 71.3 ± 8.1 years, three female and 12 male) and eight reference subjects (mean age 41.1 + 13.0 years, six female and two male) with suspected cerebrospinal fluid leakage (seven) and intracranial cyst (one). The imaging protocol included T1-weighted magnetic resonance imaging with equal sequence parameters before and at multiple time points through 24 h after intrathecal injection of the contrast agent gadobutrol at the lumbar level. All study subjects were kept in the supine position between examinations during the first day. Gadobutrol enhancement was measured at all imaging time points from regions of interest placed at predefined locations in brain parenchyma, the subarachnoid and intraventricular space, and inside the sagittal sinus. Parameters demonstrating gadobutrol enhancement and clearance in different locations were compared between idiopathic normal pressure hydrocephalus and reference subjects. A characteristic flow pattern in idiopathic normal hydrocephalus was ventricular reflux of gadobutrol from the subarachnoid space followed by transependymal gadobutrol migration. At the brain surfaces, gadobutrol propagated antegradely along large leptomeningeal arteries in all study subjects, and preceded glymphatic enhancement in adjacent brain tissue, indicating a pivotal role of intracranial pulsations for glymphatic function. In idiopathic normal pressure hydrocephalus, we found delayed enhancement (P < 0.05) and decreased clearance of gadobutrol (P < 0.05) at the Sylvian fissure. Parenchymal (glymphatic) enhancement peaked overnight in both study groups, possibly indicating a crucial role of sleep, and was larger in normal pressure hydrocephalus patients (P < 0.05 at inferior frontal gyrus). We interpret decreased gadobutrol clearance from the subarachnoid space, along with persisting enhancement in brain parenchyma, as signs of reduced glymphatic clearance in idiopathic normal hydrocephalus, and hypothesize that reduced glymphatic function is instrumental for dementia in this disease. The study shows promise for glymphatic magnetic resonance imaging as a method to assess human brain metabolic function and renders a potential for contrast enhanced brain extravascular space imaging. PMID:28969373

Brain metastasis detection by resonant Raman optical biopsy method

NASA Astrophysics Data System (ADS)

Zhou, Yan; Liu, Cheng-hui; Cheng, Gangge; Zhou, Lixin; Zhang, Chunyuan; Pu, Yang; Li, Zhongwu; Liu, Yulong; Li, Qingbo; Wang, Wei; Alfano, Robert R.

2014-03-01

Resonant Raman (RR) spectroscopy provides an effective way to enhance Raman signal from particular bonds associated with key molecules due to changes on a molecular level. In this study, RR is used for detection of human brain metastases of five kinds of primary organs of lung, breast, kidney, rectal and orbital in ex-vivo. The RR spectra of brain metastases cancerous tissues were measured and compared with those of normal brain tissues and the corresponding primary cancer tissues. The differences of five types of brain metastases tissues in key bio-components of carotene, tryptophan, lactate, alanine and methyl/methylene group were investigated. The SVM-KNN classifier was used to categorize a set of RR spectra data of brain metastasis of lung cancerous tissues from normal brain tissue, yielding diagnostic sensitivity and specificity at 100% and 75%, respectively. The RR spectroscopy may provide new moleculebased optical probe tools for diagnosis and classification of brain metastatic of cancers.

Using the Optical Fractionator to Estimate Total Cell Numbers in the Normal and Abnormal Developing Human Forebrain.

PubMed

Larsen, Karen B

2017-01-01

Human fetal brain development is a complex process which is vulnerable to disruption at many stages. Although histogenesis is well-documented, only a few studies have quantified cell numbers across normal human fetal brain growth. Due to the present lack of normative data it is difficult to gauge abnormal development. Furthermore, many studies of brain cell numbers have employed biased counting methods, whereas innovations in stereology during the past 20-30 years enable reliable and efficient estimates of cell numbers. However, estimates of cell volumes and densities in fetal brain samples are unreliable due to unpredictable shrinking artifacts, and the fragility of the fetal brain requires particular care in handling and processing. The optical fractionator design offers a direct and robust estimate of total cell numbers in the fetal brain with a minimum of handling of the tissue. Bearing this in mind, we have used the optical fractionator to quantify the growth of total cell numbers as a function of fetal age. We discovered a two-phased development in total cell numbers in the human fetal forebrain consisting of an initial steep rise in total cell numbers between 13 and 20 weeks of gestation, followed by a slower linear phase extending from mid-gestation to 40 weeks of gestation. Furthermore, we have demonstrated a reduced total cell number in the forebrain in fetuses with Down syndome at midgestation and in intrauterine growth-restricted fetuses during the third trimester.

In vivo NAD assay reveals the intracellular NAD contents and redox state in healthy human brain and their age dependences

PubMed Central

Zhu, Xiao-Hong; Lu, Ming; Lee, Byeong-Yeul; Ugurbil, Kamil; Chen, Wei

2015-01-01

NAD is an essential metabolite that exists in NAD+ or NADH form in all living cells. Despite its critical roles in regulating mitochondrial energy production through the NAD+/NADH redox state and modulating cellular signaling processes through the activity of the NAD+-dependent enzymes, the method for quantifying intracellular NAD contents and redox state is limited to a few in vitro or ex vivo assays, which are not suitable for studying a living brain or organ. Here, we present a magnetic resonance (MR) -based in vivo NAD assay that uses the high-field MR scanner and is capable of noninvasively assessing NAD+ and NADH contents and the NAD+/NADH redox state in intact human brain. The results of this study provide the first insight, to our knowledge, into the cellular NAD concentrations and redox state in the brains of healthy volunteers. Furthermore, an age-dependent increase of intracellular NADH and age-dependent reductions in NAD+, total NAD contents, and NAD+/NADH redox potential of the healthy human brain were revealed in this study. The overall findings not only provide direct evidence of declined mitochondrial functions and altered NAD homeostasis that accompany the normal aging process but also, elucidate the merits and potentials of this new NAD assay for noninvasively studying the intracellular NAD metabolism and redox state in normal and diseased human brain or other organs in situ. PMID:25730862

The autistic brain in the context of normal neurodevelopment.

PubMed

Ziats, Mark N; Edmonson, Catherine; Rennert, Owen M

2015-01-01

The etiology of autism spectrum disorders (ASDs) is complex and largely unclear. Among various lines of inquiry, many have suggested convergence onto disruptions in both neural circuitry and immune regulation/glial cell function pathways. However, the interpretation of the relationship between these two putative mechanisms has largely focused on the role of exogenous factors and insults, such as maternal infection, in activating immune pathways that in turn result in neural network abnormalities. Yet, given recent insights into our understanding of human neurodevelopment, and in particular the critical role of glia and the immune system in normal brain development, it is important to consider these putative pathological processes in their appropriate normal neurodevelopmental context. In this review, we explore the hypothesis that the autistic brain cellular phenotype likely represents intrinsic abnormalities of glial/immune processes constitutively operant in normal brain development that result in the observed neural network dysfunction. We review recent studies demonstrating the intercalated role of neural circuit development, the immune system, and glial cells in the normal developing brain, and integrate them with studies demonstrating pathological alterations in these processes in autism. By discussing known abnormalities in the autistic brain in the context of normal brain development, we explore the hypothesis that the glial/immune component of ASD may instead be related to intrinsic exaggerated/abnormal constitutive neurodevelopmental processes such as network pruning. Moreover, this hypothesis may be relevant to other neurodevelopmental disorders that share genetic, pathologic, and clinical features with autism.

Searching for Factors Underlying Cerebral Plasticity in the Normal and Injured Brain

ERIC Educational Resources Information Center

Kolb, Bryan; Muhammad, Arif; Gibb, Robbin

2011-01-01

Brain plasticity refers to the capacity of the nervous system to change its structure and ultimately its function over a lifetime. There have been major advances in our understanding of the principles of brain plasticity and behavior in laboratory animals and humans. Over the past decade there have been advances in the application of these…

Where's Waldo? The 'decapitation gambit' and the definition of death.

PubMed

Lizza, John P

2011-12-01

The 'decapitation gambit' holds that, if physical decapitation normally entails the death of the human being, then physiological decapitation, evident in cases of total brain failure, entails the death of the human being. This argument has been challenged by Franklin Miller and Robert Truog, who argue that physical decapitation does not necessarily entail the death of human beings and that therefore, by analogy, artificially sustained human bodies with total brain failure are living human beings. They thus challenge the current neurological criterion for determining death and argue for a return to the traditional criterion of the irreversible loss of circulation and respiration. In this paper, I defend the decapitation gambit and total brain failure as a criterion for determining death against Miller and Truog's criticism.

Synthesis and Preliminary Evaluation of Phenyl 4-123I-Iodophenylcarbamate for Visualization of Cholinesterases Associated with Alzheimer Disease Pathology.

PubMed

Macdonald, Ian R; Reid, G Andrew; Pottie, Ian R; Martin, Earl; Darvesh, Sultan

2016-02-01

Acetylcholinesterase and butyrylcholinesterase accumulate with brain β-amyloid (Aβ) plaques in Alzheimer disease (AD). The overall activity of acetylcholinesterase is found to decline in AD, whereas butyrylcholinesterase has been found to either increase or remain the same. Although some cognitively normal older adults also have Aβ plaques within the brain, cholinesterase-associated plaques are generally less abundant in such individuals. Thus, brain imaging of cholinesterase activity associated with Aβ plaques has the potential to distinguish AD from cognitively normal older adults, with or without Aβ accumulation, during life. Current Aβ imaging agents are not able to provide this distinction. To address this unmet need, synthesis and evaluation of a cholinesterase-binding ligand, phenyl 4-(123)I-iodophenylcarbamate ((123)I-PIP), is described. Phenyl 4-iodophenylcarbamate was synthesized and evaluated for binding potency toward acetylcholinesterase and butyrylcholinesterase using enzyme kinetic analysis. This compound was subsequently rapidly radiolabeled with (123)I and purified by high-performance liquid chromatography. Autoradiographic analyses were performed with (123)I-PIP using postmortem orbitofrontal cortex from cognitively normal and AD human brains. Comparisons were made with an Aβ imaging agent, 2-(4'-dimethylaminophenyl)-6-(123)I-iodo-imidazo[1,2-a]pyridine ((123)I-IMPY), in adjacent brain sections. Tissues were also stained for Aβ and cholinesterase activity to visualize Aβ plaque load for comparison with radioligand uptake. Synthesized and purified PIP exhibited binding to cholinesterases. (123)I was successfully incorporated into this ligand. (123)I-PIP autoradiography with human tissue revealed accumulation of radioactivity only in AD brain tissues in which Aβ plaques had cholinesterase activity. (123)I-IMPY accumulated in brain tissues with Aβ plaques from both AD and cognitively normal individuals. Radiolabeled ligands specific for cholinesterases have potential for use in neuroimaging AD plaques during life. The compound herein described, (123)I-PIP, can detect cholinesterases associated with Aβ plaques and can distinguish AD brain tissues from those of cognitively normal older adults with Aβ plaques. Imaging cholinesterase activity associated with Aβ plaques in the living brain may contribute to the definitive diagnosis of AD during life. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Quantitative Folding Pattern Analysis of Early Primary Sulci in Human Fetuses with Brain Abnormalities.

PubMed

Im, K; Guimaraes, A; Kim, Y; Cottrill, E; Gagoski, B; Rollins, C; Ortinau, C; Yang, E; Grant, P E

2017-07-01

Aberrant gyral folding is a key feature in the diagnosis of many cerebral malformations. However, in fetal life, it is particularly challenging to confidently diagnose aberrant folding because of the rapid spatiotemporal changes of gyral development. Currently, there is no resource to measure how an individual fetal brain compares with normal spatiotemporal variations. In this study, we assessed the potential for automatic analysis of early sulcal patterns to detect individual fetal brains with cerebral abnormalities. Triplane MR images were aligned to create a motion-corrected volume for each individual fetal brain, and cortical plate surfaces were extracted. Sulcal basins were automatically identified on the cortical plate surface and compared with a combined set generated from 9 normal fetal brain templates. Sulcal pattern similarities to the templates were quantified by using multivariate geometric features and intersulcal relationships for 14 normal fetal brains and 5 fetal brains that were proved to be abnormal on postnatal MR imaging. Results were compared with the gyrification index. Significantly reduced sulcal pattern similarities to normal templates were found in all abnormal individual fetuses compared with normal fetuses (mean similarity [normal, abnormal], left: 0.818, 0.752; P < .001; right: 0.810, 0.753; P < .01). Altered location and depth patterns of sulcal basins were the primary distinguishing features. The gyrification index was not significantly different between the normal and abnormal groups. Automated analysis of interrelated patterning of early primary sulci could outperform the traditional gyrification index and has the potential to quantitatively detect individual fetuses with emerging abnormal sulcal patterns. © 2017 by American Journal of Neuroradiology.

In vivo Magnetic Resonance Spectroscopy of cerebral glycogen metabolism in animals and humans.

PubMed

Khowaja, Ameer; Choi, In-Young; Seaquist, Elizabeth R; Öz, Gülin

2015-02-01

Glycogen serves as an important energy reservoir in the human body. Despite the abundance of glycogen in the liver and skeletal muscles, its concentration in the brain is relatively low, hence its significance has been questioned. A major challenge in studying brain glycogen metabolism has been the lack of availability of non-invasive techniques for quantification of brain glycogen in vivo. Invasive methods for brain glycogen quantification such as post mortem extraction following high energy microwave irradiation are not applicable in the human brain. With the advent of (13)C Magnetic Resonance Spectroscopy (MRS), it has been possible to measure brain glycogen concentrations and turnover in physiological conditions, as well as under the influence of stressors such as hypoglycemia and visual stimulation. This review presents an overview of the principles of the (13)C MRS methodology and its applications in both animals and humans to further our understanding of glycogen metabolism under normal physiological and pathophysiological conditions such as hypoglycemia unawareness.

In vivo Magnetic Resonance Spectroscopy of cerebral glycogen metabolism in animals and humans

PubMed Central

Khowaja, Ameer; Choi, In-Young; Seaquist, Elizabeth R.; Öz, Gülin

2015-01-01

Glycogen serves as an important energy reservoir in the human body. Despite the abundance of glycogen in the liver and skeletal muscles, its concentration in the brain is relatively low, hence its significance has been questioned. A major challenge in studying brain glycogen metabolism has been the lack of availability of non-invasive techniques for quantification of brain glycogen in vivo. Invasive methods for brain glycogen quantification such as post mortem extraction following high energy microwave irradiation are not applicable in the human brain. With the advent of 13C Magnetic Resonance Spectroscopy (MRS), it has been possible to measure brain glycogen concentrations and turnover in physiological conditions, as well as under the influence of stressors such as hypoglycemia and visual stimulation. This review presents an overview of the principles of the 13C MRS methodology and its applications in both animals and humans to further our understanding of glycogen metabolism under normal physiological and pathophysiological conditions such as hypoglycemia unawareness. PMID:24676563

Detection of Normal Aging Effects on Human Brain Metabolite Concentrations and Microstructure with Whole-Brain MR Spectroscopic Imaging and Quantitative MR Imaging.

PubMed

Eylers, V V; Maudsley, A A; Bronzlik, P; Dellani, P R; Lanfermann, H; Ding, X-Q

2016-03-01

Knowledge of age-related physiological changes in the human brain is a prerequisite to identify neurodegenerative diseases. Therefore, in this study whole-brain (1)H-MRS was used in combination with quantitative MR imaging to study the effects of normal aging on healthy human brain metabolites and microstructure. Sixty healthy volunteers, 21-70 years of age, were studied. Brain maps of the metabolites NAA, creatine and phosphocreatine, and Cho and the tissue irreversible and reversible transverse relaxation times T2 and T2' were derived from the datasets. The relative metabolite concentrations and the values of relaxation times were measured with ROIs placed within the frontal and parietal WM, centrum semiovale, splenium of the corpus callosum, hand motor area, occipital GM, putamen, thalamus, pons ventral/dorsal, and cerebellar white matter and posterior lobe. Linear regression analysis and Pearson correlation tests were used to analyze the data. Aging resulted in decreased NAA concentrations in the occipital GM, putamen, splenium of the corpus callosum, and pons ventral and decreased creatine and phosphocreatine concentrations in the pons dorsal and putamen. Cho concentrations did not change significantly in selected brain regions. T2 increased in the cerebellar white matter and decreased in the splenium of the corpus callosum with aging, while the T2' decreased in the occipital GM, hand motor area, and putamen, and increased in the splenium of the corpus callosum. Correlations were found between NAA concentrations and T2' in the occipital GM and putamen and between creatine and phosphocreatine concentrations and T2' in the putamen. The effects of normal aging on brain metabolites and microstructure are region-dependent. Correlations between both processes are evident in the gray matter. The obtained data could be used as references for future studies on patients. © 2016 by American Journal of Neuroradiology.

Immunocytochemical detection of the microsomal glucose-6-phosphatase in human brain astrocytes.

PubMed

Bell, J E; Hume, R; Busuttil, A; Burchell, A

1993-10-01

Using an antibody raised against the catalytic subunit of glucose-6-phosphatase, this enzyme was immunolocalized in many astrocytes in 20 normal human brains. Double immunofluorescence studies showed co-localization of glial fibrillary acidic protein (GFAP) with glucose-6-phosphatase in astrocytes. However, not all GFAP-positive cells were also glucose-6-phosphatase positive, indicating that some astrocytes do not contain demonstrable expression of this enzyme. Reactive astrocytes in a variety of abnormal brains were strongly glucose-6-phosphatase positive, but neoplastic astrocytes were often only weakly positive. Expression of the enzyme could not be demonstrated in radial glia, neurons or oligodendroglia. Astrocytes normally contain glycogen and the demonstration that some astrocytes also contain glucose-6-phosphatase indicates that they are competent for both glycogenolysis and gluconeogenesis, which may be critical for neuronal welfare.

Reversible and regionally selective downregulation of brain cannabinoid CB1 receptors in chronic daily cannabis smokers.

PubMed

Hirvonen, J; Goodwin, R S; Li, C-T; Terry, G E; Zoghbi, S S; Morse, C; Pike, V W; Volkow, N D; Huestis, M A; Innis, R B

2012-06-01

Chronic cannabis (marijuana, hashish) smoking can result in dependence. Rodent studies show reversible downregulation of brain cannabinoid CB(1) (cannabinoid receptor type 1) receptors after chronic exposure to cannabis. However, whether downregulation occurs in humans who chronically smoke cannabis is unknown. Here we show, using positron emission tomography imaging, reversible and regionally selective downregulation of brain cannabinoid CB(1) receptors in human subjects who chronically smoke cannabis. Downregulation correlated with years of cannabis smoking and was selective to cortical brain regions. After ∼4 weeks of continuously monitored abstinence from cannabis on a secure research unit, CB(1) receptor density returned to normal levels. This is the first direct demonstration of cortical cannabinoid CB(1) receptor downregulation as a neuroadaptation that may promote cannabis dependence in human brain.

Between destiny and disease: genetics and molecular pathways of human central nervous system aging.

PubMed

Glorioso, Christin; Sibille, Etienne

2011-02-01

Aging of the human brain is associated with "normal" functional, structural, and molecular changes that underlie alterations in cognition, memory, mood and motor function, amongst other processes. Normal aging also imposes a robust constraint on the onset of many neurological diseases, ranging from late onset neurodegenerative diseases, such as Alzheimer's (AD) and Parkinson's diseases (PD), to early onset psychiatric disorders, such as bipolar disorder (BPD) and schizophrenia (SCZ). The molecular mechanisms and genetic underpinnings of age-related changes in the brain are understudied, and, while they share some overlap with peripheral mechanisms of aging, many are unique to the largely non-mitotic brain. Hence, understanding mechanisms of brain aging and identifying associated modulators may have profound consequences for the prevention and treatment of age-related impairments and diseases. Here we review current knowledge on age-related functional and structural changes, their molecular and genetic underpinnings, and discuss how these pathways may contribute to the vulnerability to develop age-related neurological diseases. We highlight recent findings from human post-mortem brain microarray studies, which we hypothesize, point to a potential genetically controlled transcriptional program underlying molecular changes and age-gating of neurological diseases. Finally, we discuss the implications of this model for understanding basic mechanisms of brain aging and for the future investigation of therapeutic approaches. Copyright © 2010 Elsevier Ltd. All rights reserved.

Extracting morphologies from third harmonic generation images of structurally normal human brain tissue.

PubMed

Zhang, Zhiqing; Kuzmin, Nikolay V; Groot, Marie Louise; de Munck, Jan C

2017-06-01

The morphologies contained in 3D third harmonic generation (THG) images of human brain tissue can report on the pathological state of the tissue. However, the complexity of THG brain images makes the usage of modern image processing tools, especially those of image filtering, segmentation and validation, to extract this information challenging. We developed a salient edge-enhancing model of anisotropic diffusion for image filtering, based on higher order statistics. We split the intrinsic 3-phase segmentation problem into two 2-phase segmentation problems, each of which we solved with a dedicated model, active contour weighted by prior extreme. We applied the novel proposed algorithms to THG images of structurally normal ex-vivo human brain tissue, revealing key tissue components-brain cells, microvessels and neuropil, enabling statistical characterization of these components. Comprehensive comparison to manually delineated ground truth validated the proposed algorithms. Quantitative comparison to second harmonic generation/auto-fluorescence images, acquired simultaneously from the same tissue area, confirmed the correctness of the main THG features detected. The software and test datasets are available from the authors. z.zhang@vu.nl. Supplementary data are available at Bioinformatics online. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

Periodontal disease associates with higher brain amyloid load in normal elderly

PubMed Central

Kamer, Angela R.; Pirraglia, Elizabeth; Tsui, Wai; Rusinek, Henry; Vallabhajosula, Shankar; Mosconi, Lisa; Yi, Li; McHugh, Pauline; Craig, Ronald G.; Svetcov, Spencer; Linker, Ross; Shi, Chen; Glodzik, Lidia; Williams, Schantel; Corby, Patricia; Saxena, Deepak; de Leon, Mony J.

2015-01-01

Background The accumulation of amyloid β plaques (Aβ) is a central feature of Alzheimer’s disease (AD). First reported in animal models, it remains uncertain if peripheral inflammatory/infectious conditions in humans can promote Aβ brain accumulation. Periodontal disease, a common chronic infection, has been previously reported to be associated with AD. Methods Thirty-eight cognitively normal, healthy, community residing elderly (mean age 61; 68% female) were examined in an Alzheimer’s Disease research center and a University-based Dental School. Linear regression models (adjusted for age, ApoE and smoking) were used to test the hypothesis that periodontal disease assessed by clinical attachment loss was associated with brain Aβ load using 11C-PIB PET imaging. Results After adjusting for confounders, clinical attachment loss (≥ 3mm), representing a history of periodontal inflammatory/infectious burden, was associated with increased 11C-PIB uptake in Aβ vulnerable brain regions (p=0.002). Conclusion We show for the first time in humans an association between periodontal disease and brain Aβ load. These data are consistent with prior animal studies showing that peripheral inflammation/infections are sufficient to produce brain Aβ accumulations. PMID:25491073

Immunocytochemical Studies of Neurofibrillary Tangles

PubMed Central

Yen, Shu-Hui C.; Gaskin, Felicia; Terry, Robert D.

1981-01-01

The molecular nature of neurofibrillary tangles of senile dementia of the Alzheimer type (SDAT) was studied by immunoperoxidase and immunofluorescence techniques. Five antiserums, including anti-humanbrain-2-cycle-purified-microtubule-fractions (2 × MT), anti-calf-brain-2 × MT, anti-sea-urchin-egg-tubulin, antibeef-brain-tubulin, and anti-human-brain-neurofilament(NF)-210-kilodalton(kd)-protein were tested for their binding to neurofibrillary tangles. The antihuman-2 × MT serum stained structures resembling neurofibrillary tangles, neurites of neuritic plaques, and microglialike cells in SDAT brains, but no such staining pattern was detected in normal brain sections. In neurons isolated from SDAT brains, about 40% of the tangles were labeled by the anti-human-2×MT serum with an identical pattern. Other antiserums tested did not preferentially bind tanglelike structures in tissue sections and bound to less than 5% of the tangles in isolated neurons. These results suggest that the antigenic sites of tubulin and NF proteins are not shared by neurofibrillary tangles. Different from the calf preparation, the human-2 × MT fractions contained a prominent protein band that was identical to ferritin in molecular weight and cross-reacted with anti-human-2 × MT and anti-human-ferritin serums. However, antiserums to this ferritinlike protein, or anti-ferritin, did not stain neurofibrillary tangles. Although neither the calf 2 × MT nor two other human MT fractions failed to elicit an antiserum that stained tangles, these fractions were able to remove the antihuman-2 × MT serum activity that binds to tangles. The data suggest that the protein (or proteins) that makes up neurofibrillary tangles of SDAT is present in various quantities in microtubule fractions of normal brain. ImagesFigure 1Figure 2Figure 3Figure 4Figure 5Figure 6Figure 7Figure 8Figure 9Figure 10Figure 11Figure 12Figure 13Figure 14Figure 15Figure 16 PMID:7020426

Evaluation of [11C]TAZA for amyloid β plaque imaging in postmortem human Alzheimer's disease brain region and whole body distribution in rodent PET/CT.

PubMed

Pan, Min-Liang; Mukherjee, Meenakshi T; Patel, Himika H; Patel, Bhavin; Constantinescu, Cristian C; Mirbolooki, M Reza; Liang, Christopher; Mukherjee, Jogeshwar

2016-04-01

Alzheimer's disease (AD) is a neurodegenerative disease characterized by Aβ plaques in the brain. The aim of this study was to evaluate the effectiveness of a novel radiotracer, 4-[(11) C]methylamino-4'-N,N-dimethylaminoazobenzene ([(11)C]TAZA), for binding to Aβ plaques in postmortem human brain (AD and normal control (NC)). Radiosyntheses of [(11)C]TAZA, related [(11)C]Dalene ((11)C-methylamino-4'-dimethylaminostyrylbenzene), and reference [(11)C]PIB were carried out using [(11)C]methyltriflate prepared from [(11) C]CO(2) and purified using HPLC. In vitro binding affinities were carried out in human AD brain homogenate with Aβ plaques labeled with [(3) H]PIB. In vitro autoradiography studies with the three radiotracers were performed on hippocampus of AD and NC brains. PET/CT studies were carried out in normal rats to study brain and whole body distribution. The three radiotracers were produced in high radiochemical yields (>40%) and had specific activities >37 GBq/μmol. TAZA had an affinity, K(i) = 0.84 nM and was five times more potent than PIB. [(11)C]TAZA bound specifically to Aβ plaques present in AD brains with gray matter to white matter ratios >20. [(11)C]TAZA was displaced by PIB (>90%), suggesting similar binding site for [(11)C]TAZA and [(11)C]PIB. [(11)C]TAZA exhibited slow kinetics of uptake in the rat brain and whole body images showed uptake in interscapular brown adipose tissue (IBAT). Binding in brain and IBAT were affected by preinjection of atomoxetine, a norepinephrine transporter blocker. [(11)C]TAZA exhibited high binding to Aβ plaques in human AD hippocampus. Rat brain kinetics was slow and peripheral binding to IBAT needs to be further evaluated. © 2016 Wiley Periodicals, Inc.

Energetic and nutritional constraints on infant brain development: implications for brain expansion during human evolution.

PubMed

Cunnane, Stephen C; Crawford, Michael A

2014-12-01

The human brain confronts two major challenges during its development: (i) meeting a very high energy requirement, and (ii) reliably accessing an adequate dietary source of specific brain selective nutrients needed for its structure and function. Implicitly, these energetic and nutritional constraints to normal brain development today would also have been constraints on human brain evolution. The energetic constraint was solved in large measure by the evolution in hominins of a unique and significant layer of body fat on the fetus starting during the third trimester of gestation. By providing fatty acids for ketone production that are needed as brain fuel, this fat layer supports the brain's high energy needs well into childhood. This fat layer also contains an important reserve of the brain selective omega-3 fatty acid, docosahexaenoic acid (DHA), not available in other primates. Foremost amongst the brain selective minerals are iodine and iron, with zinc, copper and selenium also being important. A shore-based diet, i.e., fish, molluscs, crustaceans, frogs, bird's eggs and aquatic plants, provides the richest known dietary sources of brain selective nutrients. Regular access to these foods by the early hominin lineage that evolved into humans would therefore have helped free the nutritional constraint on primate brain development and function. Inadequate dietary supply of brain selective nutrients still has a deleterious impact on human brain development on a global scale today, demonstrating the brain's ongoing vulnerability. The core of the shore-based paradigm of human brain evolution proposes that sustained access by certain groups of early Homo to freshwater and marine food resources would have helped surmount both the nutritional as well as the energetic constraints on mammalian brain development. Copyright © 2014 Elsevier Ltd. All rights reserved.

Contribution of neuroinflammation and immunity to brain aging and the mitigating effects of physical and cognitive interventions.

PubMed

Di Benedetto, Svetlana; Müller, Ludmila; Wenger, Elisabeth; Düzel, Sandra; Pawelec, Graham

2017-04-01

It is widely accepted that the brain and the immune system continuously interact during normal as well as pathological functioning. Human aging is commonly accompanied by low-grade inflammation in both the immune and central nervous systems, thought to contribute to many age-related diseases. This review of the current literature focuses first on the normal neuroimmune interactions occurring in the brain, which promote learning, memory and neuroplasticity. Further, we discuss the protective and dynamic role of barriers to neuroimmune interactions, which have become clearer with the recent discovery of the meningeal lymphatic system. Next, we consider age-related changes of the immune system and possible deleterious influences of immunosenescence and low-grade inflammation (inflammaging) on neurodegenerative processes in the normally aging brain. We survey the major immunomodulators and neuroregulators in the aging brain and their highly tuned dynamic and reciprocal interactions. Finally, we consider our current understanding of how physical activity, as well as a combination of physical and cognitive interventions, may mediate anti-inflammatory effects and thus positively impact brain aging. Copyright © 2017 Elsevier Ltd. All rights reserved.

Brain white matter development is associated with a human-specific haplotype increasing the synthesis of long chain fatty acids.

PubMed

Peters, Bart D; Voineskos, Aristotle N; Szeszko, Philip R; Lett, Tristram A; DeRosse, Pamela; Guha, Saurav; Karlsgodt, Katherine H; Ikuta, Toshikazu; Felsky, Daniel; John, Majnu; Rotenberg, David J; Kennedy, James L; Lencz, Todd; Malhotra, Anil K

2014-04-30

The genetic and molecular pathways driving human brain white matter (WM) development are only beginning to be discovered. Long chain polyunsaturated fatty acids (LC-PUFAs) have been implicated in myelination in animal models and humans. The biosynthesis of LC-PUFAs is regulated by the fatty acid desaturase (FADS) genes, of which a human-specific haplotype is strongly associated with ω-3 and ω-6 LC-PUFA concentrations in blood. To investigate the relationship between LC-PUFA synthesis and human brain WM development, we examined whether this FADS haplotype is associated with age-related WM differences across the life span in healthy individuals 9-86 years of age (n = 207). Diffusion tensor imaging was performed to measure fractional anisotropy (FA), a putative measure of myelination, of the cerebral WM tracts. FADS haplotype status was determined with a single nucleotide polymorphism (rs174583) that tags this haplotype. Overall, normal age-related WM differences were observed, including higher FA values in early adulthood compared with childhood, followed by lower FA values across older age ranges. However, individuals homozygous for the minor allele (associated with lower LC-PUFA concentrations) did not display these normal age-related WM differences (significant age × genotype interactions, p(corrected) < 0.05). These findings suggest that LC-PUFAs are involved in human brain WM development from childhood into adulthood. This haplotype and LC-PUFAs may play a role in myelin-related disorders of neurodevelopmental origin.

A guide to the metabolic pathways and function of metabolites observed in human brain 1H magnetic resonance spectra.

PubMed

Rae, Caroline D

2014-01-01

The current knowledge of the normal biochemistry of compounds that give rise to resonances in human brain proton magnetic resonance spectra measureable at readily available field strengths (i.e. ≤3 T) is reviewed. Molecules covered include myo- and scyllo-inositol, glycerophospho- and phospho-choline and choline, creatine and phosphocreatine, N-acetylaspartate, N-acetylaspartylglutamate, glutamate, glutamine, γ-aminobutyrate, glucose, glutathione and lactate. The factors which influence changes in the levels of these compounds are discussed. As most proton resonances in the brain at low field are derived from a combination of moieties whose biochemistry is complex and interrelated, an understanding of the mechanisms underlying why these species change is crucial to meaningful interpretation of human brain spectra.

Enhanced cortical connectivity in absolute pitch musicians: a model for local hyperconnectivity.

PubMed

Loui, Psyche; Li, H Charles; Hohmann, Anja; Schlaug, Gottfried

2011-04-01

Connectivity in the human brain has received increased scientific interest in recent years. Although connection disorders can affect perception, production, learning, and memory, few studies have associated brain connectivity with graded variations in human behavior, especially among normal individuals. One group of normal individuals who possess unique characteristics in both behavior and brain structure is absolute pitch (AP) musicians, who can name the appropriate pitch class of any given tone without a reference. Using diffusion tensor imaging and tractography, we observed hyperconnectivity in bilateral superior temporal lobe structures linked to AP possession. Furthermore, volume of tracts connecting left superior temporal gyrus to left middle temporal gyrus predicted AP performance. These findings extend previous reports of exaggerated temporal lobe asymmetry, may explain the higher incidence of AP in special populations, and may provide a model for understanding the heightened connectivity that is thought to underlie savant skills and cases of exceptional creativity.

Enhanced Cortical Connectivity in Absolute Pitch Musicians: A Model for Local Hyperconnectivity

PubMed Central

Loui, Psyche; Charles Li, Hui C.; Hohmann, Anja; Schlaug, Gottfried

2010-01-01

Connectivity in the human brain has received increased scientific interest in recent years. Although connection disorders can affect perception, production, learning, and memory, few studies have associated brain connectivity with graded variations in human behavior, especially among normal individuals. One group of normal individuals who possess unique characteristics in both behavior and brain structure is absolute pitch (AP) musicians, who can name the appropriate pitch class of any given tone without a reference. Using diffusion tensor imaging and tractography, we observed hyperconnectivity in bilateral superior temporal lobe structures linked to AP possession. Furthermore, volume of tracts connecting left superior temporal gyrus to left middle temporal gyrus predicted AP performance. These findings extend previous reports of exaggerated temporal lobe asymmetry, may explain the higher incidence of AP in developmental disorders, and may provide a model for understanding the heightened connectivity that is thought to underlie savant skills and cases of exceptional creativity. PMID:20515408

Genome-Scale Reconstruction of the Human Astrocyte Metabolic Network

PubMed Central

Martín-Jiménez, Cynthia A.; Salazar-Barreto, Diego; Barreto, George E.; González, Janneth

2017-01-01

Astrocytes are the most abundant cells of the central nervous system; they have a predominant role in maintaining brain metabolism. In this sense, abnormal metabolic states have been found in different neuropathological diseases. Determination of metabolic states of astrocytes is difficult to model using current experimental approaches given the high number of reactions and metabolites present. Thus, genome-scale metabolic networks derived from transcriptomic data can be used as a framework to elucidate how astrocytes modulate human brain metabolic states during normal conditions and in neurodegenerative diseases. We performed a Genome-Scale Reconstruction of the Human Astrocyte Metabolic Network with the purpose of elucidating a significant portion of the metabolic map of the astrocyte. This is the first global high-quality, manually curated metabolic reconstruction network of a human astrocyte. It includes 5,007 metabolites and 5,659 reactions distributed among 8 cell compartments, (extracellular, cytoplasm, mitochondria, endoplasmic reticle, Golgi apparatus, lysosome, peroxisome and nucleus). Using the reconstructed network, the metabolic capabilities of human astrocytes were calculated and compared both in normal and ischemic conditions. We identified reactions activated in these two states, which can be useful for understanding the astrocytic pathways that are affected during brain disease. Additionally, we also showed that the obtained flux distributions in the model, are in accordance with literature-based findings. Up to date, this is the most complete representation of the human astrocyte in terms of inclusion of genes, proteins, reactions and metabolic pathways, being a useful guide for in-silico analysis of several metabolic behaviors of the astrocyte during normal and pathologic states. PMID:28243200

Rethinking schizophrenia in the context of normal neurodevelopment

PubMed Central

Catts, Vibeke S.; Fung, Samantha J.; Long, Leonora E.; Joshi, Dipesh; Vercammen, Ans; Allen, Katherine M.; Fillman, Stu G.; Rothmond, Debora A.; Sinclair, Duncan; Tiwari, Yash; Tsai, Shan-Yuan; Weickert, Thomas W.; Shannon Weickert, Cynthia

2013-01-01

The schizophrenia brain is differentiated from the normal brain by subtle changes, with significant overlap in measures between normal and disease states. For the past 25 years, schizophrenia has increasingly been considered a neurodevelopmental disorder. This frame of reference challenges biological researchers to consider how pathological changes identified in adult brain tissue can be accounted for by aberrant developmental processes occurring during fetal, childhood, or adolescent periods. To place schizophrenia neuropathology in a neurodevelopmental context requires solid, scrutinized evidence of changes occurring during normal development of the human brain, particularly in the cortex; however, too often data on normative developmental change are selectively referenced. This paper focuses on the development of the prefrontal cortex and charts major molecular, cellular, and behavioral events on a similar time line. We first consider the time at which human cognitive abilities such as selective attention, working memory, and inhibitory control mature, emphasizing that attainment of full adult potential is a process requiring decades. We review the timing of neurogenesis, neuronal migration, white matter changes (myelination), and synapse development. We consider how molecular changes in neurotransmitter signaling pathways are altered throughout life and how they may be concomitant with cellular and cognitive changes. We end with a consideration of how the response to drugs of abuse changes with age. We conclude that the concepts around the timing of cortical neuronal migration, interneuron maturation, and synaptic regression in humans may need revision and include greater emphasis on the protracted and dynamic changes occurring in adolescence. Updating our current understanding of post-natal neurodevelopment should aid researchers in interpreting gray matter changes and derailed neurodevelopmental processes that could underlie emergence of psychosis. PMID:23720610

Ascorbic acid, cognitive function, and Alzheimer’s disease: a current review and future direction

PubMed Central

Bowman, Gene L.

2013-01-01

This narrative review appraises the human and animal studies implicating ascorbic acid (AA) in normal cognitive function and Alzheimer’s disease. A research framework for how nutrition affects brain aging is proposed with emphasis on AA intake, status, metabolism, and transport into brain tissue. A final synopsis highlights areas for future research regarding AA nourishment and healthy brain aging. PMID:22419527

The biochemical, nanomechanical and chemometric signatures of brain cancer.

PubMed

Abramczyk, Halina; Imiela, Anna

2018-01-05

Raman spectroscopy and imaging combined with AFM topography and mechanical indentation by AFM have been shown to be an effective tool for analysis and discrimination of human brain tumors from normal structures. Raman methods have potential to be applied in clinical practice as they allow for identification of tumor margins during surgery. In this study, we investigate medulloblastoma (grade IV WHO) (n=5) and the tissue from the negative margins used as normal controls. We compare a high grade medulloblastoma (IV grade), and non-tumor samples from human central nervous system (CNS) tissue. Based on the properties of the Raman vibrational spectra and Raman images we provide a real-time feedback that is label-free method to monitor tumor metabolism that reveals reprogramming of biosynthesis of lipids, and proteins. We have found that the high-grade tumors of central nervous system (medulloblastoma) exhibit enhanced level of β-sheet conformation and down-regulated level of α-helix conformation when comparing against normal tissue. We have shown that the ratio of Raman intensities I2930/I2845 at 2930 and 2845cm -1 is a good source of information on the ratio of lipid and protein contents. We have found that the ratio reflects the lipid and protein contents of tumorous brain tissue compared to the non-tumor tissue. Almost all brain tumors have the Raman intensity ratios significantly higher (1.99±0.026) than that found in non-tumor brain tissue, which is 1.456±0.02, and indicates that the relative amount of lipids compared to proteins is significantly higher in the normal brain tissue. Mechanical indentation using AFM on sliced human brain tissues (medulloblastoma, grade IV) revealed that the mechanical properties of this tissue are strongly heterogeneous, between 1.8 and 75.7kPa, and the mean of 27.16kPa. The sensitivity and specificity obtained directly from PLSDA and cross validation gives a sensitivity and specificity of 98.5% and 96% and 96.3% and 92% for cross-validation, respectively. The high sensitivity and specificity demonstrates usefulness for a proper decision for a Raman diagnostic test on biochemical alterations monitored by Raman spectroscopy related to brain cancer development. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Compression stiffening of brain and its effect on mechanosensing by glioma cells

NASA Astrophysics Data System (ADS)

Pogoda, Katarzyna; Chin, LiKang; Georges, Penelope C.; Byfield, FitzRoy J.; Bucki, Robert; Kim, Richard; Weaver, Michael; Wells, Rebecca G.; Marcinkiewicz, Cezary; Janmey, Paul A.

2014-07-01

Many cell types, including neurons, astrocytes and other cells of the central nervous system, respond to changes in the extracellular matrix or substrate viscoelasticity, and increased tissue stiffness is a hallmark of several disease states, including fibrosis and some types of cancers. Whether the malignant tissue in brain, an organ that lacks the protein-based filamentous extracellular matrix of other organs, exhibits the same macroscopic stiffening characteristic of breast, colon, pancreatic and other tumors is not known. In this study we show that glioma cells, like normal astrocytes, respond strongly in vitro to substrate stiffness in the range of 100 to 2000 Pa, but that macroscopic (mm to cm) tissue samples isolated from human glioma tumors have elastic moduli in the order of 200 Pa that are indistinguishable from those of normal brain. However, both normal brain and glioma tissues increase their shear elastic moduli under modest uniaxial compression, and glioma tissue stiffens more strongly under compression than normal brain. These findings suggest that local tissue stiffness has the potential to alter glial cell function, and that stiffness changes in brain tumors might arise not from increased deposition or crosslinking of the collagen-rich extracellular matrix, but from pressure gradients that form within the tumors in vivo.

Evolutionary aspects of diet: the omega-6/omega-3 ratio and the brain.

PubMed

Simopoulos, Artemis P

2011-10-01

Several sources of information suggest that human beings evolved on a diet that had a ratio of omega-6 to omega-3 fatty acids (FA) of about 1/1; whereas today, Western diets have a ratio of 10/1 to 20-25/1, indicating that Western diets are deficient in omega-3 FA compared with the diet on which humans evolved and their genetic patterns were established. Omega-6 and omega-3 FA are not interconvertible in the human body and are important components of practically all cell membranes. Studies with nonhuman primates and human newborns indicate that docosahexaenoic acid (DHA) is essential for the normal functional development of the brain and retina, particularly in premature infants. DHA accounts for 40% of the membrane phospholipid FA in the brain. Both eicosapentaenoic acid (EPA) and DHA have an effect on membrane receptor function and even neurotransmitter generation and metabolism. There is growing evidence that EPA and DHA could play a role in hostility and violence in addition to the beneficial effects in substance abuse disorders and alcoholism. The balance of omega-6 and omega-3 FA is important for homeostasis and normal development throughout the life cycle.

Markers for human brain pericytes and smooth muscle cells.

PubMed

Smyth, Leon C D; Rustenhoven, Justin; Scotter, Emma L; Schweder, Patrick; Faull, Richard L M; Park, Thomas I H; Dragunow, Mike

2018-06-07

Brain pericytes and vascular smooth muscle cells (vSMCs) are a critical component of the neurovascular unit and are important in regulating cerebral blood flow and blood-brain barrier integrity. Identification of subtypes of mural cells in tissue and in vitro is important to any study of their function, therefore we identified distinct mural cell morphologies in neurologically normal post-mortem human brain. Further, the distribution of mural cell markers platelet-derived growth factor receptor-β (PDGFRβ), α-smooth muscle actin (αSMA), CD13, neural/glial antigen-2 (NG2), CD146 and desmin was examined. We determined that PDGFRβ, NG2, CD13, and CD146 were expressed in capillary-associated pericytes. NG2, and CD13 were also present on vSMCs in large vessels, however abundant CD146 and desmin staining was also detected in vSMCs on large vessels, co-labelling with αSMA. To determine whether cultures recapitulated observations from tissue, primary human brain pericytes derived from neurologically normal autopsies were analysed for the presence of pericyte markers by immunocytochemistry, western blotting and qPCR. The proteins observed in brain pericytes in tissue (PDGFRβ, αSMA, desmin, CD146, CD13, and NG2) were present in vitro, validating a panel of proteins that can be used to label brain pericytes and vSMCs in tissue and in vitro. Finally, we showed that the proteins CD146 and desmin that are expressed on large vessels in situ, are also selective markers of a smooth muscle cell phenotype in vitro. Copyright © 2018 Elsevier B.V. All rights reserved.

Sense of agency in the human brain.

PubMed

Haggard, Patrick

2017-04-01

In adult life, people normally know what they are doing. This experience of controlling one's own actions and, through them, the course of events in the outside world is called 'sense of agency'. It forms a central feature of human experience; however, the brain mechanisms that produce the sense of agency have only recently begun to be investigated systematically. This recent progress has been driven by the development of better measures of the experience of agency, improved design of cognitive and behavioural experiments, and a growing understanding of the brain circuits that generate this distinctive but elusive experience. The sense of agency is a mental and neural state of cardinal importance in human civilization, because it is frequently altered in psychopathology and because it underpins the concept of responsibility in human societies.

Positron Spectroscopy Investigation of Normal Brain Section and Brain Section with Glioma Derived from a Rat Glioma Model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, SH.; Ballmann, C.; Quarles, C. A.

2009-03-10

The application of positron annihilation lifetime spectroscopy (PALS) and Doppler broadening spectroscopy (DBS) to the study of animal or human tissue has only recently been reported [G. Liu, et al. phys. stat. sol. (C) 4, Nos. 10, 3912-3915 (2007)]. We have initiated a study of normal brain section and brain section with glioma derived from a rat glioma model. For the rat glioma model, 200,000 C6 cells were implanted in the basal ganglion of adult Sprague Dawley rats. The rats were sacrificed at 21 days after implantation. The brains were harvested, sliced into 2 mm thick coronal sections, and fixedmore » in 4% formalin. PALS lifetime runs were made with the samples soaked in formalin, and there was not significant evaporation of formalin during the runs. The lifetime spectra were analyzed into two lifetime components. While early results suggested a small decrease in ortho-Positronium (o-Ps) pickoff lifetime between the normal brain section and brain section with glioma, further runs with additional samples have showed no statistically significant difference between the normal and tumor tissue for this type of tumor. The o-Ps lifetime in formalin alone was lower than either the normal tissue or glioma sample. So annihilation in the formalin absorbed in the samples would lower the o-Ps lifetime and this may have masked any difference due to the glioma itself. DBS was also used to investigate the difference in positronium formation between tumor and normal tissue. Tissue samples are heterogeneous and this needs to be carefully considered if PALS and DBS are to become useful tools in distinguishing tissue samples.« less

The Role of Standardized and Study-specific Human Brain Diffusion Tensor Templates in Inter-subject Spatial Normalization

PubMed Central

Zhang, Shengwei; Arfanakis, Konstantinos

2012-01-01

Purpose To investigate the effect of standardized and study-specific human brain diffusion tensor templates on the accuracy of spatial normalization, without ignoring the important roles of data quality and registration algorithm effectiveness. Materials and Methods Two groups of diffusion tensor imaging (DTI) datasets, with and without visible artifacts, were normalized to two standardized diffusion tensor templates (IIT2, ICBM81) as well as study-specific templates, using three registration approaches. The accuracy of inter-subject spatial normalization was compared across templates, using the most effective registration technique for each template and group of data. Results It was demonstrated that, for DTI data with visible artifacts, the study-specific template resulted in significantly higher spatial normalization accuracy than standardized templates. However, for data without visible artifacts, the study-specific template and the standardized template of higher quality (IIT2) resulted in similar normalization accuracy. Conclusion For DTI data with visible artifacts, a carefully constructed study-specific template may achieve higher normalization accuracy than that of standardized templates. However, as DTI data quality improves, a high-quality standardized template may be more advantageous than a study-specific template, since in addition to high normalization accuracy, it provides a standard reference across studies, as well as automated localization/segmentation when accompanied by anatomical labels. PMID:23034880

Toward Developmental Connectomics of the Human Brain

PubMed Central

Cao, Miao; Huang, Hao; Peng, Yun; Dong, Qi; He, Yong

2016-01-01

Imaging connectomics based on graph theory has become an effective and unique methodological framework for studying structural and functional connectivity patterns of the developing brain. Normal brain development is characterized by continuous and significant network evolution throughout infancy, childhood, and adolescence, following specific maturational patterns. Disruption of these normal changes is associated with neuropsychiatric developmental disorders, such as autism spectrum disorders or attention-deficit hyperactivity disorder. In this review, we focused on the recent progresses regarding typical and atypical development of human brain networks from birth to early adulthood, using a connectomic approach. Specifically, by the time of birth, structural networks already exhibit adult-like organization, with global efficient small-world and modular structures, as well as hub regions and rich-clubs acting as communication backbones. During development, the structure networks are fine-tuned, with increased global integration and robustness and decreased local segregation, as well as the strengthening of the hubs. In parallel, functional networks undergo more dramatic changes during maturation, with both increased integration and segregation during development, as brain hubs shift from primary regions to high order functioning regions, and the organization of modules transitions from a local anatomical emphasis to a more distributed architecture. These findings suggest that structural networks develop earlier than functional networks; meanwhile functional networks demonstrate more dramatic maturational changes with the evolution of structural networks serving as the anatomical backbone. In this review, we also highlighted topologically disorganized characteristics in structural and functional brain networks in several major developmental neuropsychiatric disorders (e.g., autism spectrum disorders, attention-deficit hyperactivity disorder and developmental dyslexia). Collectively, we showed that delineation of the brain network from a connectomics perspective offers a unique and refreshing view of both normal development and neuropsychiatric disorders. PMID:27064378

[Factor structure of regional CBF and CMRglu values as a tool for the study of default mode of the brain].

PubMed

Kataev, G V; Korotkov, A D; Kireev, M V; Medvedev, S V

2013-01-01

In the present article it was shown that the functional connectivity of brain structures, revealed by factor analysis of resting PET CBF and rCMRglu data, is an adequate tool to study the default mode of the human brain. The identification of neuroanatomic systems of default mode (default mode network) during routine clinical PET investigations is important for further studying the functional organization of the normal brain and its reorganizations in pathological conditions.

A pediatric brain structure atlas from T1-weighted MR images

NASA Astrophysics Data System (ADS)

Shan, Zuyao Y.; Parra, Carlos; Ji, Qing; Ogg, Robert J.; Zhang, Yong; Laningham, Fred H.; Reddick, Wilburn E.

2006-03-01

In this paper, we have developed a digital atlas of the pediatric human brain. Human brain atlases, used to visualize spatially complex structures of the brain, are indispensable tools in model-based segmentation and quantitative analysis of brain structures. However, adult brain atlases do not adequately represent the normal maturational patterns of the pediatric brain, and the use of an adult model in pediatric studies may introduce substantial bias. Therefore, we proposed to develop a digital atlas of the pediatric human brain in this study. The atlas was constructed from T1 weighted MR data set of a 9 year old, right-handed girl. Furthermore, we extracted and simplified boundary surfaces of 25 manually defined brain structures (cortical and subcortical) based on surface curvature. Higher curvature surfaces were simplified with more reference points; lower curvature surfaces, with fewer. We constructed a 3D triangular mesh model for each structure by triangulation of the structure's reference points. Kappa statistics (cortical, 0.97; subcortical, 0.91) indicated substantial similarities between the mesh-defined and the original volumes. Our brain atlas and structural mesh models (www.stjude.org/BrainAtlas) can be used to plan treatment, to conduct knowledge and modeldriven segmentation, and to analyze the shapes of brain structures in pediatric patients.

The hubs of the human connectome are generally implicated in the anatomy of brain disorders.

PubMed

Crossley, Nicolas A; Mechelli, Andrea; Scott, Jessica; Carletti, Francesco; Fox, Peter T; McGuire, Philip; Bullmore, Edward T

2014-08-01

Brain networks or 'connectomes' include a minority of highly connected hub nodes that are functionally valuable, because their topological centrality supports integrative processing and adaptive behaviours. Recent studies also suggest that hubs have higher metabolic demands and longer-distance connections than other brain regions, and therefore could be considered biologically costly. Assuming that hubs thus normally combine both high topological value and high biological cost, we predicted that pathological brain lesions would be concentrated in hub regions. To test this general hypothesis, we first identified the hubs of brain anatomical networks estimated from diffusion tensor imaging data on healthy volunteers (n = 56), and showed that computational attacks targeted on hubs disproportionally degraded the efficiency of brain networks compared to random attacks. We then prepared grey matter lesion maps, based on meta-analyses of published magnetic resonance imaging data on more than 20 000 subjects and 26 different brain disorders. Magnetic resonance imaging lesions that were common across all brain disorders were more likely to be located in hubs of the normal brain connectome (P < 10(-4), permutation test). Specifically, nine brain disorders had lesions that were significantly more likely to be located in hubs (P < 0.05, permutation test), including schizophrenia and Alzheimer's disease. Both these disorders had significantly hub-concentrated lesion distributions, although (almost completely) distinct subsets of cortical hubs were lesioned in each disorder: temporal lobe hubs specifically were associated with higher lesion probability in Alzheimer's disease, whereas in schizophrenia lesions were concentrated in both frontal and temporal cortical hubs. These results linking pathological lesions to the topological centrality of nodes in the normal diffusion tensor imaging connectome were generally replicated when hubs were defined instead by the meta-analysis of more than 1500 task-related functional neuroimaging studies of healthy volunteers to create a normative functional co-activation network. We conclude that the high cost/high value hubs of human brain networks are more likely to be anatomically abnormal than non-hubs in many (if not all) brain disorders. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain.

A link between FTO, ghrelin, and impaired brain food-cue responsivity

PubMed Central

Karra, Efthimia; O’Daly, Owen G.; Choudhury, Agharul I.; Yousseif, Ahmed; Millership, Steven; Neary, Marianne T.; Scott, William R.; Chandarana, Keval; Manning, Sean; Hess, Martin E.; Iwakura, Hiroshi; Akamizu, Takashi; Millet, Queensta; Gelegen, Cigdem; Drew, Megan E.; Rahman, Sofia; Emmanuel, Julian J.; Williams, Steven C.R.; Rüther, Ulrich U.; Brüning, Jens C.; Withers, Dominic J.; Zelaya, Fernando O.; Batterham, Rachel L.

2013-01-01

Polymorphisms in the fat mass and obesity-associated gene (FTO) are associated with human obesity and obesity-prone behaviors, including increased food intake and a preference for energy-dense foods. FTO demethylates N6-methyladenosine, a potential regulatory RNA modification, but the mechanisms by which FTO predisposes humans to obesity remain unclear. In adiposity-matched, normal-weight humans, we showed that subjects homozygous for the FTO “obesity-risk” rs9939609 A allele have dysregulated circulating levels of the orexigenic hormone acyl-ghrelin and attenuated postprandial appetite reduction. Using functional MRI (fMRI) in normal-weight AA and TT humans, we found that the FTO genotype modulates the neural responses to food images in homeostatic and brain reward regions. Furthermore, AA and TT subjects exhibited divergent neural responsiveness to circulating acyl-ghrelin within brain regions that regulate appetite, reward processing, and incentive motivation. In cell models, FTO overexpression reduced ghrelin mRNA N6-methyladenosine methylation, concomitantly increasing ghrelin mRNA and peptide levels. Furthermore, peripheral blood cells from AA human subjects exhibited increased FTO mRNA, reduced ghrelin mRNA N6-methyladenosine methylation, and increased ghrelin mRNA abundance compared with TT subjects. Our findings show that FTO regulates ghrelin, a key mediator of ingestive behavior, and offer insight into how FTO obesity-risk alleles predispose to increased energy intake and obesity in humans. PMID:23867619

A link between FTO, ghrelin, and impaired brain food-cue responsivity.

PubMed

Karra, Efthimia; O'Daly, Owen G; Choudhury, Agharul I; Yousseif, Ahmed; Millership, Steven; Neary, Marianne T; Scott, William R; Chandarana, Keval; Manning, Sean; Hess, Martin E; Iwakura, Hiroshi; Akamizu, Takashi; Millet, Queensta; Gelegen, Cigdem; Drew, Megan E; Rahman, Sofia; Emmanuel, Julian J; Williams, Steven C R; Rüther, Ulrich U; Brüning, Jens C; Withers, Dominic J; Zelaya, Fernando O; Batterham, Rachel L

2013-08-01

Polymorphisms in the fat mass and obesity-associated gene (FTO) are associated with human obesity and obesity-prone behaviors, including increased food intake and a preference for energy-dense foods. FTO demethylates N6-methyladenosine, a potential regulatory RNA modification, but the mechanisms by which FTO predisposes humans to obesity remain unclear. In adiposity-matched, normal-weight humans, we showed that subjects homozygous for the FTO "obesity-risk" rs9939609 A allele have dysregulated circulating levels of the orexigenic hormone acyl-ghrelin and attenuated postprandial appetite reduction. Using functional MRI (fMRI) in normal-weight AA and TT humans, we found that the FTO genotype modulates the neural responses to food images in homeostatic and brain reward regions. Furthermore, AA and TT subjects exhibited divergent neural responsiveness to circulating acyl-ghrelin within brain regions that regulate appetite, reward processing, and incentive motivation. In cell models, FTO overexpression reduced ghrelin mRNA N6-methyladenosine methylation, concomitantly increasing ghrelin mRNA and peptide levels. Furthermore, peripheral blood cells from AA human subjects exhibited increased FTO mRNA, reduced ghrelin mRNA N6-methyladenosine methylation, and increased ghrelin mRNA abundance compared with TT subjects. Our findings show that FTO regulates ghrelin, a key mediator of ingestive behavior, and offer insight into how FTO obesity-risk alleles predispose to increased energy intake and obesity in humans.

Resonance Raman Spectroscopy of human brain metastasis of lung cancer analyzed by blind source separation

NASA Astrophysics Data System (ADS)

Zhou, Yan; Liu, Cheng-Hui; Pu, Yang; Cheng, Gangge; Yu, Xinguang; Zhou, Lixin; Lin, Dongmei; Zhu, Ke; Alfano, Robert R.

2017-02-01

Resonance Raman (RR) spectroscopy offers a novel Optical Biopsy method in cancer discrimination by a means of enhancement in Raman scattering. It is widely acknowledged that the RR spectrum of tissue is a superposition of spectra of various key building block molecules. In this study, the Resonance Raman (RR) spectra of human metastasis of lung cancerous and normal brain tissues excited by a visible selected wavelength at 532 nm are used to explore spectral changes caused by the tumor evolution. The potential application of RR spectra human brain metastasis of lung cancer was investigated by Blind Source Separation such as Principal Component Analysis (PCA). PCA is a statistical procedure that uses an orthogonal transformation to convert a set of observations of possibly correlated variables into a set of values of linearly uncorrelated variables called principal components (PCs). The results show significant RR spectra difference between human metastasis of lung cancerous and normal brain tissues analyzed by PCA. To evaluate the efficacy of for cancer detection, a linear discriminant analysis (LDA) classifier is utilized to calculate the sensitivity, and specificity and the receiver operating characteristic (ROC) curves are used to evaluate the performance of this criterion. Excellent sensitivity of 0.97, specificity (close to 1.00) and the Area Under ROC Curve (AUC) of 0.99 values are achieved under best optimal circumstance. This research demonstrates that RR spectroscopy is effective for detecting changes of tissues due to the development of brain metastasis of lung cancer. RR spectroscopy analyzed by blind source separation may have potential to be a new armamentarium.

[ARTCEREB irrigation and perfusion solution for cerebrospinal surgery: pharmacological assessment using human astrocytes exposed to test solutions].

PubMed

Nishimura, Masuhiro; Doi, Kazuhisa; Enomoto, Riyo; Lee, Eibai; Naito, Shinsaku; Yamauchi, Aiko

2009-09-01

ARTCEREB irrigation and perfusion solution (Artcereb) is a preparation intended for the irrigation and perfusion of the cerebral ventricles, and it is therefore important to evaluate the effects of Artcereb on brain cells. In vitro assessment of the effects of Artcereb in cell cultures of human fetal astrocytes was conducted in comparison with normal saline and lactated Ringer's solution. The effects of exposure to Artcereb were evaluated based on microscopic images of the mitochondria stained with rhodamine 123. The effects of exposure to Artcereb on cell function were also evaluated by quantitative analysis of mitochondrial activity based on rhodamine 123 and (3)H-thymidine incorporation. Morphological changes in nuclear structure were also evaluated. The results of the present study showed that cell function in cell cultures of human astrocytes was relatively unaffected by exposure to Artcereb as compared with normal saline or lactated Ringer's solution, suggesting that Artcereb has less effect on brain cells than normal saline or lactated Ringer's solution when used for the irrigation or perfusion of the cerebral ventricles.

[Is abortion murder?].

PubMed

Werning, C

1995-09-01

Discussions about Paragraph 218 of the German federal abortion law have spawned antithetical opinions: on the one hand, the full right of the mother or parents to decide about the incipient human life; and on the other hand, under the dogma of abortion is murder, providing abortion is rejected even when the pregnancy is the result of rape and it is unwanted. Two questions are closely related to this issue: 1) what makes human beings human and 2) when does human life begin. From a medical point of view the function of the brain is fundamentally linked to being human. The brain controls almost all functions of the body and determines its psychological makeup, such as intellect and, in a theological sense, the soul. Without the brain such functioning is not possible, since brain death means the death of human life. Children born with anencephaly and microencephaly can never live a human life. At the end of life various diseases (stroke, Alzheimer disease) can severely damage the brain. In these cases normal living is also no longer possible. Yet ethically it is untenable to actively kill these human beings. But when one considers that life-threatening diseases can require life-support intervention, then often the pragmatic intervention is not far removed from active euthanasia. The other question related to the beginning of human life is even more difficult to answer. It is the fertilization of the egg cells; but a conglomeration of cells in the early phase of pregnancy can hardly be characterized as a human person. The human identity, personality, and worth is associated with the functioning of the brain, so only when the brain is fully developed can there be any talk about an unborn human being.

Asymmetry of Hemispheric Network Topology Reveals Dissociable Processes between Functional and Structural Brain Connectome in Community-Living Elders

PubMed Central

Sun, Yu; Li, Junhua; Suckling, John; Feng, Lei

2017-01-01

Human brain is structurally and functionally asymmetrical and the asymmetries of brain phenotypes have been shown to change in normal aging. Recent advances in graph theoretical analysis have showed topological lateralization between hemispheric networks in the human brain throughout the lifespan. Nevertheless, apparent discrepancies of hemispheric asymmetry were reported between the structural and functional brain networks, indicating the potentially complex asymmetry patterns between structural and functional networks in aging population. In this study, using multimodal neuroimaging (resting-state fMRI and structural diffusion tensor imaging), we investigated the characteristics of hemispheric network topology in 76 (male/female = 15/61, age = 70.08 ± 5.30 years) community-dwelling older adults. Hemispheric functional and structural brain networks were obtained for each participant. Graph theoretical approaches were then employed to estimate the hemispheric topological properties. We found that the optimal small-world properties were preserved in both structural and functional hemispheric networks in older adults. Moreover, a leftward asymmetry in both global and local levels were observed in structural brain networks in comparison with a symmetric pattern in functional brain network, suggesting a dissociable process of hemispheric asymmetry between structural and functional connectome in healthy older adults. Finally, the scores of hemispheric asymmetry in both structural and functional networks were associated with behavioral performance in various cognitive domains. Taken together, these findings provide new insights into the lateralized nature of multimodal brain connectivity, highlight the potentially complex relationship between structural and functional brain network alterations, and augment our understanding of asymmetric structural and functional specializations in normal aging. PMID:29209197

DUF1220 protein domains drive proliferation in human neural stem cells and are associated with increased cortical volume in anthropoid primates.

PubMed

Keeney, J G; Davis, J M; Siegenthaler, J; Post, M D; Nielsen, B S; Hopkins, W D; Sikela, J M

2015-09-01

Genome sequences encoding DUF1220 protein domains show a burst in copy number among anthropoid species and especially humans, where they have undergone the greatest human lineage-specific copy number expansion of any protein coding sequence in the genome. While DUF1220 copy number shows a dosage-related association with brain size in both normal populations and in 1q21.1-associated microcephaly and macrocephaly, a function for these domains has not yet been described. Here we provide multiple lines of evidence supporting the view that DUF1220 domains function as drivers of neural stem cell proliferation among anthropoid species including humans. First, we show that brain MRI data from 131 individuals across 7 anthropoid species shows a strong correlation between DUF1220 copy number and multiple brain size-related measures. Using in situ hybridization analyses of human fetal brain, we also show that DUF1220 domains are expressed in the ventricular zone and primarily during human cortical neurogenesis, and are therefore expressed at the right time and place to be affecting cortical brain development. Finally, we demonstrate that in vitro expression of DUF1220 sequences in neural stem cells strongly promotes proliferation. Taken together, these data provide the strongest evidence so far reported implicating DUF1220 dosage in anthropoid and human brain expansion through mechanisms involving increasing neural stem cell proliferation.

Novel strategies of Raman imaging for brain tumor research.

PubMed

Anna, Imiela; Bartosz, Polis; Lech, Polis; Halina, Abramczyk

2017-10-17

Raman diagnostics and imaging have been shown to be an effective tool for the analysis and discrimination of human brain tumors from normal structures. Raman spectroscopic methods have potential to be applied in clinical practice as they allow for identification of tumor margins during surgery. In this study, we investigate medulloblastoma (grade IV WHO) (n= 5), low-grade astrocytoma (grades I-II WHO) (n =4), ependymoma (n=3) and metastatic brain tumors (n= 1) and the tissue from the negative margins used as normal controls. We compare a high grade medulloblastoma, low grade astrocytoma and non-tumor samples from human central nervous system (CNS) tissue. Based on the properties of the Raman vibrational features and Raman images we provide a real-time feedback method that is label-free to monitor tumor metabolism that reveals reprogramming of biosynthesis of lipids, proteins, DNA and RNA. Our results indicate marked metabolic differences between low and high grade brain tumors. We discuss molecular mechanisms causing these metabolic changes, particularly lipid alterations in malignant medulloblastoma and low grade gliomas that may shed light on the mechanisms driving tumor recurrence thereby revealing new approaches for the treatment of malignant glioma. We have found that the high-grade tumors of central nervous system (medulloblastoma) exhibit enhanced level of β-sheet conformation and down-regulated level of α-helix conformation when comparing against normal tissue. We have found that almost all tumors studied in the paper have increased Raman signals of nucleic acids. This increase can be interpreted as increased DNA/RNA turnover in brain tumors. We have shown that the ratio of Raman intensities I 2930 /I 2845 at 2930 and 2845 cm -1 is a good source of information on the ratio of lipid and protein contents. We have found that the ratio reflects the different lipid and protein contents of cancerous brain tissue compared to the non-tumor tissue. We found that levels of the saturated fatty acids were significantly reduced in the high grade medulloblastoma samples compared with non-tumor brain samples and low grade astrocytoma. Differences were also noted in the n-6/n-3 polyunsaturated fatty acids (PUFA) content between medulloblastoma and non-tumor brain samples. The content of the oleic acid (OA) was significantly smaller in almost all brain high grade brain tumors than that observed in the control samples. It indicates that the fatty acid composition of human brain tumors differs from that found in non-tumor brain tissue. The iodine number N I for the normal brain tissue is 60. For comparison OA has 87, docosahexaenoic acid (DHA) 464, α-linolenic acid (ALA) 274. The high grade tumors have the iodine numbers between that for palmitic acid, stearic acid, arachidic acid (N I =0) and oleic acid (N I =87). Most low grade tumors have N I similar to that of OA. The iodine number for arachidonic acid (AA) (N I =334) is much higher than those observed for all studied samples.

Novel strategies of Raman imaging for brain tumor research

PubMed Central

Anna, Imiela; Bartosz, Polis; Lech, Polis; Halina, Abramczyk

2017-01-01

Raman diagnostics and imaging have been shown to be an effective tool for the analysis and discrimination of human brain tumors from normal structures. Raman spectroscopic methods have potential to be applied in clinical practice as they allow for identification of tumor margins during surgery. In this study, we investigate medulloblastoma (grade IV WHO) (n= 5), low-grade astrocytoma (grades I-II WHO) (n =4), ependymoma (n=3) and metastatic brain tumors (n= 1) and the tissue from the negative margins used as normal controls. We compare a high grade medulloblastoma, low grade astrocytoma and non-tumor samples from human central nervous system (CNS) tissue. Based on the properties of the Raman vibrational features and Raman images we provide a real–time feedback method that is label-free to monitor tumor metabolism that reveals reprogramming of biosynthesis of lipids, proteins, DNA and RNA. Our results indicate marked metabolic differences between low and high grade brain tumors. We discuss molecular mechanisms causing these metabolic changes, particularly lipid alterations in malignant medulloblastoma and low grade gliomas that may shed light on the mechanisms driving tumor recurrence thereby revealing new approaches for the treatment of malignant glioma. We have found that the high-grade tumors of central nervous system (medulloblastoma) exhibit enhanced level of β-sheet conformation and down-regulated level of α-helix conformation when comparing against normal tissue. We have found that almost all tumors studied in the paper have increased Raman signals of nucleic acids. This increase can be interpreted as increased DNA/RNA turnover in brain tumors. We have shown that the ratio of Raman intensities I2930/I2845 at 2930 and 2845 cm-1 is a good source of information on the ratio of lipid and protein contents. We have found that the ratio reflects the different lipid and protein contents of cancerous brain tissue compared to the non-tumor tissue. We found that levels of the saturated fatty acids were significantly reduced in the high grade medulloblastoma samples compared with non-tumor brain samples and low grade astrocytoma. Differences were also noted in the n-6/n-3 polyunsaturated fatty acids (PUFA) content between medulloblastoma and non-tumor brain samples. The content of the oleic acid (OA) was significantly smaller in almost all brain high grade brain tumors than that observed in the control samples. It indicates that the fatty acid composition of human brain tumors differs from that found in non-tumor brain tissue. The iodine number NI for the normal brain tissue is 60. For comparison OA has 87, docosahexaenoic acid (DHA) 464, α-linolenic acid (ALA) 274. The high grade tumors have the iodine numbers between that for palmitic acid, stearic acid, arachidic acid (NI=0) and oleic acid (NI=87). Most low grade tumors have NI similar to that of OA. The iodine number for arachidonic acid (AA) (NI=334) is much higher than those observed for all studied samples. PMID:29156720

A Hybrid CPU-GPU Accelerated Framework for Fast Mapping of High-Resolution Human Brain Connectome

PubMed Central

Ren, Ling; Xu, Mo; Xie, Teng; Gong, Gaolang; Xu, Ningyi; Yang, Huazhong; He, Yong

2013-01-01

Recently, a combination of non-invasive neuroimaging techniques and graph theoretical approaches has provided a unique opportunity for understanding the patterns of the structural and functional connectivity of the human brain (referred to as the human brain connectome). Currently, there is a very large amount of brain imaging data that have been collected, and there are very high requirements for the computational capabilities that are used in high-resolution connectome research. In this paper, we propose a hybrid CPU-GPU framework to accelerate the computation of the human brain connectome. We applied this framework to a publicly available resting-state functional MRI dataset from 197 participants. For each subject, we first computed Pearson’s Correlation coefficient between any pairs of the time series of gray-matter voxels, and then we constructed unweighted undirected brain networks with 58 k nodes and a sparsity range from 0.02% to 0.17%. Next, graphic properties of the functional brain networks were quantified, analyzed and compared with those of 15 corresponding random networks. With our proposed accelerating framework, the above process for each network cost 80∼150 minutes, depending on the network sparsity. Further analyses revealed that high-resolution functional brain networks have efficient small-world properties, significant modular structure, a power law degree distribution and highly connected nodes in the medial frontal and parietal cortical regions. These results are largely compatible with previous human brain network studies. Taken together, our proposed framework can substantially enhance the applicability and efficacy of high-resolution (voxel-based) brain network analysis, and have the potential to accelerate the mapping of the human brain connectome in normal and disease states. PMID:23675425

Default network connectivity decodes brain states with simulated microgravity.

PubMed

Zeng, Ling-Li; Liao, Yang; Zhou, Zongtan; Shen, Hui; Liu, Yadong; Liu, Xufeng; Hu, Dewen

2016-04-01

With great progress of space navigation technology, it becomes possible to travel beyond Earth's gravity. So far, it remains unclear whether the human brain can function normally within an environment of microgravity and confinement. Particularly, it is a challenge to figure out some neuroimaging-based markers for rapid screening diagnosis of disrupted brain function in microgravity environment. In this study, a 7-day -6° head down tilt bed rest experiment was used to simulate the microgravity, and twenty healthy male participants underwent resting-state functional magnetic resonance imaging scans at baseline and after the simulated microgravity experiment. We used a multivariate pattern analysis approach to distinguish the brain states with simulated microgravity from normal gravity based on the functional connectivity within the default network, resulting in an accuracy of no less than 85 % via cross-validation. Moreover, most discriminative functional connections were mainly located between the limbic system and cortical areas and were enhanced after simulated microgravity, implying a self-adaption or compensatory enhancement to fulfill the need of complex demand in spatial navigation and motor control functions in microgravity environment. Overall, the findings suggest that the brain states in microgravity are likely different from those in normal gravity and that brain connectome could act as a biomarker to indicate the brain state in microgravity.

Declarative and nondeclarative memory: multiple brain systems supporting learning and memory.

PubMed

Squire, L R

1992-01-01

Abstract The topic of multiple forms of memory is considered from a biological point of view. Fact-and-event (declarative, explicit) memory is contrasted with a collection of non conscious (non-declarative, implicit) memory abilities including skills and habits, priming, and simple conditioning. Recent evidence is reviewed indicating that declarative and non declarative forms of memory have different operating characteristics and depend on separate brain systems. A brain-systems framework for understanding memory phenomena is developed in light of lesion studies involving rats, monkeys, and humans, as well as recent studies with normal humans using the divided visual field technique, event-related potentials, and positron emission tomography (PET).

Do glutathione levels decline in aging human brain?

PubMed

Tong, Junchao; Fitzmaurice, Paul S; Moszczynska, Anna; Mattina, Katie; Ang, Lee-Cyn; Boileau, Isabelle; Furukawa, Yoshiaki; Sailasuta, Napapon; Kish, Stephen J

2016-04-01

For the past 60 years a major theory of "aging" is that age-related damage is largely caused by excessive uncompensated oxidative stress. The ubiquitous tripeptide glutathione is a major antioxidant defense mechanism against reactive free radicals and has also served as a marker of changes in oxidative stress. Some (albeit conflicting) animal data suggest a loss of glutathione in brain senescence, which might compromise the ability of the aging brain to meet the demands of oxidative stress. Our objective was to establish whether advancing age is associated with glutathione deficiency in human brain. We measured reduced glutathione (GSH) levels in multiple regions of autopsied brain of normal subjects (n=74) aged one day to 99 years. Brain GSH levels during the infancy/teenage years were generally similar to those in the oldest examined adult group (76-99 years). During adulthood (23-99 years) GSH levels remained either stable (occipital cortex) or increased (caudate nucleus, frontal and cerebellar cortices). To the extent that GSH levels represent glutathione antioxidant capacity, our postmortem data suggest that human brain aging is not associated with declining glutathione status. We suggest that aged healthy human brains can maintain antioxidant capacity related to glutathione and that an age-related increase in GSH levels in some brain regions might possibly be a compensatory response to increased oxidative stress. Since our findings, although suggestive, suffer from the generic limitations of all postmortem brain studies, we also suggest the need for "replication" investigations employing the new (1)H MRS imaging procedures in living human brain. Copyright © 2016 Elsevier Inc. All rights reserved.

BrainNet Viewer: a network visualization tool for human brain connectomics.

PubMed

Xia, Mingrui; Wang, Jinhui; He, Yong

2013-01-01

The human brain is a complex system whose topological organization can be represented using connectomics. Recent studies have shown that human connectomes can be constructed using various neuroimaging technologies and further characterized using sophisticated analytic strategies, such as graph theory. These methods reveal the intriguing topological architectures of human brain networks in healthy populations and explore the changes throughout normal development and aging and under various pathological conditions. However, given the huge complexity of this methodology, toolboxes for graph-based network visualization are still lacking. Here, using MATLAB with a graphical user interface (GUI), we developed a graph-theoretical network visualization toolbox, called BrainNet Viewer, to illustrate human connectomes as ball-and-stick models. Within this toolbox, several combinations of defined files with connectome information can be loaded to display different combinations of brain surface, nodes and edges. In addition, display properties, such as the color and size of network elements or the layout of the figure, can be adjusted within a comprehensive but easy-to-use settings panel. Moreover, BrainNet Viewer draws the brain surface, nodes and edges in sequence and displays brain networks in multiple views, as required by the user. The figure can be manipulated with certain interaction functions to display more detailed information. Furthermore, the figures can be exported as commonly used image file formats or demonstration video for further use. BrainNet Viewer helps researchers to visualize brain networks in an easy, flexible and quick manner, and this software is freely available on the NITRC website (www.nitrc.org/projects/bnv/).

Establishing Mouse Models for Zika Virus-induced Neurological Disorders Using Intracerebral Injection Strategies: Embryonic, Neonatal, and Adult.

PubMed

Herrlinger, Stephanie A; Shao, Qiang; Ma, Li; Brindley, Melinda; Chen, Jian-Fu

2018-04-26

The Zika virus (ZIKV) is a flavivirus currently endemic in North, Central, and South America. It is now established that the ZIKV can cause microcephaly and additional brain abnormalities. However, the mechanism underlying the pathogenesis of ZIKV in the developing brain remains unclear. Intracerebral surgical methods are frequently used in neuroscience research to address questions about both normal and abnormal brain development and brain function. This protocol utilizes classical surgical techniques and describes methods that allow one to model ZIKV-associated human neurological disease in the mouse nervous system. While direct brain inoculation does not model the normal mode of virus transmission, the method allows investigators to ask targeted questions concerning the consequence after ZIKV infection of the developing brain. This protocol describes embryonic, neonatal, and adult stages of intraventricular inoculation of ZIKV. Once mastered, this method can become a straightforward and reproducible technique that only takes a few hours to perform.

Gold nanoparticle imaging and radiotherapy of brain tumors in mice

PubMed Central

Hainfeld, James F; Smilowitz, Henry M; O'Connor, Michael J; Dilmanian, Farrokh Avraham; Slatkin, Daniel N

2013-01-01

Aim To test intravenously injected gold nanoparticles for x-ray imaging and radiotherapy enhancement of large, imminently lethal, intracerebral malignant gliomas. Materials & methods Gold nanoparticles approximately 11 nm in size were injected intravenously and brains imaged using microcomputed tomography. A total of 15 h after an intravenous dose of 4 g Au/kg was administered, brains were irradiated with 30 Gy 100 kVp x-rays. Results Gold uptake gave a 19:1 tumor-to-normal brain ratio with 1.5% w/w gold in tumor, calculated to increase local radiation dose by approximately 300%. Mice receiving gold and radiation (30 Gy) demonstrated 50% long term (>1 year) tumor-free survival, whereas all mice receiving radiation only died. Conclusion Intravenously injected gold nanoparticles cross the blood–tumor barrier, but are largely blocked by the normal blood–brain barrier, enabling high-resolution computed tomography tumor imaging. Gold radiation enhancement significantly improved long-term survival compared with radiotherapy alone. This approach holds promise to improve therapy of human brain tumors and other cancers. PMID:23265347

On aerobic exercise and behavioral and neural plasticity.

PubMed

Swain, Rodney A; Berggren, Kiersten L; Kerr, Abigail L; Patel, Ami; Peplinski, Caitlin; Sikorski, Angela M

2012-11-29

Aerobic exercise promotes rapid and profound alterations in the brain. Depending upon the pattern and duration of exercise, these changes in the brain may extend beyond traditional motor areas to regions and structures normally linked to learning, cognition, and emotion. Exercise-induced alterations may include changes in blood flow, hormone and growth factor release, receptor expression, angiogenesis, apoptosis, neurogenesis, and synaptogenesis. Together, we believe that these changes underlie elevations of mood and prompt the heightened behavioral plasticity commonly observed following adoption of a chronic exercise regimen. In the following paper, we will explore both the psychological and psychobiological literatures relating to exercise effects on brain in both human and non-human animals and will attempt to link plastic changes in these neural structures to modifications in learned behavior and emotional expression. In addition, we will explore the therapeutic potential of exercise given recent reports that aerobic exercise may serve as a neuroprotectant and can also slow cognitive decline during normal and pathological aging.

On Aerobic Exercise and Behavioral and Neural Plasticity

PubMed Central

Swain, Rodney A.; Berggren, Kiersten L.; Kerr, Abigail L.; Patel, Ami; Peplinski, Caitlin; Sikorski, Angela M.

2012-01-01

Aerobic exercise promotes rapid and profound alterations in the brain. Depending upon the pattern and duration of exercise, these changes in the brain may extend beyond traditional motor areas to regions and structures normally linked to learning, cognition, and emotion. Exercise-induced alterations may include changes in blood flow, hormone and growth factor release, receptor expression, angiogenesis, apoptosis, neurogenesis, and synaptogenesis. Together, we believe that these changes underlie elevations of mood and prompt the heightened behavioral plasticity commonly observed following adoption of a chronic exercise regimen. In the following paper, we will explore both the psychological and psychobiological literatures relating to exercise effects on brain in both human and non-human animals and will attempt to link plastic changes in these neural structures to modifications in learned behavior and emotional expression. In addition, we will explore the therapeutic potential of exercise given recent reports that aerobic exercise may serve as a neuroprotectant and can also slow cognitive decline during normal and pathological aging. PMID:24961267

Human amniotic fluid contaminants alter thyroid hormone signalling and early brain development in Xenopus embryos

NASA Astrophysics Data System (ADS)

Fini, Jean-Baptiste; Mughal, Bilal B.; Le Mével, Sébastien; Leemans, Michelle; Lettmann, Mélodie; Spirhanzlova, Petra; Affaticati, Pierre; Jenett, Arnim; Demeneix, Barbara A.

2017-03-01

Thyroid hormones are essential for normal brain development in vertebrates. In humans, abnormal maternal thyroid hormone levels during early pregnancy are associated with decreased offspring IQ and modified brain structure. As numerous environmental chemicals disrupt thyroid hormone signalling, we questioned whether exposure to ubiquitous chemicals affects thyroid hormone responses during early neurogenesis. We established a mixture of 15 common chemicals at concentrations reported in human amniotic fluid. An in vivo larval reporter (GFP) assay served to determine integrated thyroid hormone transcriptional responses. Dose-dependent effects of short-term (72 h) exposure to single chemicals and the mixture were found. qPCR on dissected brains showed significant changes in thyroid hormone-related genes including receptors, deiodinases and neural differentiation markers. Further, exposure to mixture also modified neural proliferation as well as neuron and oligodendrocyte size. Finally, exposed tadpoles showed behavioural responses with dose-dependent reductions in mobility. In conclusion, exposure to a mixture of ubiquitous chemicals at concentrations found in human amniotic fluid affect thyroid hormone-dependent transcription, gene expression, brain development and behaviour in early embryogenesis. As thyroid hormone signalling is strongly conserved across vertebrates the results suggest that ubiquitous chemical mixtures could be exerting adverse effects on foetal human brain development.

Revealing the cerebello-ponto-hypothalamic pathway in the human brain.

PubMed

Kamali, Arash; Karbasian, Niloofar; Rabiei, Pejman; Cano, Andres; Riascos, Roy F; Tandon, Nitin; Arevalo, Octavio; Ocasio, Laura; Younes, Kyan; Khayat-Khoei, Mahsa; Mirbagheri, Saeedeh; Hasan, Khader M

2018-06-11

The cerebellum is shown to be involved in some limbic functions of the human brain such as emotion and affect. The major connection of the cerebellum with the limbic system is known to be through the cerebello-hypothalamic pathways. The consensus is that the projections from the cerebellar nuclei to the limbic system, and particularly the hypothalamus, or from the hypothalamus to the cerebellar nuclei, are through multisynaptic pathways in the bulbar reticular formation. The detailed anatomy of the pathways responsible for mediating these responses, however, is yet to be determined. Diffusion tensor imaging may be helpful in better visualizing the surgical anatomy of the cerebello-ponto-hypothalamic (CPH) pathway. This study aimed to investigate the utility of high-spatial-resolution diffusion tensor tractography for mapping the trajectory of the CPH tract in the human brain. Fifteen healthy adults were studied. We delineated, for the first time, the detailed trajectory of the CPH tract of the human brain in fifteen normal adult subjects using high-spatial-resolution diffusion tensor tractography. We further revealed the close relationship of the CPH tract with the optic tract, temporo-pontine tract, amygdalofugal tract and the fornix in the human brain. Copyright © 2018 Elsevier B.V. All rights reserved.

Brain glucose metabolism in chronic marijuana users at baseline and during marijuana intoxication.

PubMed

Volkow, N D; Gillespie, H; Mullani, N; Tancredi, L; Grant, C; Valentine, A; Hollister, L

1996-05-31

Despite the widespread abuse of marijuana, knowledge about its effects in the human brain is limited. Brain glucose metabolism with and without delta 9 tetrahydrocannabinol (THC) (main psychoactive component of marijuana) was evaluated in eight normal subjects and eight chronic marijuana abusers with positron emission tomography. At baseline, marijuana abusers showed lower relative cerebellar metabolism than normal subjects. THC increased relative cerebellar metabolism in all subjects, but only abusers showed increases in orbitofrontal cortex, prefrontal cortex, and basal ganglia. Cerebellar metabolism during THC intoxication was significantly correlated with the subjective sense of intoxication. The decreased cerebellar metabolism in marijuana abusers at baseline could account for the motor deficits previously reported in these subjects. The activation of orbitofrontal cortex and basal ganglia by THC in the abusers but not in the normal subjects could underlie one of the mechanisms leading to the drive and the compulsion to self-administer the drug observed in addicted individuals.

CEREBRAL BLOOD FLOW AND METABOLISM IN ANXIETY AND ANXIETY DISORDERS

PubMed Central

Mathew, Roy J.

1994-01-01

Anxiety disorders are some of the commonest psychiatric disorders and anxiety commonly co-exists with other psychiatric conditions. Anxiety can also be a normal emotion. Thus, study of the neurobiological effects of anxiety is of considerable significance. In the normal brain, cerebral blood flow (CBF) and metabolism (CMR) serve as indices of brain function. CBF/CMR research is expected to provide new insight into alterations in brain function in anxiety disorders and other psychiatric disorders. Possible associations between stress I anxiety I panic and cerebral ischemia I stroke give additional significance to the effects of anxiety on CBF. With the advent of non-invasive techniques, study of CBF/CMR in anxiety disorders became easier. A large numbers of research reports are available on the effects of stress, anxiety and panic on CBF/CMR in normals and anxiety disorder patients. This article reviews the available human research on this topic. PMID:21743685

Systems biology of human epilepsy applied to patients with brain tumors.

PubMed

Mittal, Sandeep; Shah, Aashit K; Barkmeier, Daniel T; Loeb, Jeffrey A

2013-12-01

Epilepsy is a disease of recurrent seizures that can be associated with a wide variety of acquired and developmental brain lesions. Current medications for patients with epilepsy can suppress seizures; they do not cure or modify the underlying disease process. On the other hand, surgical removal of focal brain regions that produce seizures can be curative. This surgical procedure can be more precise with the placement of intracranial recording electrodes to identify brain regions that generate seizure activity as well as those that are critical for normal brain function. The detail that goes into these surgeries includes extensive neuroimaging, electrophysiology, and clinical data. Combined with precisely localized tissues removed, these data provide an unparalleled opportunity to learn about the interrelationships of many "systems" in the human brain not possible in just about any other human brain disorder. Herein, we describe a systems biology approach developed to study patients who undergo brain surgery for epilepsy and how we have begun to apply these methods to patients whose seizures are associated with brain tumors. A central goal of this clinical and translational research program is to improve our understanding of epilepsy and brain tumors and to improve diagnosis and treatment outcomes of both. Wiley Periodicals, Inc. © 2013 International League Against Epilepsy.

Higher resting-state activity in reward-related brain circuits in obese versus normal-weight females independent of food intake.

PubMed

Hogenkamp, P S; Zhou, W; Dahlberg, L S; Stark, J; Larsen, A L; Olivo, G; Wiemerslage, L; Larsson, E-M; Sundbom, M; Benedict, C; Schiöth, H B

2016-11-01

In response to food cues, obese vs normal-weight individuals show greater activation in brain regions involved in the regulation of food intake under both fasted and sated conditions. Putative effects of obesity on task-independent low-frequency blood-oxygenation-level-dependent signals-that is, resting-state brain activity-in the context of food intake are, however, less well studied. To compare eyes closed, whole-brain low-frequency BOLD signals between severely obese and normal-weight females, as assessed by functional magnetic resonance imaging (fMRI). Fractional amplitude of low-frequency fluctuations were measured in the morning following an overnight fast in 17 obese (age: 39±11 years, body mass index (BMI): 42.3±4.8 kg m - 2 ) and 12 normal-weight females (age: 36±12 years, BMI: 22.7±1.8 kg m - 2 ), both before and 30 min after consumption of a standardized meal (~260 kcal). Compared with normal-weight controls, obese females had increased low-frequency activity in clusters located in the putamen, claustrum and insula (P<0.05). This group difference was not altered by food intake. Self-reported hunger dropped and plasma glucose concentrations increased after food intake (P<0.05); however, these changes did not differ between the BMI groups. Reward-related brain regions are more active under resting-state conditions in obese than in normal-weight females. This difference was independent of food intake under the experimental settings applied in the current study. Future studies involving males and females, as well as utilizing repeated post-prandial resting-state fMRI scans and various types of meals are needed to further investigate how food intake alters resting-state brain activity in obese humans.

Vulnerability of complex networks

NASA Astrophysics Data System (ADS)

Mishkovski, Igor; Biey, Mario; Kocarev, Ljupco

2011-01-01

We consider normalized average edge betweenness of a network as a metric of network vulnerability. We suggest that normalized average edge betweenness together with is relative difference when certain number of nodes and/or edges are removed from the network is a measure of network vulnerability, called vulnerability index. Vulnerability index is calculated for four synthetic networks: Erdős-Rényi (ER) random networks, Barabási-Albert (BA) model of scale-free networks, Watts-Strogatz (WS) model of small-world networks, and geometric random networks. Real-world networks for which vulnerability index is calculated include: two human brain networks, three urban networks, one collaboration network, and two power grid networks. We find that WS model of small-world networks and biological networks (human brain networks) are the most robust networks among all networks studied in the paper.

Systemic combinatorial peptide selection yields a non-canonical iron-mimicry mechanism for targeting tumors in a mouse model of human glioblastoma

PubMed Central

Staquicini, Fernanda I.; Ozawa, Michael G.; Moya, Catherine A.; Driessen, Wouter H.P.; Barbu, E. Magda; Nishimori, Hiroyuki; Soghomonyan, Suren; Flores, Leo G.; Liang, Xiaowen; Paolillo, Vincenzo; Alauddin, Mian M.; Basilion, James P.; Furnari, Frank B.; Bogler, Oliver; Lang, Frederick F.; Aldape, Kenneth D.; Fuller, Gregory N.; Höök, Magnus; Gelovani, Juri G.; Sidman, Richard L.; Cavenee, Webster K.; Pasqualini, Renata; Arap, Wadih

2010-01-01

The management of CNS tumors is limited by the blood-brain barrier (BBB), a vascular interface that restricts the passage of most molecules from the blood into the brain. Here we show that phage particles targeted with certain ligand motifs selected in vivo from a combinatorial peptide library can cross the BBB under normal and pathological conditions. Specifically, we demonstrated that phage clones displaying an iron-mimic peptide were able to target a protein complex of transferrin and transferrin receptor (TfR) through a non-canonical allosteric binding mechanism and that this functional protein complex mediated transport of the corresponding viral particles into the normal mouse brain. We also showed that, in an orthotopic mouse model of human glioblastoma, a combination of TfR overexpression plus extended vascular permeability and ligand retention resulted in remarkable brain tumor targeting of chimeric adeno-associated virus/phage particles displaying the iron-mimic peptide and carrying a gene of interest. As a proof of concept, we delivered the HSV thymidine kinase gene for molecular-genetic imaging and targeted therapy of intracranial xenografted tumors. Finally, we established that these experimental findings might be clinically relevant by determining through human tissue microarrays that many primary astrocytic tumors strongly express TfR. Together, our combinatorial selection system and results may provide a translational avenue for the targeted detection and treatment of brain tumors. PMID:21183793

Gene expression in the aging human brain: an overview.

PubMed

Mohan, Adith; Mather, Karen A; Thalamuthu, Anbupalam; Baune, Bernhard T; Sachdev, Perminder S

2016-03-01

The review aims to provide a summary of recent developments in the study of gene expression in the aging human brain. Profiling differentially expressed genes or 'transcripts' in the human brain over the course of normal aging has provided valuable insights into the biological pathways that appear activated or suppressed in late life. Genes mediating neuroinflammation and immune system activation in particular, show significant age-related upregulation creating a state of vulnerability to neurodegenerative and neuropsychiatric disease in the aging brain. Cellular ionic dyshomeostasis and age-related decline in a host of molecular influences on synaptic efficacy may underlie neurocognitive decline in later life. Critically, these investigations have also shed light on the mobilization of protective genetic responses within the aging human brain that help determine health and disease trajectories in older age. There is growing interest in the study of pre and posttranscriptional regulators of gene expression, and the role of noncoding RNAs in particular, as mediators of the phenotypic diversity that characterizes human brain aging. Gene expression studies in healthy brain aging offer an opportunity to unravel the intricately regulated cellular underpinnings of neurocognitive aging as well as disease risk and resiliency in late life. In doing so, new avenues for early intervention in age-related neurodegenerative disease could be investigated with potentially significant implications for the development of disease-modifying therapies.

Several methods to determine heavy metals in the human brain

NASA Astrophysics Data System (ADS)

Andrási, Erzsébet; Igaz, Sarolta; Szoboszlai, Norbert; Farkas, Éva; Ajtony, Zsolt

1999-05-01

The determination of naturally occurring heavy metals in various parts of the human brain is discussed. The patients had no diseases in their central nervous systems (five individuals, mean age 70 years). Twenty brain parts were selected from both hemispheres. The analysis was carried out by graphite furnace atomic absorption spectrometry, inductively coupled plasma atomic emission spectrometry and instrumental neutron activation analysis methods. Accuracy and precision of the applied techniques were tested by using standard reference materials. Two digestion methods were used to dissolve the brain samples for ICP-AES and GF-AAS. One was performed in a Parr-bomb and the second in a microwave oven. The present results show a non-homogeneous distribution of the essential elements (Cu, Fe, Mn, Zn) in normal human brain. Corresponding regions in both hemispheres showed an almost identical concentration of these elements. In the case of toxic elements (Pb, Cd) an average value in different brain regions can not be established because of the high variability of individual data. This study indicates that beside differences in Pb and Cd intake with foods or cigarette smoke inhalation, the main factors of the high inter-individual variability of these element concentrations in human brain parts may be a marked difference in individual elimination or accumulation capabilities.

A Head and Neck Simulator for Radiology and Radiotherapy

NASA Astrophysics Data System (ADS)

Thompson, Larissa; Campos, Tarcísio P. R.

2013-06-01

Phantoms are suitable tools to simulate body tissues and organs in radiology and radiation therapy. This study presents the development of a physical head and neck phantom and its radiological response for simulating brain pathology. The following features on the phantom are addressed and compared to human data: mass density, chemical composition, anatomical shape, computerized tomography images and Hounsfield Units. Mass attenuation and kerma coefficients of the synthetic phantom and normal tissues, as well as their deviations, were also investigated. Radiological experiments were performed, including brain tumors and subarachnoid hemorrhage simulations. Computerized tomography images of such pathologies in phantom and human were obtained. The anthropometric dimensions of the phantom present anatomical conformation similar to a human head and neck. Elemental weight percentages of the equivalent tissues match the human ones. Hounsfield Unit values of the main developed structures are presented, approaching human data. Kerma and mass attenuation coefficients spectra from human and phantom are presented, demonstrating smaller deviations in the radiological X-ray spectral domain. In conclusion, the phantom presented suitable normal and pathological radiological responses relative to those observed in humans. It may improve radiological protocols and education in medical imaging.

Superior pattern processing is the essence of the evolved human brain

PubMed Central

Mattson, Mark P.

2014-01-01

Humans have long pondered the nature of their mind/brain and, particularly why its capacities for reasoning, communication and abstract thought are far superior to other species, including closely related anthropoids. This article considers superior pattern processing (SPP) as the fundamental basis of most, if not all, unique features of the human brain including intelligence, language, imagination, invention, and the belief in imaginary entities such as ghosts and gods. SPP involves the electrochemical, neuronal network-based, encoding, integration, and transfer to other individuals of perceived or mentally-fabricated patterns. During human evolution, pattern processing capabilities became increasingly sophisticated as the result of expansion of the cerebral cortex, particularly the prefrontal cortex and regions involved in processing of images. Specific patterns, real or imagined, are reinforced by emotional experiences, indoctrination and even psychedelic drugs. Impaired or dysregulated SPP is fundamental to cognitive and psychiatric disorders. A broader understanding of SPP mechanisms, and their roles in normal and abnormal function of the human brain, may enable the development of interventions that reduce irrational decisions and destructive behaviors. PMID:25202234

5-HT Radioligands for Human Brain Imaging With PET and SPECT

PubMed Central

Paterson, Louise M.; Kornum, Birgitte R.; Nutt, David J.; Pike, Victor W.; Knudsen, Gitte M.

2014-01-01

The serotonergic system plays a key modulatory role in the brain and is the target for many drug treatments for brain disorders either through reuptake blockade or via interactions at the 14 subtypes of 5-HT receptors. This review provides the history and current status of radioligands used for positron emission tomography (PET) and single photon emission computerized tomography (SPECT) imaging of human brain serotonin (5-HT) receptors, the 5-HT transporter (SERT), and 5-HT synthesis rate. Currently available radioligands for in vivo brain imaging of the 5-HT system in humans include antagonists for the 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT4 receptors, and for SERT. Here we describe the evolution of these radioligands, along with the attempts made to develop radioligands for additional serotonergic targets. We describe the properties needed for a radioligand to become successful and the main caveats. The success of a PET or SPECT radioligand can ultimately be assessed by its frequency of use, its utility in humans, and the number of research sites using it relative to its invention date, and so these aspects are also covered. In conclusion, the development of PET and SPECT radioligands to image serotonergic targets is of high interest, and successful evaluation in humans is leading to invaluable insight into normal and abnormal brain function, emphasizing the need for continued development of both SPECT and PET radioligands for human brain imaging. PMID:21674551

Glycoblotting method allows for rapid and efficient glycome profiling of human Alzheimer's disease brain, serum and cerebrospinal fluid towards potential biomarker discovery.

PubMed

Gizaw, Solomon T; Ohashi, Tetsu; Tanaka, Masakazu; Hinou, Hiroshi; Nishimura, Shin-Ichiro

2016-08-01

Understanding of the significance of posttranslational glycosylation in Alzheimer's disease (AD) is of growing importance for the investigation of the pathogenesis of AD as well as discovery research of the disease-specific serum biomarkers. We designed a standard protocol for the glycoblotting combined with MALDI-TOFMS to perform rapid and quantitative profiling of the glycan parts of glycoproteins (N-glycans) and glycosphingolipids (GSLs) using human AD's post-mortem samples such as brain tissues (dissected cerebral cortices such as frontal, parietal, occipital, and temporal domains), serum and cerebrospinal fluid (CSF). The structural profiles of the major N-glycans released from glycoproteins and the total expression levels of the glycans were found to be mostly similar between the brain tissues of the AD patients and those of the normal control group. In contrast, the expression levels of the serum and CSF protein N-glycans such as bisect-type and multiply branched glycoforms were increased significantly in AD patient group. In addition, the levels of some gangliosides such as GM1, GM2 and GM3 appeared to alter in the AD patient brain and serum samples when compared with the normal control groups. Alteration of the expression levels of major N- and GSL-glycans in human brain tissues, serum and CSF of AD patients can be monitored quantitatively by means of the glycoblotting-based standard protocols. The changes in the expression levels of the glycans derived from the human post-mortem samples uncovered by the standardized glycoblotting method provides potential serum biomarkers in central nervous system disorders and can contribute to the insight into the molecular mechanisms in the pathogenesis of neurodegenerative diseases and future drug discovery. Most importantly, the present preliminary trials using human post-mortem samples of AD patients suggest that large-scale serum glycomics cohort by means of various-types of human AD patients as well as the normal control sera can facilitate the discovery research of highly sensitive and reliable serum biomarkers for an early diagnosis of AD. This article is part of a Special Issue entitled "Glycans in personalised medicine" Guest Editor: Professor Gordan Lauc. Copyright © 2016 Elsevier B.V. All rights reserved.

Integrative Understanding of Emergent Brain Properties, Quantum Brain Hypotheses, and Connectome Alterations in Dementia are Key Challenges to Conquer Alzheimer's Disease.

PubMed

Kuljiš, Rodrigo O

2010-01-01

The biological substrate for cognition remains a challenge as much as defining this function of living beings. Here, we examine some of the difficulties to understand normal and disordered cognition in humans. We use aspects of Alzheimer's disease and related disorders to illustrate how the wealth of information at many conceptually separate, even intellectually decoupled, physical scales - in particular at the Molecular Neuroscience versus Systems Neuroscience/Neuropsychology levels - presents a challenge in terms of true interdisciplinary integration towards a coherent understanding. These unresolved dilemmas include critically the as yet untested quantum brain hypothesis, and the embryonic attempts to develop and define the so-called connectome in humans and in non-human models of disease. To mitigate these challenges, we propose a scheme incorporating the vast array of scales of the space and time (space-time) manifold from at least the subatomic through cognitive-behavioral dimensions of inquiry, to achieve a new understanding of both normal and disordered cognition, that is essential for a new era of progress in the Generative Sciences and its application to translational efforts for disease prevention and treatment.

Neocortical Transplants in the Mammalian Brain Lack a Blood-Brain Barrier to Macromolecules

NASA Astrophysics Data System (ADS)

Rosenstein, Jeffrey M.

1987-02-01

In order to determine whether the blood-brain barrier was present in transplants of central nervous tissue, fetal neocortex, which already possesses blood-brain and blood-cerebrospinal fluid barriers to protein, was grafted into the undamaged fourth ventricle or directly into the neocortex of recipient rats. Horseradish peroxidase or a conjugated human immunoglobulin G-peroxidase molecule was systemically administered into the host. These proteins were detected within the cortical transplants within 2 minutes regardless of the age of the donor or postoperative time. At later times these compounds, which normally do not cross the blood-brain barrier, inundated the grafts and adjacent host brain and also entered the cerebrospinal fluid. Endogenous serum albumin detected immunocytochemically in untreated hosts had a comparable although less extensive distribution. Thus, transplants of fetal central nervous tissue have permanent barrier dysfunction, probably due to microvascular changes, and are not integrated physiologically within the host. Blood-borne compounds, either systemically administered or naturally occurring, which should never contact normal brain tissue, have direct access to these transplants and might affect neuronal function.

Relationship between brain R(2) and liver and serum iron concentrations in elderly men.

PubMed

House, Michael J; St Pierre, Timothy G; Milward, Elizabeth A; Bruce, David G; Olynyk, John K

2010-02-01

Studies of iron overload in humans and animals suggest that brain iron concentrations may be related in a regionally specific way to body iron status. However, few quantitative studies have investigated the associations between peripheral and regional brain iron in a normal elderly cohort. To examine these relationships, we used MRI to measure the proton transverse relaxation rate (R(2)) in 13 gray and white matter brain regions in 18 elderly men (average age, 75.5 years) with normal cognition. Brain R(2) values were compared with liver iron concentrations measured using the FerriScan MRI technique and serum iron indices. R(2) values in high-iron gray matter regions were significantly correlated (positively) with liver iron concentrations (globus pallidus, ventral pallidum) and serum transferrin saturation (caudate nucleus, globus pallidus, putamen) measured concurrently with brain R(2), and with serum iron concentrations (caudate nucleus, globus pallidus) measured three years before the current study. Our results suggest that iron levels in specific gray matter brain regions are influenced by systemic iron status in elderly men.

Research of Hubs Location Method for Weighted Brain Network Based on NoS-FA.

PubMed

Weng, Zhengkui; Wang, Bin; Xue, Jie; Yang, Baojie; Liu, Hui; Xiong, Xin

2017-01-01

As a complex network of many interlinked brain regions, there are some central hub regions which play key roles in the structural human brain network based on T1 and diffusion tensor imaging (DTI) technology. Since most studies about hubs location method in the whole human brain network are mainly concerned with the local properties of each single node but not the global properties of all the directly connected nodes, a novel hubs location method based on global importance contribution evaluation index is proposed in this study. The number of streamlines (NoS) is fused with normalized fractional anisotropy (FA) for more comprehensive brain bioinformation. The brain region importance contribution matrix and information transfer efficiency value are constructed, respectively, and then by combining these two factors together we can calculate the importance value of each node and locate the hubs. Profiting from both local and global features of the nodes and the multi-information fusion of human brain biosignals, the experiment results show that this method can detect the brain hubs more accurately and reasonably compared with other methods. Furthermore, the proposed location method is used in impaired brain hubs connectivity analysis of schizophrenia patients and the results are in agreement with previous studies.

Diagnostic segregation of human brain tumours using Fourier-transform infrared and/or Raman spectroscopy coupled with discriminant analysis†

PubMed Central

Gajjar, Ketan; Heppenstall, Lara D.; Pang, Weiyi; Ashton, Katherine M.; Trevisan, Júlio; Patel, Imran I.; Llabjani, Valon; Stringfellow, Helen F.; Martin-Hirsch, Pierre L.; Dawson, Timothy; Martin, Francis L.

2013-01-01

The most common initial treatment received by patients with a brain tumour is surgical removal of the growth. Precise histopathological diagnosis of brain tumours is to some extent subjective. Furthermore, currently available diagnostic imaging techniques to delineate the excision border during cytoreductive surgery lack the required spatial precision to aid surgeons. We set out to determine whether infrared (IR) and/or Raman spectroscopy combined with multivariate analysis could be applied to discriminate between normal brain tissue and different tumour types (meningioma, glioma and brain metastasis) based on the unique spectral “fingerprints” of their biochemical composition. Formalin-fixed paraffin-embedded tissue blocks of normal brain and different brain tumours were de-waxed, mounted on low-E slides and desiccated before being analyzed using attenuated total reflection Fourier-transform IR (ATR-FTIR) and Raman spectroscopy. ATR-FTIR spectroscopy showed a clear segregation between normal and different tumour subtypes. Discrimination of tumour classes was also apparent with Raman spectroscopy. Further analysis of spectral data revealed changes in brain biochemical structure associated with different tumours. Decreased tentatively-assigned lipid-to-protein ratio was associated with increased tumour progression. Alteration in cholesterol esters-to-phenylalanine ratio was evident in grade IV glioma and metastatic tumours. The current study indicates that IR and/or Raman spectroscopy have the potential to provide a novel diagnostic approach in the accurate diagnosis of brain tumours and have potential for application in intra-operative diagnosis. PMID:24098310

Neural connectivity of the posterior body of the fornix in the human brain: diffusion tensor imaging study.

PubMed

Jang, Sung Ho; Kwon, Hyeok Gyu

2013-08-09

Little is known about the neural connectivity of the fornix in the human brain. In the current study, using diffusion tensor imaging, we attempted to investigate the neural connectivity of the posterior body of the fornix in the normal human brain. A total of 43 healthy subjects were recruited for this study. DTIs were acquired using a sensitivity-encoding head coil at 1.5T. For connectivity of the posterior body of the fornix, a seed region of interest was used on the posterior body of the fornix. Connectivity was defined as the incidence of connection between the posterior body of the fornix and any neural structure of the brain at the threshold of 5, 25, and 50 streamline. At the threshold of 5, 25, and 50, the posterior body of the fornix showed connectivity to the precentral gyrus (37%, 19%, and 15%), the postcentral gyrus (25%, 11.5%, and 7%), the posterior parietal cortex (16.5%, 5%, and 5%), the brainstem (12%, 4.5%, and 3.5%), the crus of the fornix (34%, 10.5%, and 7%), the contralateral splenium of the corpus callosum (12.5%, 5%, and 0%), and the ipsilateral splenium of the CC (69.8%%, 33.7%, and 23.3%), respectively. Findings of this study showed that the posterior body of the fornix had connectivity with the cerebral cortex, the brainstem, the fornical crus, and the contralateral splenium through the splenium of the corpus callosum in normal subjects. We believe that the results of this study would be helpful in investigation of the neural network related to memory and recovery mechanisms following fornical injury in the human brain. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Eyes Open on Sleep and Wake: In Vivo to In Silico Neural Networks

PubMed Central

Vanvinckenroye, Amaury; Vandewalle, Gilles; Chellappa, Sarah L.

2016-01-01

Functional and effective connectivity of cortical areas are essential for normal brain function under different behavioral states. Appropriate cortical activity during sleep and wakefulness is ensured by the balanced activity of excitatory and inhibitory circuits. Ultimately, fast, millisecond cortical rhythmic oscillations shape cortical function in time and space. On a much longer time scale, brain function also depends on prior sleep-wake history and circadian processes. However, much remains to be established on how the brain operates at the neuronal level in humans during sleep and wakefulness. A key limitation of human neuroscience is the difficulty in isolating neuronal excitation/inhibition drive in vivo. Therefore, computational models are noninvasive approaches of choice to indirectly access hidden neuronal states. In this review, we present a physiologically driven in silico approach, Dynamic Causal Modelling (DCM), as a means to comprehend brain function under different experimental paradigms. Importantly, DCM has allowed for the understanding of how brain dynamics underscore brain plasticity, cognition, and different states of consciousness. In a broader perspective, noninvasive computational approaches, such as DCM, may help to puzzle out the spatial and temporal dynamics of human brain function at different behavioural states. PMID:26885400

A survey of human brain transcriptome diversity at the single cell level.

PubMed

Darmanis, Spyros; Sloan, Steven A; Zhang, Ye; Enge, Martin; Caneda, Christine; Shuer, Lawrence M; Hayden Gephart, Melanie G; Barres, Ben A; Quake, Stephen R

2015-06-09

The human brain is a tissue of vast complexity in terms of the cell types it comprises. Conventional approaches to classifying cell types in the human brain at single cell resolution have been limited to exploring relatively few markers and therefore have provided a limited molecular characterization of any given cell type. We used single cell RNA sequencing on 466 cells to capture the cellular complexity of the adult and fetal human brain at a whole transcriptome level. Healthy adult temporal lobe tissue was obtained during surgical procedures where otherwise normal tissue was removed to gain access to deeper hippocampal pathology in patients with medical refractory seizures. We were able to classify individual cells into all of the major neuronal, glial, and vascular cell types in the brain. We were able to divide neurons into individual communities and show that these communities preserve the categorization of interneuron subtypes that is typically observed with the use of classic interneuron markers. We then used single cell RNA sequencing on fetal human cortical neurons to identify genes that are differentially expressed between fetal and adult neurons and those genes that display an expression gradient that reflects the transition between replicating and quiescent fetal neuronal populations. Finally, we observed the expression of major histocompatibility complex type I genes in a subset of adult neurons, but not fetal neurons. The work presented here demonstrates the applicability of single cell RNA sequencing on the study of the adult human brain and constitutes a first step toward a comprehensive cellular atlas of the human brain.

Rich-club organization of the newborn human brain

PubMed Central

Ball, Gareth; Aljabar, Paul; Zebari, Sally; Tusor, Nora; Arichi, Tomoki; Merchant, Nazakat; Robinson, Emma C.; Ogundipe, Enitan; Rueckert, Daniel; Edwards, A. David; Counsell, Serena J.

2014-01-01

Combining diffusion magnetic resonance imaging and network analysis in the adult human brain has identified a set of highly connected cortical hubs that form a “rich club”—a high-cost, high-capacity backbone thought to enable efficient network communication. Rich-club architecture appears to be a persistent feature of the mature mammalian brain, but it is not known when this structure emerges during human development. In this longitudinal study we chart the emergence of structural organization in mid to late gestation. We demonstrate that a rich club of interconnected cortical hubs is already present by 30 wk gestation. Subsequently, until the time of normal birth, the principal development is a proliferation of connections between core hubs and the rest of the brain. We also consider the impact of environmental factors on early network development, and compare term-born neonates to preterm infants at term-equivalent age. Though rich-club organization remains intact following premature birth, we reveal significant disruptions in both in cortical–subcortical connectivity and short-distance corticocortical connections. Rich club organization is present well before the normal time of birth and may provide the fundamental structural architecture for the subsequent emergence of complex neurological functions. Premature exposure to the extrauterine environment is associated with altered network architecture and reduced network capacity, which may in part account for the high prevalence of cognitive problems in preterm infants. PMID:24799693

Cystic fibrosis transmembrane conductance regulator protein (CFTR) expression in the developing human brain: comparative immunohistochemical study between patients with normal and mutated CFTR.

PubMed

Marcorelles, Pascale; Friocourt, Gaëlle; Uguen, Arnaud; Ledé, Françoise; Férec, Claude; Laquerrière, Annie

2014-11-01

Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein has recently been shown to be expressed in the human adult central nervous system (CNS). As CFTR expression has also been documented during embryonic development in several organs, such as the respiratory tract, the intestine and the male reproductive system, suggesting a possible role during development we decided to investigate the expression of CFTR in the human developing CNS. In addition, as some, although rare, neurological symptoms have been reported in patients with CF, we compared the expression of normal and mutated CFTR at several fetal stages. Immunohistochemistry was performed on brain and spinal cord samples of foetuses between 13 and 40 weeks of gestation and compared with five patients with cystic fibrosis (CF) of similar ages. We showed in this study that CFTR is only expressed in neurons and has an early and widespread distribution during development. Although we did not observe any cerebral abnormality in patients with CF, we observed a slight delay in the maturation of several brain structures. We also observed different expression and localization of CFTR depending on the brain structure or the cell maturation stage. Our findings, along with a literature review on the neurological phenotypes of patients with CF, suggest that this gene may play previously unsuspected roles in neuronal maturation or function. © The Author(s) 2014.

Low-Dimensional Chaos in an Instance of Epilepsy

NASA Astrophysics Data System (ADS)

Babloyantz, A.; Destexhe, A.

1986-05-01

Using a time series obtained from the electroencephalogram recording of a human epileptic seizure, we show the existence of a chaotic attractor, the latter being the direct consequence of the deterministic nature of brain activity. This result is compared with other attractors seen in normal human brain dynamics. A sudden jump is observed between the dimensionalities of these brain attractors 4.05 ± 0.05 for deep sleep) and the very low dimensionality of the epileptic state (2.05 ± 0.09). The evaluation of the autocorrelation function and of the largest Lyapunov exponent allows us to sharpen further the main features of underlying dynamics. Possible implications in biological and medical research are briefly discussed.

Intraoperative detection of glioma invasion beyond MRI enhancement with Raman spectroscopy in humans

NASA Astrophysics Data System (ADS)

Jermyn, Michael; Mok, Kelvin; Mercier, Jeanne; Desroches, Joannie; Pichette, Julien; Saint-Arnaud, Karl; Guiot, Marie-Christine; Petrecca, Kevin; Leblond, Frédéric

2015-03-01

Cancer tissue is frequently impossible to distinguish from normal brain during surgery. Gliomas are a class of brain cancer which invade into the normal brain. If left unresected, these invasive cancer cells are the source of glioma recurrence. Moreover, these invasion areas do not show up on standard-of-care pre-operative Magnetic Resonance Imaging (MRI). This inability to fully visualize invasive brain cancers results in subtotal surgical resections, negatively impacting patient survival. To address this issue, we have demonstrated the efficacy of single-point in vivo Raman spectroscopy using a contact hand-held fiber optic probe for rapid detection of cancer invasion in 8 patients with low and high grade gliomas. Using a supervised machine learning algorithm to analyze the Raman spectra obtained in vivo, we were able to distinguish normal brain from the presence of cancer cells with sensitivity and specificity greater than 90%. Moreover, by correlating these results with pre-operative MRI we demonstrate the ability to detect low density cancer invasion up to 1.5cm beyond the cancer extent visible using MRI. This represents the potential for significant improvements in progression-free and overall patient survival, by identifying previously undetectable residual cancer cell populations and preventing the resection of normal brain tissue. While the importance of maximizing the volume of tumor resection is important for all grades of gliomas, the impact for low grade gliomas can be dramatic because surgery can even be curative. This convenient technology can rapidly classify cancer invasion in real-time, making it ideal for intraoperative use in brain tumor resection.

Aging and Gene Expression in the Primate Brain

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fraser, Hunter B.; Khaitovich, Philipp; Plotkin, Joshua B.

2005-02-18

It is well established that gene expression levels in many organisms change during the aging process, and the advent of DNA microarrays has allowed genome-wide patterns of transcriptional changes associated with aging to be studied in both model organisms and various human tissues. Understanding the effects of aging on gene expression in the human brain is of particular interest, because of its relation to both normal and pathological neurodegeneration. Here we show that human cerebral cortex, human cerebellum, and chimpanzee cortex each undergo different patterns of age-related gene expression alterations. In humans, many more genes undergo consistent expression changes inmore » the cortex than in the cerebellum; in chimpanzees, many genes change expression with age in cortex, but the pattern of changes in expression bears almost no resemblance to that of human cortex. These results demonstrate the diversity of aging patterns present within the human brain, as well as how rapidly genome-wide patterns of aging can evolve between species; they may also have implications for the oxidative free radical theory of aging, and help to improve our understanding of human neurodegenerative diseases.« less

On children's dyslexia with NIRS

NASA Astrophysics Data System (ADS)

Gan, Zhuo; Li, Chengjun; Gong, Hui; Luo, Qingming; Yao, Bin; Song, Ranran; Wu, Hanrong

2003-12-01

Developmental dyslexia is a kind of prevalent psychologic disease. Some functional imaging technologies, such as FMRI and PET, have been used to study the brain activities of dyslexics. NIRS is a kind of novel technology which is more and more widely being used for study of the cognitive psychology. However, there aren"t reports about the dyslexic research using NIRS to be found until now. This paper introduces a NIRS system of four measuring channels. Brain activities of dyslexic subjects and normal subjects during reading task were studied with the NIRS system. Two groups of subjects, the group of dyslexia and the group of normal, were appointed to perform two reading tasks. At the same time, their cortical activities were measured with the NIRS system. This experimental result indicates that the brain activities of the dyslexic group were significantly higher than the control group in BA 48 and that NIRS can be used for the study of human brain activity.

Moral Enhancement Using Non-invasive Brain Stimulation

PubMed Central

Darby, R. Ryan; Pascual-Leone, Alvaro

2017-01-01

Biomedical enhancement refers to the use of biomedical interventions to improve capacities beyond normal, rather than to treat deficiencies due to diseases. Enhancement can target physical or cognitive capacities, but also complex human behaviors such as morality. However, the complexity of normal moral behavior makes it unlikely that morality is a single capacity that can be deficient or enhanced. Instead, our central hypothesis will be that moral behavior results from multiple, interacting cognitive-affective networks in the brain. First, we will test this hypothesis by reviewing evidence for modulation of moral behavior using non-invasive brain stimulation. Next, we will discuss how this evidence affects ethical issues related to the use of moral enhancement. We end with the conclusion that while brain stimulation has the potential to alter moral behavior, such alteration is unlikely to improve moral behavior in all situations, and may even lead to less morally desirable behavior in some instances. PMID:28275345

Using chaotic artificial neural networks to model memory in the brain

NASA Astrophysics Data System (ADS)

Aram, Zainab; Jafari, Sajad; Ma, Jun; Sprott, Julien C.; Zendehrouh, Sareh; Pham, Viet-Thanh

2017-03-01

In the current study, a novel model for human memory is proposed based on the chaotic dynamics of artificial neural networks. This new model explains a biological fact about memory which is not yet explained by any other model: There are theories that the brain normally works in a chaotic mode, while during attention it shows ordered behavior. This model uses the periodic windows observed in a previously proposed model for the brain to store and then recollect the information.

Glial dysfunction in abstinent methamphetamine abusers

PubMed Central

Sailasuta, Napapon; Abulseoud, Osama; Harris, Kent C; Ross, Brian D

2010-01-01

Persistent neurochemical abnormalities in frontal brain structures are believed to result from methamphetamine use. We developed a localized 13C magnetic resonance spectroscopy (MRS) assay on a conventional MR scanner, to quantify selectively glial metabolic flux rate in frontal brain of normal subjects and a cohort of recovering abstinent methamphetamine abusers. Steady-state bicarbonate concentrations were similar, between 11 and 15 mmol/L in mixed gray-white matter of frontal brain of normal volunteers and recovering methamphetamine-abusing subjects (P>0.1). However, glial 13C-bicarbonate production rate from [1-13C]acetate, equating with glial tricarboxylic acid (TCA) cycle rate, was significantly reduced in frontal brain of abstinent methamphetamine-addicted women (methamphetamine 0.04 μmol/g per min (N=5) versus controls 0.11 μmol/g per min (N=5), P=0.001). This is equivalent to 36% of the normal glial TCA cycle rate. Severe reduction in glial TCA cycle rate that normally comprises 10% of total cerebral metabolic rate may impact operation of the neuronal glial glutamate cycle and result in accumulation of frontal brain glutamate, as observed in these recovering methamphetamine abusers. Although these are the first studies to define directly an abnormality in glial metabolism in human methamphetamine abuse, sequential studies using analogous 13C MRS methods may determine ‘cause and effect' between glial failure and neuronal injury. PMID:20040926

Low values of 5-hydroxymethylcytosine (5hmC), the "sixth base," are associated with anaplasia in human brain tumors.

PubMed

Kraus, Theo F J; Globisch, Daniel; Wagner, Mirko; Eigenbrod, Sabina; Widmann, David; Münzel, Martin; Müller, Markus; Pfaffeneder, Toni; Hackner, Benjamin; Feiden, Wolfgang; Schüller, Ulrich; Carell, Thomas; Kretzschmar, Hans A

2012-10-01

5-Methylcytosine (5 mC) in genomic DNA has important epigenetic functions in embryonic development and tumor biology. 5-Hydroxymethylcytosine (5 hmC) is generated from 5 mC by the action of the TET (Ten-Eleven-Translocation) enzymes and may be an intermediate to further oxidation and finally demethylation of 5 mC. We have used immunohistochemistry (IHC) and isotope-based liquid chromatography mass spectrometry (LC-MS) to investigate the presence and distribution of 5 hmC in human brain and brain tumors. In the normal adult brain, IHC identified 61.5% 5 hmC positive cells in the cortex and 32.4% 5 hmC in white matter (WM) areas. In tumors, positive staining of cells ranged from 1.1% in glioblastomas (GBMs) (WHO Grade IV) to 8.9% in Grade I gliomas (pilocytic astrocytomas). In the normal adult human brain, LC-MS also showed highest values in cortical areas (1.17% 5 hmC/dG [deoxyguanosine]), in the cerebral WM we measured around 0.70% 5 hmC/dG. levels were related to tumor differentiation, ranging from lowest values of 0.078% 5 hmC/dG in GBMs (WHO Grade IV) to 0.24% 5 hmC/dG in WHO Grade II diffuse astrocytomas. 5 hmC measurements were unrelated to 5 mC values. We find that the number of 5 hmC positive cells and the amount of 5 hmC/dG in the genome that has been proposed to be related to pluripotency and lineage commitment in embryonic stem cells is also associated with brain tumor differentiation and anaplasia. Copyright © 2012 UICC.

Rsu1 regulates ethanol consumption in Drosophila and humans.

PubMed

Ojelade, Shamsideen A; Jia, Tianye; Rodan, Aylin R; Chenyang, Tao; Kadrmas, Julie L; Cattrell, Anna; Ruggeri, Barbara; Charoen, Pimphen; Lemaitre, Hervé; Banaschewski, Tobias; Büchel, Christian; Bokde, Arun L W; Carvalho, Fabiana; Conrod, Patricia J; Flor, Herta; Frouin, Vincent; Gallinat, Jürgen; Garavan, Hugh; Gowland, Penny A; Heinz, Andreas; Ittermann, Bernd; Lathrop, Mark; Lubbe, Steven; Martinot, Jean-Luc; Paus, Tomás; Smolka, Michael N; Spanagel, Rainer; O'Reilly, Paul F; Laitinen, Jaana; Veijola, Juha M; Feng, Jianfeng; Desrivières, Sylvane; Jarvelin, Marjo-Riitta; Schumann, Gunter; Rothenfluh, Adrian

2015-07-28

Alcohol abuse is highly prevalent, but little is understood about the molecular causes. Here, we report that Ras suppressor 1 (Rsu1) affects ethanol consumption in flies and humans. Drosophila lacking Rsu1 show reduced sensitivity to ethanol-induced sedation. We show that Rsu1 is required in the adult nervous system for normal sensitivity and that it acts downstream of the integrin cell adhesion molecule and upstream of the Ras-related C3 botulinum toxin substrate 1 (Rac1) GTPase to regulate the actin cytoskeleton. In an ethanol preference assay, global loss of Rsu1 causes high naïve preference. In contrast, flies lacking Rsu1 only in the mushroom bodies of the brain show normal naïve preference but then fail to acquire ethanol preference like normal flies. Rsu1 is, thus, required in distinct neurons to modulate naïve and acquired ethanol preference. In humans, we find that polymorphisms in RSU1 are associated with brain activation in the ventral striatum during reward anticipation in adolescents and alcohol consumption in both adolescents and adults. Together, these data suggest a conserved role for integrin/Rsu1/Rac1/actin signaling in modulating reward-related phenotypes, including ethanol consumption, across phyla.

The Brain/MINDS 3D digital marmoset brain atlas

PubMed Central

Woodward, Alexander; Hashikawa, Tsutomu; Maeda, Masahide; Kaneko, Takaaki; Hikishima, Keigo; Iriki, Atsushi; Okano, Hideyuki; Yamaguchi, Yoko

2018-01-01

We present a new 3D digital brain atlas of the non-human primate, common marmoset monkey (Callithrix jacchus), with MRI and coregistered Nissl histology data. To the best of our knowledge this is the first comprehensive digital 3D brain atlas of the common marmoset having normalized multi-modal data, cortical and sub-cortical segmentation, and in a common file format (NIfTI). The atlas can be registered to new data, is useful for connectomics, functional studies, simulation and as a reference. The atlas was based on previously published work but we provide several critical improvements to make this release valuable for researchers. Nissl histology images were processed to remove illumination and shape artifacts and then normalized to the MRI data. Brain region segmentation is provided for both hemispheres. The data is in the NIfTI format making it easy to integrate into neuroscience pipelines, whereas the previous atlas was in an inaccessible file format. We also provide cortical, mid-cortical and white matter boundary segmentations useful for visualization and analysis. PMID:29437168

Physical Activity Protects the Human Brain against Metabolic Stress Induced by a Postprandial and Chronic Inflammation.

PubMed

Pruimboom, Leo; Raison, Charles L; Muskiet, Frits A J

2015-01-01

In recent years, it has become clear that chronic systemic low-grade inflammation is at the root of many, if not all, typically Western diseases associated with the metabolic syndrome. While much focus has been given to sedentary lifestyle as a cause of chronic inflammation, it is less often appreciated that chronic inflammation may also promote a sedentary lifestyle, which in turn causes chronic inflammation. Given that even minor increases in chronic inflammation reduce brain volume in otherwise healthy individuals, the bidirectional relationship between inflammation and sedentary behaviour may explain why humans have lost brain volume in the last 30,000 years and also intelligence in the last 30 years. We review evidence that lack of physical activity induces chronic low-grade inflammation and, consequently, an energy conflict between the selfish immune system and the selfish brain. Although the notion that increased physical activity would improve health in the modern world is widespread, here we provide a novel perspective on this truism by providing evidence that recovery of normal human behaviour, such as spontaneous physical activity, would calm proinflammatory activity, thereby allocating more energy to the brain and other organs, and by doing so would improve human health.

Preclinical Characterization of 18F-MK-6240, a Promising PET Tracer for In Vivo Quantification of Human Neurofibrillary Tangles.

PubMed

Hostetler, Eric D; Walji, Abbas M; Zeng, Zhizhen; Miller, Patricia; Bennacef, Idriss; Salinas, Cristian; Connolly, Brett; Gantert, Liza; Haley, Hyking; Holahan, Marie; Purcell, Mona; Riffel, Kerry; Lohith, Talakad G; Coleman, Paul; Soriano, Aileen; Ogawa, Aimie; Xu, Serena; Zhang, Xiaoping; Joshi, Elizabeth; Della Rocca, Joseph; Hesk, David; Schenk, David J; Evelhoch, Jeffrey L

2016-10-01

A PET tracer is desired to help guide the discovery and development of disease-modifying therapeutics for neurodegenerative diseases characterized by neurofibrillary tangles (NFTs), the predominant tau pathology in Alzheimer disease (AD). We describe the preclinical characterization of the NFT PET tracer 18 F-MK-6240. In vitro binding studies were conducted with 3 H-MK-6240 in tissue slices and homogenates from cognitively normal and AD human brain donors to evaluate tracer affinity and selectivity for NFTs. Immunohistochemistry for phosphorylated tau was performed on human brain slices for comparison with 3 H-MK-6240 binding patterns on adjacent brain slices. PET studies were performed with 18 F-MK-6240 in monkeys to evaluate tracer kinetics and distribution in the brain. 18 F-MK-6240 monkey PET studies were conducted after dosing with unlabeled MK-6240 to evaluate tracer binding selectivity in vivo. The 3 H-MK-6240 binding pattern was consistent with the distribution of phosphorylated tau in human AD brain slices. 3 H-MK-6240 bound with high affinity to human AD brain cortex homogenates containing abundant NFTs but bound poorly to amyloid plaque-rich, NFT-poor AD brain homogenates. 3 H-MK-6240 showed no displaceable binding in the subcortical regions of human AD brain slices and in the hippocampus/entorhinal cortex of non-AD human brain homogenates. In monkey PET studies, 18 F-MK-6240 displayed rapid and homogeneous distribution in the brain. The 18 F-MK-6240 volume of distribution stabilized rapidly, indicating favorable tracer kinetics. No displaceable binding was observed in self-block studies in rhesus monkeys, which do not natively express NFTs. Moderate defluorination was observed as skull uptake. 18 F-MK-6240 is a promising PET tracer for the in vivo quantification of NFTs in AD patients. © 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Brain Arteriovenous Malformation Pathogenesis: A Response-to-Injury Paradigm

PubMed Central

Kim, Helen; Su, Hua; Weinsheimer, Shantel; Pawlikowska, Ludmila; Young, William L.

2011-01-01

Brain arteriovenous malformations (AVMs) are a rare but important cause of intracranial hemorrhage (ICH) in young adults. In this paper, we review both human and animal studies of brain AVM, focusing on the: (1) natural history of AVM hemorrhage; (2) genetic and expression studies of AVM susceptibility and hemorrhage; and (3) strategies for development of a brain AVM model in adult mice. These data target various mechanisms which must act in concert to regulate normal angiogenic response to injury. Based on the various lines of evidence reviewed in this paper, we propose a “response-to-injury” model of brain AVM pathogenesis. PMID:21725736

Primary cortical folding in the human newborn: an early marker of later functional development.

PubMed

Dubois, J; Benders, M; Borradori-Tolsa, C; Cachia, A; Lazeyras, F; Ha-Vinh Leuchter, R; Sizonenko, S V; Warfield, S K; Mangin, J F; Hüppi, P S

2008-08-01

In the human brain, the morphology of cortical gyri and sulci is complex and variable among individuals, and it may reflect pathological functioning with specific abnormalities observed in certain developmental and neuropsychiatric disorders. Since cortical folding occurs early during brain development, these structural abnormalities might be present long before the appearance of functional symptoms. So far, the precise mechanisms responsible for such alteration in the convolution pattern during intra-uterine or post-natal development are still poorly understood. Here we compared anatomical and functional brain development in vivo among 45 premature newborns who experienced different intra-uterine environments: 22 normal singletons, 12 twins and 11 newborns with intrauterine growth restriction (IUGR). Using magnetic resonance imaging (MRI) and dedicated post-processing tools, we investigated early disturbances in cortical formation at birth, over the developmental period critical for the emergence of convolutions (26-36 weeks of gestational age), and defined early 'endophenotypes' of sulcal development. We demonstrated that twins have a delayed but harmonious maturation, with reduced surface and sulcation index compared to singletons, whereas the gyrification of IUGR newborns is discordant to the normal developmental trajectory, with a more pronounced reduction of surface in relation to the sulcation index compared to normal newborns. Furthermore, we showed that these structural measurements of the brain at birth are predictors of infants' outcome at term equivalent age, for MRI-based cerebral volumes and neurobehavioural development evaluated with the assessment of preterm infant's behaviour (APIB).

Iron, transferrin and myelinogenesis

NASA Astrophysics Data System (ADS)

Sergeant, C.; Vesvres, M. H.; Devès, G.; Baron, B.; Guillou, F.

2003-09-01

Transferrin (Tf), the iron binding protein of vertebrates serum, is known to be synthesized by oligodendrocytes (Ols) in the central nervous system. It has been postulated that Tf is involved in Ols maturation and myelinogenesis. This link is particularly important in the understanding of a severe human pathology: the multiple sclerosis, which remains without efficient treatment. We generated transgenic mice containing the complete human Tf gene and extensive regulatory sequences from the 5 ' and 3 ' untranslated regions that specifically overexpress Tf in Ols. Brain cytoarchitecture of the transgenic mice appears to be normal in all brain regions examined, total myelin content is increased by 30% and motor coordination is significantly improved when compared with non-transgenic littermates. Tf role in the central nervous system may be related to its affinity for metallic cations. Normal and transgenic mice were used for determination of trace metals (iron, copper and zinc) and minerals (potassium and calcium) concentration in cerebellum and corpus callosum. The freeze-dried samples were prepared to allow proton-induced X-ray emission and Rutherford backscattering spectrometry analyses with the nuclear microprobe in Bordeaux. Preliminary results were obtained and carbon distribution was revealed as a very good analysis to distinguish precisely the white matter region. A comparison of metallic and mineral elements contents in brain between normal and transgenic mice shows that iron, copper and zinc levels remained constant. This result provides evidence that effects of Tf overexpression in the brain do not solely relate to iron transport.

Abnormal tuning of saccade-related cells in pontine reticular formation of strabismic monkeys.

PubMed

Walton, Mark M G; Mustari, Michael J

2015-08-01

Strabismus is a common disorder, characterized by a chronic misalignment of the eyes and numerous visual and oculomotor abnormalities. For example, saccades are often highly disconjugate. For humans with pattern strabismus, the horizontal and vertical disconjugacies vary with eye position. In monkeys, manipulations that disturb binocular vision during the first several weeks of life result in a chronic strabismus with characteristics that closely match those in human patients. Early onset strabismus is associated with altered binocular sensitivity of neurons in visual cortex. Here we test the hypothesis that brain stem circuits specific to saccadic eye movements are abnormal. We targeted the pontine paramedian reticular formation, a structure that directly projects to the ipsilateral abducens nucleus. In normal animals, neurons in this structure are characterized by a high-frequency burst of spikes associated with ipsiversive saccades. We recorded single-unit activity from 84 neurons from four monkeys (two normal, one exotrope, and one esotrope), while they made saccades to a visual target on a tangent screen. All 24 neurons recorded from the normal animals had preferred directions within 30° of pure horizontal. For the strabismic animals, the distribution of preferred directions was normal on one side of the brain, but highly variable on the other. In fact, 12/60 neurons recorded from the strabismic animals preferred vertical saccades. Many also had unusually weak or strong bursts. These data suggest that the loss of corresponding binocular vision during infancy impairs the development of normal tuning characteristics for saccade-related neurons in brain stem. Copyright © 2015 the American Physiological Society.

Automated data processing of { 1H-decoupled} 13C MR spectra acquired from human brain in vivo

NASA Astrophysics Data System (ADS)

Shic, Frederick; Ross, Brian

2003-06-01

In clinical 13C infusion studies, broadband excitation of 200 ppm of the human brain yields 13C MR spectra with a time resolution of 2-5 min and generates up to 2000 metabolite peaks over 2 h. We describe a fast, automated, observer-independent technique for processing { 1H-decoupled} 13C spectra. Quantified 13C spectroscopic signals, before and after the administration of [1- 13C]glucose and/or [1- 13C]acetate in human subjects are determined. Stepwise improvements of data processing are illustrated by examples of normal and pathological results. Variation in analysis of individual 13C resonances ranged between 2 and 14%. Using this method it is possible to reliably identify subtle metabolic effects of brain disease including Alzheimer's disease and epilepsy.

Human Mesenchymal Stem Cell Treatment Normalizes Cortical Gene Expression after Traumatic Brain Injury.

PubMed

Darkazalli, Ali; Vied, Cynthia; Badger, Crystal-Dawn; Levenson, Cathy W

2017-01-01

Traumatic brain injury (TBI) results in a progressive disease state with many adverse and long-term neurological consequences. Mesenchymal stem cells (MSCs) have emerged as a promising cytotherapy and have been previously shown to reduce secondary apoptosis and cognitive deficits associated with TBI. Consistent with the established literature, we observed that systemically administered human MSCs (hMSCs) accumulate with high specificity at the TBI lesion boundary zone known as the penumbra. Substantial work has been done to illuminate the mechanisms by which MSCs, and the bioactive molecules they secrete, exert their therapeutic effect. However, no such work has been published to examine the effect of MSC treatment on gene expression in the brain post-TBI. In the present study, we use high-throughput RNA sequencing (RNAseq) of cortical tissue from the TBI penumbra to assess the molecular effects of both TBI and subsequent treatment with intravenously delivered hMSCs. RNAseq revealed that expression of almost 7000 cortical genes in the penumbra were differentially regulated by TBI. Pathway analysis using the KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway database revealed that TBI regulated a large number of genes belonging to pathways involved in metabolism, receptor-mediated cell signaling, neuronal plasticity, immune cell recruitment and infiltration, and neurodegenerative disease. Remarkably, hMSC treatment was found to normalize 49% of all genes disrupted by TBI, with notably robust normalization of specific pathways within the categories mentioned above, including neuroactive receptor-ligand interactions (57%), glycolysis and gluconeogenesis (81%), and Parkinson's disease (100%). These data provide evidence in support of the multi-mechanistic nature of stem cell therapy and suggest that hMSC treatment is capable of simultaneously normalizing a wide variety of important molecular pathways that are disrupted by brain injury.

Resonance Raman imaging for detecting and monitoring molecular pathological changes in human brain tumors related to Warburg effect

NASA Astrophysics Data System (ADS)

Zhou, Yan; Liu, Cheng-hui; Zhu, Ke; Zhang, Chunyuan; Yang, Yang; Yu, Xinguang; Hu, Hailong; Cheng, Gangge; Wu, Binlin; Shi, Lingyan; Alfano, Robert R.

2018-02-01

The goal of the research is to determine the prognostic molecular pathological changes in components and composition, for human brain glioma gradings in comparison with normal tissues in three-dimensional Raman imaging profiles by visible Resonance Raman (VRR) imaging. VRR images from twenty-five specimens including three healthy tissues, one normal control, and twenty-one glioma tissues of grades II, II-III and III-IV with histology examination were measured and investigated using WITec300R confocal micro Raman imaging system with laser excitation of 532nm. Two-dimensional RR spectral mappings performed in 20μm x 20μm generated 400 images which integrated the intensity of the specific biochemical bonds as the third dimension. The three-dimension (3D) map demonstrated the spatial distributions of three selected sets of RR spectra of molecular biomarkers, and revealed significant differences in the spectra between normal and glioma tissues of different grades due to the composition changes in key molimageecules. These RR molecular spectral fingerprints have displayed: a clear enhancement of RR vibrational modes at 1129-1131cm-1 and 2934cm-1 which are supposed to be arising from lipoproteins; evident decreased RR vibrational modes at 1442cm-1 and 2854cm-1 which are from saturated fatty acids bonds in all-grades of glioma brain tissues compared with normal tissues; and the enhanced RR spectral modes of 1129 cm-1 and 2938cm-1 which suggest contribution from lactate. These findings may provide a novel proof for anaerobic glycolysis metabolic process in brain glioma cancer tissues that has been explained by Warburg effects.

Correlation of tissue-plasma partition coefficients between normal tissues and subcutaneous xenografts of human tumor cell lines in mouse as a prediction tool of drug penetration in tumors.

PubMed

Poulin, Patrick; Hop, Cornelis Eca; Salphati, Laurent; Liederer, Bianca M

2013-04-01

Understanding drug distribution and accumulation in tumors would be informative in the assessment of efficacy in targeted therapy; however, existing methods for predicting tissue drug distribution focus on normal tissues and do not incorporate tumors. The main objective of this study was to describe the relationships between tissue-plasma concentration ratios (Kp ) of normal tissues and those of subcutaneous xenograft tumors under nonsteady-state conditions, and establish regression equations that could potentially be used for the prediction of drug levels in several human tumor xenografts in mouse, based solely on a Kp value determined in a normal tissue (e.g., muscle). A dataset of 17 compounds was collected from the literature and from Genentech. Tissue and plasma concentration data in mouse were obtained following oral gavage or intraperitoneal administration. Linear regression analyses were performed between Kp values in several normal tissues (muscle, lung, liver, or brain) and those in human tumor xenografts (CL6, EBC-1, HT-29, PC3, U-87, MCF-7-neo-Her2, or BT474M1.1). The tissue-plasma ratios in normal tissues reasonably correlated with the tumor-plasma ratios in CL6, EBC-1, HT-29, U-87, BT474M1.1, and MCF-7-neo-Her2 xenografts (r(2) in the range 0.62-1) but not with the PC3 xenograft. In general, muscle and lung exhibited the strongest correlation with tumor xenografts, followed by liver. Regression coefficients from brain were low, except between brain and the glioblastoma U-87 xenograft (r(2) in the range 0.62-0.94). Furthermore, reasonably strong correlations were observed between muscle and lung and between muscle and liver (r(2) in the range 0.67-0.96). The slopes of the regressions differed depending on the class of drug (strong vs. weak base) and type of tissue (brain vs. other tissues and tumors). Overall, this study will contribute to our understanding of tissue-plasma partition coefficients for tumors and facilitate the use of physiologically based pharmacokinetics (PBPK) modeling for chemotherapy in oncology studies. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 102:1355-1369, 2013. Copyright © 2013 Wiley Periodicals, Inc.

Epigenetic and gene expression changes in the adolescent brain: What have we learned from animal models?

PubMed

Mychasiuk, Richelle; Metz, Gerlinde A S

2016-11-01

Adolescence is defined as the gradual period of transition between childhood and adulthood that is characterized by significant brain maturation, growth spurts, sexual maturation, and heightened social interaction. Although originally believed to be a uniquely human aspect of development, rodent and non-human primates demonstrate maturational patterns that distinctly support an adolescent stage. As epigenetic processes are essential for development and differentiation, but also transpire in mature cells in response to environmental influences, they are an important aspect of adolescent brain maturation. The purpose of this review article was to examine epigenetic programming in animal models of brain maturation during adolescence. The discussion focuses on animal models to examine three main concepts; epigenetic processes involved in normal adolescent brain maturation, the influence of fetal programming on adolescent brain development and the epigenome, and finally, postnatal experiences such as exercise and drugs that modify epigenetic processes important for adolescent brain maturation. This corollary emphasizes the utility of animal models to further our understanding of complex processes such as epigenetic regulation and brain development. Copyright © 2016 Elsevier Ltd. All rights reserved.

Effect of Exercise Training on Hippocampal Volume in Humans: A Pilot Study

ERIC Educational Resources Information Center

Parker, Beth A.; Thompson, Paul D.; Jordan, Kathryn C.; Grimaldi, Adam S.; Assaf, Michal; Jagannathan, Kanchana; Pearlson, Godfrey D.

2011-01-01

The hippocampus is the primary site of memory and learning in the brain. Both normal aging and various disease pathologies (e.g., alcoholism, schizophrenia, and major depressive disorder) are associated with lower hippocampal volumes in humans and hippocampal atrophy predicts progression of Alzheimers disease. In animals, there is convincing…

Default, Cognitive and Affective Brain Networks in Human Tinnitus

DTIC Science & Technology

Tinnitus is a major health problem among those currently and formerly in military service. This project hypothesizes that many of the clinically...significant, non-auditory aspects of the tinnitus condition involve two major brain networks: the cognitive control network (CCN) and the default mode...function can be assessed. Subjects in three groups are being compared: (1) control subjects with clinically-normal hearing thresholds and no tinnitus

Insights into TREM2 biology by network analysis of human brain gene expression data

PubMed Central

Forabosco, Paola; Ramasamy, Adaikalavan; Trabzuni, Daniah; Walker, Robert; Smith, Colin; Bras, Jose; Levine, Adam P.; Hardy, John; Pocock, Jennifer M.; Guerreiro, Rita; Weale, Michael E.; Ryten, Mina

2013-01-01

Rare variants in TREM2 cause susceptibility to late-onset Alzheimer's disease. Here we use microarray-based expression data generated from 101 neuropathologically normal individuals and covering 10 brain regions, including the hippocampus, to understand TREM2 biology in human brain. Using network analysis, we detect a highly preserved TREM2-containing module in human brain, show that it relates to microglia, and demonstrate that TREM2 is a hub gene in 5 brain regions, including the hippocampus, suggesting that it can drive module function. Using enrichment analysis we show significant overrepresentation of genes implicated in the adaptive and innate immune system. Inspection of genes with the highest connectivity to TREM2 suggests that it plays a key role in mediating changes in the microglial cytoskeleton necessary not only for phagocytosis, but also migration. Most importantly, we show that the TREM2-containing module is significantly enriched for genes genetically implicated in Alzheimer's disease, multiple sclerosis, and motor neuron disease, implying that these diseases share common pathways centered on microglia and that among the genes identified are possible new disease-relevant genes. PMID:23855984

Forthergillian Lecture. Imaging human brain function.

PubMed

Frackowiak, R S

The non-invasive brain scanning techniques introduced a quarter of a century ago have become crucial for diagnosis in clinical neurology. They have also been used to investigate brain function and have provided information about normal activity and pathogenesis. They have been used to investigate functional specialization in the brain and how specialized areas communicate to generate complex integrated functions such as speech, memory, the emotions and so on. The phenomenon of brain plasticity is poorly understood and yet clinical neurologists are aware, from everyday observations, that spontaneous recovery from brain lesions is common. An improved understanding of the mechanisms of recovery may generate new therapeutic strategies and indicate ways of modulating mechanisms that promote plastic compensation for loss of function. The main methods used to investigate these issues are positron emission tomography and magnetic resonance imaging (M.R.I.). M.R.I. is also used to map brain structure. The techniques of functional brain mapping and computational morphometrics depend on high performance scanners and a validated set of analytic statistical procedures that generate reproducible data and meaningful inferences from brain scanning data. The motor system presents a good paradigm to illustrate advances made by scanning towards an understanding of plasticity at the level of brain areas. The normal motor system is organized in a nested hierarchy. Recovery from paralysis caused by internal capsule strokes involves functional reorganization manifesting itself as changed patterns of activity in the component brain areas of the normal motor system. The pattern of plastic modification depends in part on patterns of residual or disturbed connectivity after brain injury. Therapeutic manipulations in patients with Parkinson's disease using deep brain stimulation, dopaminergic agents or fetal mesencephalic transplantation provide a means to examine mechanisms underpinning plastic change. Other models of plastic change, such as normal visuospatial learning or re-establishing speech comprehension after cochlear implantation in the deaf illustrate how patterns of brain function adapt over time. Limitations of the scanning techniques and prospects for the future are discussed in relation to new developments in the neuroimaging field.

Wavelet multiresolution complex network for decoding brain fatigued behavior from P300 signals

NASA Astrophysics Data System (ADS)

Gao, Zhong-Ke; Wang, Zi-Bo; Yang, Yu-Xuan; Li, Shan; Dang, Wei-Dong; Mao, Xiao-Qian

2018-09-01

Brain-computer interface (BCI) enables users to interact with the environment without relying on neural pathways and muscles. P300 based BCI systems have been extensively used to achieve human-machine interaction. However, the appearance of fatigue symptoms during operation process leads to the decline in classification accuracy of P300. Characterizing brain cognitive process underlying normal and fatigue conditions constitutes a problem of vital importance in the field of brain science. We in this paper propose a novel wavelet decomposition based complex network method to efficiently analyze the P300 signals recorded in the image stimulus test based on classical 'Oddball' paradigm. Initially, multichannel EEG signals are decomposed into wavelet coefficient series. Then we construct complex network by treating electrodes as nodes and determining the connections according to the 2-norm distances between wavelet coefficient series. The analysis of topological structure and statistical index indicates that the properties of brain network demonstrate significant distinctions between normal status and fatigue status. More specifically, the brain network reconfiguration in response to the cognitive task in fatigue status is reflected as the enhancement of the small-worldness.

Construction and comparative evaluation of different activity detection methods in brain FDG-PET.

PubMed

Buchholz, Hans-Georg; Wenzel, Fabian; Gartenschläger, Martin; Thiele, Frank; Young, Stewart; Reuss, Stefan; Schreckenberger, Mathias

2015-08-18

We constructed and evaluated reference brain FDG-PET databases for usage by three software programs (Computer-aided diagnosis for dementia (CAD4D), Statistical Parametric Mapping (SPM) and NEUROSTAT), which allow a user-independent detection of dementia-related hypometabolism in patients' brain FDG-PET. Thirty-seven healthy volunteers were scanned in order to construct brain FDG reference databases, which reflect the normal, age-dependent glucose consumption in human brain, using either software. Databases were compared to each other to assess the impact of different stereotactic normalization algorithms used by either software package. In addition, performance of the new reference databases in the detection of altered glucose consumption in the brains of patients was evaluated by calculating statistical maps of regional hypometabolism in FDG-PET of 20 patients with confirmed Alzheimer's dementia (AD) and of 10 non-AD patients. Extent (hypometabolic volume referred to as cluster size) and magnitude (peak z-score) of detected hypometabolism was statistically analyzed. Differences between the reference databases built by CAD4D, SPM or NEUROSTAT were observed. Due to the different normalization methods, altered spatial FDG patterns were found. When analyzing patient data with the reference databases created using CAD4D, SPM or NEUROSTAT, similar characteristic clusters of hypometabolism in the same brain regions were found in the AD group with either software. However, larger z-scores were observed with CAD4D and NEUROSTAT than those reported by SPM. Better concordance with CAD4D and NEUROSTAT was achieved using the spatially normalized images of SPM and an independent z-score calculation. The three software packages identified the peak z-scores in the same brain region in 11 of 20 AD cases, and there was concordance between CAD4D and SPM in 16 AD subjects. The clinical evaluation of brain FDG-PET of 20 AD patients with either CAD4D-, SPM- or NEUROSTAT-generated databases from an identical reference dataset showed similar patterns of hypometabolism in the brain regions known to be involved in AD. The extent of hypometabolism and peak z-score appeared to be influenced by the calculation method used in each software package rather than by different spatial normalization parameters.

The Interleukin 3 Gene (IL3) Contributes to Human Brain Volume Variation by Regulating Proliferation and Survival of Neural Progenitors

PubMed Central

Huang, Liang; Nho, Kwangsik; Deng, Min; Chen, Qiang; Weinberger, Daniel R.; Vasquez, Alejandro Arias; Rijpkema, Mark; Mattay, Venkata S.; Saykin, Andrew J.; Shen, Li; Fernández, Guillén; Franke, Barbara; Chen, Jing-chun; Chen, Xiang-ning; Wang, Jin-kai; Xiao, Xiao; Qi, Xue-bin; Xiang, Kun; Peng, Ying-Mei; Cao, Xiang-yu; Li, Yi; Shi, Xiao-dong; Gan, Lin; Su, Bing

2012-01-01

One of the most significant evolutionary changes underlying the highly developed cognitive abilities of humans is the greatly enlarged brain volume. In addition to being far greater than in most other species, the volume of the human brain exhibits extensive variation and distinct sexual dimorphism in the general population. However, little is known about the genetic mechanisms underlying normal variation as well as the observed sex difference in human brain volume. Here we show that interleukin-3 (IL3) is strongly associated with brain volume variation in four genetically divergent populations. We identified a sequence polymorphism (rs31480) in the IL3 promoter which alters the expression of IL3 by affecting the binding affinity of transcription factor SP1. Further analysis indicated that IL3 and its receptors are continuously expressed in the developing mouse brain, reaching highest levels at postnatal day 1–4. Furthermore, we found IL3 receptor alpha (IL3RA) was mainly expressed in neural progenitors and neurons, and IL3 could promote proliferation and survival of the neural progenitors. The expression level of IL3 thus played pivotal roles in the expansion and maintenance of the neural progenitor pool and the number of surviving neurons. Moreover, we found that IL3 activated both estrogen receptors, but estrogen didn’t directly regulate the expression of IL3. Our results demonstrate that genetic variation in the IL3 promoter regulates human brain volume and reveals novel roles of IL3 in regulating brain development. PMID:23226269

Comprehensive Analysis of Human Endogenous Retrovirus Group HERV-W Locus Transcription in Multiple Sclerosis Brain Lesions by High-Throughput Amplicon Sequencing

PubMed Central

Schmitt, Katja; Richter, Christin; Backes, Christina; Meese, Eckart; Ruprecht, Klemens

2013-01-01

Human endogenous retroviruses (HERVs) of the HERV-W group comprise hundreds of loci in the human genome. Deregulated HERV-W expression and HERV-W locus ERVWE1-encoded Syncytin-1 protein have been implicated in the pathogenesis of multiple sclerosis (MS). However, the actual transcription of HERV-W loci in the MS context has not been comprehensively analyzed. We investigated transcription of HERV-W in MS brain lesions and white matter brain tissue from healthy controls by employing next-generation amplicon sequencing of HERV-W env-specific reverse transcriptase (RT) PCR products, thus revealing transcribed HERV-W loci and the relative transcript levels of those loci. We identified more than 100 HERV-W loci that were transcribed in the human brain, with a limited number of loci being predominantly transcribed. Importantly, relative transcript levels of HERV-W loci were very similar between MS and healthy brain tissue samples, refuting deregulated transcription of HERV-W env in MS brain lesions, including the high-level-transcribed ERVWE1 locus encoding Syncytin-1. Quantitative RT-PCR likewise did not reveal differences in MS regarding HERV-W env general transcript or ERVWE1- and ERVWE2-specific transcript levels. However, we obtained evidence for interindividual differences in HERV-W transcript levels. Reporter gene assays indicated promoter activity of many HERV-W long terminal repeats (LTRs), including structurally incomplete LTRs. Our comprehensive analysis of HERV-W transcription in the human brain thus provides important information on the biology of HERV-W in MS lesions and normal human brain, implications for study design, and mechanisms by which HERV-W may (or may not) be involved in MS. PMID:24109235

In vitro terahertz spectroscopy of gelatin-embedded human brain tumors: a pilot study

NASA Astrophysics Data System (ADS)

Chernomyrdin, N. V.; Gavdush, A. A.; Beshplav, S.-I. T.; Malakhov, K. M.; Kucheryavenko, A. S.; Katyba, G. M.; Dolganova, I. N.; Goryaynov, S. A.; Karasik, V. E.; Spektor, I. E.; Kurlov, V. N.; Yurchenko, S. O.; Komandin, G. A.; Potapov, A. A.; Tuchin, V. V.; Zaytsev, K. I.

2018-04-01

We have performed the in vitro terahertz (THz) spectroscopy of human brain tumors. In order to fix tissues for the THz measurements, we have applied the gelatin embedding. It allows for preserving tissues from hydration/dehydration and sustaining their THz response similar to that of the freshly-excised tissues for a long time after resection. We have assembled an experimental setup for the reflection-mode measurements of human brain tissues based on the THz pulsed spectrometer. We have used this setup to study in vitro the refractive index and the amplitude absorption coefficient of 2 samples of malignant glioma (grade IV), 1 sample of meningioma (grade I), and samples of intact tissues. We have observed significant differences between the THz responses of normal and pathological tissues of the brain. The results of this paper highlight the potential of the THz technology in the intraoperative neurodiagnosis of tumors relying on the endogenous labels of tumorous tissues.

Is the ferret a suitable species for studying perinatal brain injury?

PubMed Central

Empie, Kristen; Rangarajan, Vijayeta; Juul, Sandra E.

2016-01-01

Complications of prematurity often disrupt normal brain development and/or cause direct damage to the developing brain, resulting in poor neurodevelopmental outcomes. Physiologically relevant animal models of perinatal brain injury can advance our understanding of these influences and thereby provide opportunities to develop therapies and improve long-term outcomes. While there are advantages to currently available small animal models, there are also significant drawbacks that have limited translation of research findings to humans. Large animal models such as newborn pig, sheep and nonhuman primates have complex brain development more similar to humans, but these animals are expensive, and developmental testing of sheep and piglets is limited. Ferrets (Mustela putorius furo) are born lissencephalic and undergo postnatal cortical folding to form complex gyrencephalic brains. This review examines whether ferrets might provide a novel intermediate animal model of neonatal brain disease that has the benefit of a gyrified, altricial brain in a small animal. It summarizes attributes of ferret brain growth and development that make it an appealing animal in which to model perinatal brain injury. We postulate that because of their innate characteristics, ferrets have great potential in neonatal neurodevelopmental studies. PMID:26102988

A Method for Whole Brain Ex Vivo Magnetic Resonance Imaging with Minimal Susceptibility Artifacts

PubMed Central

Shatil, Anwar S.; Matsuda, Kant M.; Figley, Chase R.

2016-01-01

Magnetic resonance imaging (MRI) is a non-destructive technique that is capable of localizing pathologies and assessing other anatomical features (e.g., tissue volume, microstructure, and white matter connectivity) in postmortem, ex vivo human brains. However, when brains are removed from the skull and cerebrospinal fluid (i.e., their normal in vivo magnetic environment), air bubbles and air–tissue interfaces typically cause magnetic susceptibility artifacts that severely degrade the quality of ex vivo MRI data. In this report, we describe a relatively simple and cost-effective experimental setup for acquiring artifact-free ex vivo brain images using a clinical MRI system with standard hardware. In particular, we outline the necessary steps, from collecting an ex vivo human brain to the MRI scanner setup, and have also described changing the formalin (as might be necessary in longitudinal postmortem studies). Finally, we share some representative ex vivo MRI images that have been acquired using the proposed setup in order to demonstrate the efficacy of this approach. We hope that this protocol will provide both clinicians and researchers with a straight-forward and cost-effective solution for acquiring ex vivo MRI data from whole postmortem human brains. PMID:27965620

The Epigenetic Link between Prenatal Adverse Environments and Neurodevelopmental Disorders

PubMed Central

Kundakovic, Marija; Jaric, Ivana

2017-01-01

Prenatal adverse environments, such as maternal stress, toxicological exposures, and viral infections, can disrupt normal brain development and contribute to neurodevelopmental disorders, including schizophrenia, depression, and autism. Increasing evidence shows that these short- and long-term effects of prenatal exposures on brain structure and function are mediated by epigenetic mechanisms. Animal studies demonstrate that prenatal exposure to stress, toxins, viral mimetics, and drugs induces lasting epigenetic changes in the brain, including genes encoding glucocorticoid receptor (Nr3c1) and brain-derived neurotrophic factor (Bdnf). These epigenetic changes have been linked to changes in brain gene expression, stress reactivity, and behavior, and often times, these effects are shown to be dependent on the gestational window of exposure, sex, and exposure level. Although evidence from human studies is more limited, gestational exposure to environmental risks in humans is associated with epigenetic changes in peripheral tissues, and future studies are required to understand whether we can use peripheral biomarkers to predict neurobehavioral outcomes. An extensive research effort combining well-designed human and animal studies, with comprehensive epigenomic analyses of peripheral and brain tissues over time, will be necessary to improve our understanding of the epigenetic basis of neurodevelopmental disorders. PMID:28335457

Creating an anthropomorphic digital MR phantom—an extensible tool for comparing and evaluating quantitative imaging algorithms

NASA Astrophysics Data System (ADS)

Bosca, Ryan J.; Jackson, Edward F.

2016-01-01

Assessing and mitigating the various sources of bias and variance associated with image quantification algorithms is essential to the use of such algorithms in clinical research and practice. Assessment is usually accomplished with grid-based digital reference objects (DRO) or, more recently, digital anthropomorphic phantoms based on normal human anatomy. Publicly available digital anthropomorphic phantoms can provide a basis for generating realistic model-based DROs that incorporate the heterogeneity commonly found in pathology. Using a publicly available vascular input function (VIF) and digital anthropomorphic phantom of a normal human brain, a methodology was developed to generate a DRO based on the general kinetic model (GKM) that represented realistic and heterogeneously enhancing pathology. GKM parameters were estimated from a deidentified clinical dynamic contrast-enhanced (DCE) MRI exam. This clinical imaging volume was co-registered with a discrete tissue model, and model parameters estimated from clinical images were used to synthesize a DCE-MRI exam that consisted of normal brain tissues and a heterogeneously enhancing brain tumor. An example application of spatial smoothing was used to illustrate potential applications in assessing quantitative imaging algorithms. A voxel-wise Bland-Altman analysis demonstrated negligible differences between the parameters estimated with and without spatial smoothing (using a small radius Gaussian kernel). In this work, we reported an extensible methodology for generating model-based anthropomorphic DROs containing normal and pathological tissue that can be used to assess quantitative imaging algorithms.

Loss of pons-to-hypothalamic white matter tracks in brainstem obesity.

PubMed

Purnell, J Q; Lahna, D L; Samuels, M H; Rooney, W D; Hoffman, W F

2014-12-01

Hyperphagia and obesity have been reported following damage to the hypothalamus in humans. Other brain sites are also postulated to be involved in the control of food intake and body weight regulation, such as the amygdala and brainstem. The brainstem, however, is thought to primarily integrate short-term meal-related signals but not affect long-term alterations in body weight, which is controlled by higher centers. The objective of this study was to identify structural pathways damaged in a patient with a brainstem cavernoma who experienced sudden onset of hyperphagia and >50 kg weight gain in <1 year following surgical drainage via a midline suboccipital craniotomy. Diffusion tensor imaging revealed loss of nerve fiber connections between her brainstem, hypothalamus and higher brain centers with preservation of motor tracks. Imaging and endocrine testing confirmed normal hypothalamic structure and function. Gastric bypass surgery restored normal appetite and body weight to baseline. This is the first report of 'brainstem obesity' and adds to the brain regions that can determine the long-term body weight set point in humans.

Ribosome Profiling Reveals a Cell-Type-Specific Translational Landscape in Brain Tumors

PubMed Central

Gonzalez, Christian; Sims, Jennifer S.; Hornstein, Nicholas; Mela, Angeliki; Garcia, Franklin; Lei, Liang; Gass, David A.; Amendolara, Benjamin; Bruce, Jeffrey N.

2014-01-01

Glioma growth is driven by signaling that ultimately regulates protein synthesis. Gliomas are also complex at the cellular level and involve multiple cell types, including transformed and reactive cells in the brain tumor microenvironment. The distinct functions of the various cell types likely lead to different requirements and regulatory paradigms for protein synthesis. Proneural gliomas can arise from transformation of glial progenitors that are driven to proliferate via mitogenic signaling that affects translation. To investigate translational regulation in this system, we developed a RiboTag glioma mouse model that enables cell-type-specific, genome-wide ribosome profiling of tumor tissue. Infecting glial progenitors with Cre-recombinant retrovirus simultaneously activates expression of tagged ribosomes and delivers a tumor-initiating mutation. Remarkably, we find that although genes specific to transformed cells are highly translated, their translation efficiencies are low compared with normal brain. Ribosome positioning reveals sequence-dependent regulation of ribosomal activity in 5′-leaders upstream of annotated start codons, leading to differential translation in glioma compared with normal brain. Additionally, although transformed cells express a proneural signature, untransformed tumor-associated cells, including reactive astrocytes and microglia, express a mesenchymal signature. Finally, we observe the same phenomena in human disease by combining ribosome profiling of human proneural tumor and non-neoplastic brain tissue with computational deconvolution to assess cell-type-specific translational regulation. PMID:25122893

IGF-1: The Jekyll & Hyde of the aging brain.

PubMed

Gubbi, Sriram; Quipildor, Gabriela Farias; Barzilai, Nir; Huffman, Derek M; Milman, Sofiya

2018-05-08

The IGF-1 signaling pathway has emerged as a major regulator of the aging process, from rodents to humans. However, given the pleiotropic actions of IGF-1, its role in the aging brain remains complex and controversial. While IGF-1 is clearly essential for normal development of the central nervous system, conflicting evidence has emerged from preclinical and human studies regarding its relationship to cognitive function, as well as cerebrovascular and neurodegenerative disorders. This review delves into the current state of the evidence examining the role of IGF-1 in the aging brain, encompassing preclinical and clinical studies. A broad examination of the data indicates that IGF-1 may indeed play opposing roles in the aging brain, depending on the underlying pathology and context. Some evidence suggests that in the setting of neurodegenerative diseases that manifest with abnormal protein deposition in the brain, such as Alzheimer's disease, reducing IGF-1 signaling may serve a protective role by slowing disease progression and augmenting clearance of pathologic proteins to maintain cellular homeostasis. In contrast, inducing IGF-1 deficiency has also been implicated in dysregulated function of cognition and the neurovascular system, suggesting that some IGF-1 signaling may be necessary for normal brain function. Furthermore, states of acute neuronal injury, which necessitate growth, repair and survival signals to persevere, typically demonstrate salutary effects of IGF-1 in that context. Appreciating the dual, at times opposing "Dr. Jekyll" and "Mr. Hyde" characteristics of IGF-1 in the aging brain, will bring us closer to understanding its impact and devising more targeted IGF-1-related interventions.

Wavelet-domain de-noising of OCT images of human brain malignant glioma

NASA Astrophysics Data System (ADS)

Dolganova, I. N.; Aleksandrova, P. V.; Beshplav, S.-I. T.; Chernomyrdin, N. V.; Dubyanskaya, E. N.; Goryaynov, S. A.; Kurlov, V. N.; Reshetov, I. V.; Potapov, A. A.; Tuchin, V. V.; Zaytsev, K. I.

2018-04-01

We have proposed a wavelet-domain de-noising technique for imaging of human brain malignant glioma by optical coherence tomography (OCT). It implies OCT image decomposition using the direct fast wavelet transform, thresholding of the obtained wavelet spectrum and further inverse fast wavelet transform for image reconstruction. By selecting both wavelet basis and thresholding procedure, we have found an optimal wavelet filter, which application improves differentiation of the considered brain tissue classes - i.e. malignant glioma and normal/intact tissue. Namely, it allows reducing the scattering noise in the OCT images and retaining signal decrement for each tissue class. Therefore, the observed results reveals the wavelet-domain de-noising as a prospective tool for improved characterization of biological tissue using the OCT.

High frequency oscillations are associated with cognitive processing in human recognition memory.

PubMed

Kucewicz, Michal T; Cimbalnik, Jan; Matsumoto, Joseph Y; Brinkmann, Benjamin H; Bower, Mark R; Vasoli, Vincent; Sulc, Vlastimil; Meyer, Fred; Marsh, W R; Stead, S M; Worrell, Gregory A

2014-08-01

High frequency oscillations are associated with normal brain function, but also increasingly recognized as potential biomarkers of the epileptogenic brain. Their role in human cognition has been predominantly studied in classical gamma frequencies (30-100 Hz), which reflect neuronal network coordination involved in attention, learning and memory. Invasive brain recordings in animals and humans demonstrate that physiological oscillations extend beyond the gamma frequency range, but their function in human cognitive processing has not been fully elucidated. Here we investigate high frequency oscillations spanning the high gamma (50-125 Hz), ripple (125-250 Hz) and fast ripple (250-500 Hz) frequency bands using intracranial recordings from 12 patients (five males and seven females, age 21-63 years) during memory encoding and recall of a series of affectively charged images. Presentation of the images induced high frequency oscillations in all three studied bands within the primary visual, limbic and higher order cortical regions in a sequence consistent with the visual processing stream. These induced oscillations were detected on individual electrodes localized in the amygdala, hippocampus and specific neocortical areas, revealing discrete oscillations of characteristic frequency, duration and latency from image presentation. Memory encoding and recall significantly modulated the number of induced high gamma, ripple and fast ripple detections in the studied structures, which was greater in the primary sensory areas during the encoding (Wilcoxon rank sum test, P = 0.002) and in the higher-order cortical association areas during the recall (Wilcoxon rank sum test, P = 0.001) of memorized images. Furthermore, the induced high gamma, ripple and fast ripple responses discriminated the encoded and the affectively charged images. In summary, our results show that high frequency oscillations, spanning a wide range of frequencies, are associated with memory processing and generated along distributed cortical and limbic brain regions. These findings support an important role for fast network synchronization in human cognition and extend our understanding of normal physiological brain activity during memory processing. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

EGFR-directed Affibody for fluorescence-guided glioma surgery: time-dose analysis (Conference Presentation)

NASA Astrophysics Data System (ADS)

Ribeiro de Souza, Ana Luiza; Marra, Kayla; Gunn, Jason R.; Elliott, Jonathan T.; Samkoe, Kimberley S.; Paulsen, Keith D.; Draney, Daniel R.; Feldwisch, Joachim

2016-03-01

The key to fluorescence guided surgical oncology is the ability to create specific contrast between normal and glioma tissue. The blood brain barrier that limits the delivery of substances to the normal brain is broken in tumors, allowing accumulation of agents in the tumor interior. However, for a clinical success, imaging agents should be in the infiltrative edges to minimize the resection of normal brain while enable the removal of tumor. The aberrant overexpression and/or activation of EGFR is associated with many types of cancers, including glioblastoma and the injection of a fluorescent molecule targeted to these receptors would improve tumor contrast during fluorescence guided surgery. Affibody molecules have intentional medium affinity and high potential specificity, which are the desirable features of a good surgical imaging agent. The aim of this study was evaluate the brain/glioma uptake of ABY029 labeled with near-infrared dye IRDye800CW after intravenous injection. Rats were either inoculated with orthotopic implantations of U251 human glioma cell line or PBS (shams control) in the brain. The tumors were allowed to grow for 2-3 weeks before carrying out fluorescent tracer experiments. Fluorescent imaging of ex vivo brain slices from rats was acquired at different time points after infection of fluorescently labeled EGFR-specific affibody to verify which time provided maximal contrast tumor to normal brain. Although the tumor was most clearly visualized after 1h of IRDye800CW-labeled ABY029 injection, the tumor location could be identified from the background after 48h. These results suggest that the NIR-labeled affibody examined shows excellent potential to increase surgical visualization for confirmed EGFR positive tumors.

2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH) in a nude rat glioma model: implications for photodynamic therapy.

PubMed

Lobel, J; MacDonald, I J; Ciesielski, M J; Barone, T; Potter, W R; Pollina, J; Plunkett, R J; Fenstermaker, R A; Dougherty, T J

2001-01-01

In this study, we evaluated 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-alpha (HPPH or Photochlor) as a photosensitizer for the treatment of malignant gliomas by photodynamic therapy (PDT). We performed in vivo reflection spectroscopy in athymic rats to measure the attenuation of light in normal brain tissue. We also studied HPPH pharmacokinetics and PDT effects in nude rats with brain tumors derived from stereotactically implanted U87 human glioma cells. Rats implanted with tumors were sacrificed at designated time points to determine the pharmacokinetics of HPPH in serum, tumor, normal brain, and brain adjacent to tumor (BAT). HPPH concentrations in normal brain, BAT and tumor were determined using fluorescence spectroscopy. Twenty-four hours after intravenous injection of HPPH, we administered interstitial PDT treatment at a wavelength of 665 nm. Light was given in doses of 3.5, 7.5 or 15 J/cm at the tumor site and at a rate of 50 mW/cm. In vivo spectroscopy of normal brain tissue showed that the attenuation depth of 665 nm light is approximately 30% greater than that of 630 nm light used to activate Photofrin, which is currently being evaluated for PDT as an adjuvant to surgery for malignant gliomas. The t1/2 of disappearance of drug from serum and tumor was 25 and 30 hours, respectively. Twenty-four hours after injection of 0.5 mg/kg HPPH, tumor-to-brain drug ratios ranged from 5:1 to 15:1. Enhanced survival was observed in each of the HPPH/PDT-treated animal groups. These data suggest that HPPH may be a useful adjuvant for the treatment of malignant gliomas.

Increased IMP dehydrogenase gene expression in solid tumor tissues and tumor cell lines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Collart, F.R.; Chubb, C.B.; Mirkin, B.L.

1992-07-10

IMP dehydrogenase, a regulatory enzyme of guanine nucleotide biosynthesis, may play a role in cell proliferation and malignancy. To assess this possibility, we examined IMP dehydrogenase expression in a series of human solid tumor tissues and tumor cell lines in comparison with their normal counterparts. Increased IMP dehydrogenase gene expression was observed in brain tumors relative to normal brain tissue and in sarcoma cells relative to normal fibroblasts. Similarly, in several B- and T-lymphoid leukemia cell lines, elevated levels of IMP dehydrogenase mRNA and cellular enzyme were observed in comparison with the levels in peripheral blood lymphocytes. These results aremore » consistent with an association between increased IMP dehydrogenase expression and either enhanced cell proliferation or malignant transformation.« less

Autofluorescence of normal and neoplastic human brain tissue: an aid for intraoperative delineation of tumor resection margins

NASA Astrophysics Data System (ADS)

Bottiroli, Giovanni F.; Croce, Anna C.; Locatelli, Donata; Nano, Rosanna; Giombelli, Ermanno; Messina, Alberto; Benericetti, Eugenio

1998-01-01

Light-induced autofluorescence measurements were made on normal and tumor brain tissues to assess their spectroscopic properties and to verify the potential of this parameter for an intraoperative delineation of tumor resection margins. Spectrofluorometric analysis was performed both at the microscope on tissue sections from surgical resection, and on patients affected by glioblastoma, during surgical operation. Significant differences in autofluorescence emission properties were found between normal and tumor tissues in both ex vivo and in vivo measurements, indicating that the lesion can be distinguished from the informal surrounding tissues by the signal amplitude and the spectral shape. The non-invasiveness of the technique opens interesting prospects for improving the efficacy of neurosurgical operation, by allowing an intraoperative delimitation of tumor resection margins.

Forebrain Mechanisms of Nociception and Pain: Analysis through Imaging

NASA Astrophysics Data System (ADS)

Casey, Kenneth L.

1999-07-01

Pain is a unified experience composed of interacting discriminative, affective-motivational, and cognitive components, each of which is mediated and modulated through forebrain mechanisms acting at spinal, brainstem, and cerebral levels. The size of the human forebrain in relation to the spinal cord gives anatomical emphasis to forebrain control over nociceptive processing. Human forebrain pathology can cause pain without the activation of nociceptors. Functional imaging of the normal human brain with positron emission tomography (PET) shows synaptically induced increases in regional cerebral blood flow (rCBF) in several regions specifically during pain. We have examined the variables of gender, type of noxious stimulus, and the origin of nociceptive input as potential determinants of the pattern and intensity of rCBF responses. The structures most consistently activated across genders and during contact heat pain, cold pain, cutaneous laser pain or intramuscular pain were the contralateral insula and anterior cingulate cortex, the bilateral thalamus and premotor cortex, and the cerebellar vermis. These regions are commonly activated in PET studies of pain conducted by other investigators, and the intensity of the brain rCBF response correlates parametrically with perceived pain intensity. To complement the human studies, we developed an animal model for investigating stimulus-induced rCBF responses in the rat. In accord with behavioral measures and the results of human PET, there is a progressive and selective activation of somatosensory and limbic system structures in the brain and brainstem following the subcutaneous injection of formalin. The animal model and human PET studies should be mutually reinforcing and thus facilitate progress in understanding forebrain mechanisms of normal and pathological pain.

Bioimaging of metals in brain tissue by laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) and metallomics.

PubMed

Becker, J Sabine; Matusch, Andreas; Palm, Christoph; Salber, Dagmar; Morton, Kathryn A; Becker, J Susanne

2010-02-01

Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) has been developed and established as an emerging technique in the generation of quantitative images of metal distributions in thin tissue sections of brain samples (such as human, rat and mouse brain), with applications in research related to neurodegenerative disorders. A new analytical protocol is described which includes sample preparation by cryo-cutting of thin tissue sections and matrix-matched laboratory standards, mass spectrometric measurements, data acquisition, and quantitative analysis. Specific examples of the bioimaging of metal distributions in normal rodent brains are provided. Differences to the normal were assessed in a Parkinson's disease and a stroke brain model. Furthermore, changes during normal aging were studied. Powerful analytical techniques are also required for the determination and characterization of metal-containing proteins within a large pool of proteins, e.g., after denaturing or non-denaturing electrophoretic separation of proteins in one-dimensional and two-dimensional gels. LA-ICP-MS can be employed to detect metalloproteins in protein bands or spots separated after gel electrophoresis. MALDI-MS can then be used to identify specific metal-containing proteins in these bands or spots. The combination of these techniques is described in the second section.

Human serum albumin nanoparticles modified with apolipoprotein A-I cross the blood-brain barrier and enter the rodent brain.

PubMed

Zensi, Anja; Begley, David; Pontikis, Charles; Legros, Celine; Mihoreanu, Larisa; Büchel, Claudia; Kreuter, Jörg

2010-12-01

Nanoparticles made of human serum albumin (HSA) and modified with apolipoproteins have previously been shown to transport drugs, which normally do not enter the brain, across the blood-brain barrier (BBB). However the precise mechanism by which nanoparticles with different apolipoproteins on their surface can target to the brain, as yet, has not been totally elucidated. In the present study, HSA nanoparticles with covalently bound apolipoprotein A-I (Apo A-I) as a targetor for brain capillary endothelial cells were injected intravenously into SV 129 mice and Wistar rats. The rodents were sacrificed after 15 or 30 min, and their brains were examined by transmission electron microscopy. Apo A-I nanoparticles could be found inside the endothelial cells of brain capillaries as well as within parenchymal brain tissue of both, mice and rats, whereas control particles without Apo A-I on their surface did not cross the BBB during our experiments. The maintenance of tight junction integrity and barrier function during treatment with nanoparticles was demonstrated by perfusion with a fixative containing lanthanum nitrate as an electron dense marker for the permeability of tight junctions.

Chemical mapping of anxiety in the brain of healthy humans: an in vivo 1H-MRS study on the effects of sex, age, and brain region.

PubMed

Grachev, I D; Apkarian, A V

2000-12-01

We recently presented results in an in vivo study of human brain chemistry in 'physiologic' anxiety, i.e., the anxiety of normal everyday life. Normal subjects with high anxiety demonstrated increased concentration of chemicals in orbital frontal cortex (OFC) as compared to lower anxiety. In a separate study of aging we demonstrated a decrease of total chemical concentration in OFC of middle-aged subjects, as compared with younger age. This brain region also showed gender dependence; men demonstrating decreased chemical concentration compared to women. We hypothesized that these sex- and age-dependent differences in OFC chemistry changes are a result of anxiety effects on this brain region. In the present study we examined these sex- and age-differential regional brain chemistry changes (as identified by localized in vivo proton magnetic resonance spectroscopy [1H-MRS]) in relation to the state-trait-anxiety (as measured by the State-Trait Anxiety Inventory) in 35 healthy subjects. The concentrations for all nine chemicals of 1H-MRS spectra were measured relative to creatine across multiple brain regions, including OFC in the left hemisphere. Analysis of variance showed anxiety-specific effects on chemical concentration changes in OFC, which were different for both sexes and age groups. Male subjects showed larger effect of anxiety on OFC chemistry as compared to females when the same sex high-anxiety subjects were compared to lower anxiety. Similarly, middle-aged subjects showed larger effect of anxiety on OFC chemistry as compared to younger age when the same age subjects with high anxiety were compared to lower anxiety. Largest effect of anxiety on OFC chemistry was due to changes of N-Acetyl aspartate. The results indicate that the state-trait anxiety has sex- and age-differential patterns on OFC chemistry in healthy humans, providing new information about the neurobiological roots of anxiety.

Agrin in Alzheimer's Disease: Altered Solubility and Abnormal Distribution within Microvasculature and Brain Parenchyma

NASA Astrophysics Data System (ADS)

Donahue, John E.; Berzin, Tyler M.; Rafii, Michael S.; Glass, David J.; Yancopoulos, George D.; Fallon, Justin R.; Stopa, Edward G.

1999-05-01

Agrin is a heparan sulfate proteoglycan that is widely expressed in neurons and microvascular basal lamina in the rodent and avian central nervous system. Agrin induces the differentiation of nerve-muscle synapses, but its function in either normal or diseased brains is not known. Alzheimer's disease (AD) is characterized by loss of synapses, changes in microvascular architecture, and formation of neurofibrillary tangles and senile plaques. Here we have asked whether AD causes changes in the distribution and biochemical properties of agrin. Immunostaining of normal, aged human central nervous system revealed that agrin is expressed in neurons in multiple brain areas. Robust agrin immunoreactivity was observed uniformly in the microvascular basal lamina. In AD brains, agrin is highly concentrated in both diffuse and neuritic plaques as well as neurofibrillary tangles; neuronal expression of agrin also was observed. Furthermore, patients with AD had microvascular alterations characterized by thinning and fragmentation of the basal lamina. Detergent extraction and Western blotting showed that virtually all the agrin in normal brain is soluble in 1% SDS. In contrast, a large fraction of the agrin in AD brains is insoluble under these conditions, suggesting that it is tightly associated with β -amyloid. Together, these data indicate that the agrin abnormalities observed in AD are closely linked to β -amyloid deposition. These observations suggest that altered agrin expression in the microvasculature and the brain parenchyma contribute to the pathogenesis of AD.

Genetics Home Reference: deafness and myopia syndrome

MedlinePlus

... This Page Aruga J, Yokota N, Mikoshiba K. Human SLITRK family genes: genomic organization and expression profiling in normal brain ... AH. SLITRK6 mutations cause myopia and deafness in humans and mice. J Clin Invest. 2013 May;123(5):2094-102. doi: 10.1172/JCI65853. Epub ... are genome editing and CRISPR-Cas9? What is precision medicine? What ...

Weight Perturbation Alters Leptin Signal Transduction in a Region-Specific Manner throughout the Brain

PubMed Central

Morabito, Michael V.; Ravussin, Yann; Mueller, Bridget R.; Skowronski, Alicja A.; Watanabe, Kazuhisa; Foo, Kylie S.; Lee, Samuel X.; Lehmann, Anders; Hjorth, Stephan; Zeltser, Lori M.; LeDuc, Charles A.; Leibel, Rudolph L.

2017-01-01

Diet-induced obesity (DIO) resulting from consumption of a high fat diet (HFD) attenuates normal neuronal responses to leptin and may contribute to the metabolic defense of an acquired higher body weight in humans; the molecular bases for the persistence of this defense are unknown. We measured the responses of 23 brain regions to exogenous leptin in 4 different groups of weight- and/or diet-perturbed mice. Responses to leptin were assessed by quantifying pSTAT3 levels in brain nuclei 30 minutes following 3 mg/kg intraperitoneal leptin. HFD attenuated leptin sensing throughout the brain, but weight loss did not restore central leptin signaling to control levels in several brain regions important in energy homeostasis, including the arcuate and dorsomedial hypothalamic nuclei. Effects of diet on leptin signaling varied by brain region, with results dependent on the method of weight loss (restriction of calories of HFD, ad lib intake of standard mouse chow). High fat diet attenuates leptin signaling throughout the brain, but some brain regions maintain their ability to sense leptin. Weight loss restores leptin sensing to some degree in most (but not all) brain regions, while other brain regions display hypersensitivity to leptin following weight loss. Normal leptin sensing was restored in several brain regions, with the pattern of restoration dependent on the method of weight loss. PMID:28107353

Electromagnetic Treatment to Old Alzheimer's Mice Reverses β-Amyloid Deposition, Modifies Cerebral Blood Flow, and Provides Selected Cognitive Benefit

PubMed Central

Arendash, Gary W.; Mori, Takashi; Dorsey, Maggie; Gonzalez, Rich; Tajiri, Naoki; Borlongan, Cesar

2012-01-01

Few studies have investigated physiologic and cognitive effects of “long-term" electromagnetic field (EMF) exposure in humans or animals. Our recent studies have provided initial insight into the long-term impact of adulthood EMF exposure (GSM, pulsed/modulated, 918 MHz, 0.25–1.05 W/kg) by showing 6+ months of daily EMF treatment protects against or reverses cognitive impairment in Alzheimer's transgenic (Tg) mice, while even having cognitive benefit to normal mice. Mechanistically, EMF-induced cognitive benefits involve suppression of brain β-amyloid (Aβ) aggregation/deposition in Tg mice and brain mitochondrial enhancement in both Tg and normal mice. The present study extends this work by showing that daily EMF treatment given to very old (21–27 month) Tg mice over a 2-month period reverses their very advanced brain Aβ aggregation/deposition. These very old Tg mice and their normal littermates together showed an increase in general memory function in the Y-maze task, although not in more complex tasks. Measurement of both body and brain temperature at intervals during the 2-month EMF treatment, as well as in a separate group of Tg mice during a 12-day treatment period, revealed no appreciable increases in brain temperature (and no/slight increases in body temperature) during EMF “ON" periods. Thus, the neuropathologic/cognitive benefits of EMF treatment occur without brain hyperthermia. Finally, regional cerebral blood flow in cerebral cortex was determined to be reduced in both Tg and normal mice after 2 months of EMF treatment, most probably through cerebrovascular constriction induced by freed/disaggregated Aβ (Tg mice) and slight body hyperthermia during “ON" periods. These results demonstrate that long-term EMF treatment can provide general cognitive benefit to very old Alzheimer's Tg mice and normal mice, as well as reversal of advanced Aβ neuropathology in Tg mice without brain heating. Results further underscore the potential for EMF treatment against AD. PMID:22558216

Hyperpolarized 13C MR Markers of Renal Tumor Aggressiveness

DTIC Science & Technology

2015-12-01

production in two human glioblastoma xenograft models where the blood–brain barrier (BBB) was disrupted relative to normal brain, suggesting that HP...rodent mammary adenocarcinoma and murine lymphoma xenografts ) has shown ample conversion to leucine.98 In this preclinical study, SNR and contrast were...4 depletes stem-like glioblastoma cells and inhibits HIF transcriptional response in a lactate-independent manner, Oncogene 33 (2013) 4433–4441. Real

L1 retrotransposons and somatic mosaicism in the brain.

PubMed

Richardson, Sandra R; Morell, Santiago; Faulkner, Geoffrey J

2014-01-01

Long interspersed element 1 (LINE-1 or L1) retrotransposons have generated one-third of the human genome, and their ongoing mobility is a source of inter- and intraindividual genetic diversity. Although retrotransposition in metazoans has long been considered a germline phenomenon, recent experiments using cultured cells, animal models, and human tissues have revealed extensive L1 mobilization in rodent and human neurons, as well as mobile element activity in the Drosophila brain. In this review, we evaluate the available evidence for L1 retrotransposition in the brain and discuss mechanisms that may regulate neuronal retrotransposition in vivo. We compare experimental strategies used to map de novo somatic retrotransposition events and present the optimal criteria to identify a somatic L1 insertion. Finally, we discuss the unresolved impact of L1-mediated somatic mosaicism upon normal neurobiology, as well as its potential to drive neurological disease.

Artistic creativity, style and brain disorders.

PubMed

Bogousslavsky, Julien

2005-01-01

The production of novel, motivated or useful material defines creativity, which appears to be one of the higher, specific, human brain functions. While creativity can express itself in virtually any domain, art might particularly well illustrate how creativity may be modulated by the normal or pathological brain. Evidence emphasizes global brain functioning in artistic creativity and output, but critical steps which link perception processing to execution of a work, such as extraction-abstraction, as well as major developments of non-esthetic values attached to art also underline complex activation and inhibition processes mainly localized in the frontal lobe. Neurological diseases in artists provide a unique opportunity to study brain-creativity relationships, in particular through the stylistic changes which may develop after brain lesion. (c) 2005 S. Karger AG, Basel

Alternative Polyadenylation in Glioblastoma Multiforme and Changes in Predicted RNA Binding Protein Profiles

PubMed Central

Shao, Jiaofang; Zhang, Jing; Zhang, Zengming; Jiang, Huawei; Lou, Xiaoyan; Foltz, Gregory; Lan, Qing; Huang, Qiang

2013-01-01

Abstract Alternative polyadenylation (APA) is widely present in the human genome and plays a key role in carcinogenesis. We conducted a comprehensive analysis of the APA products in glioblastoma multiforme (GBM, one of the most lethal brain tumors) and normal brain tissues and further developed a computational pipeline, RNAelements (http://sysbio.zju.edu.cn/RNAelements/), using covariance model from known RNA binding protein (RBP) targets acquired by RNA Immunoprecipitation (RIP) analysis. We identified 4530 APA isoforms for 2733 genes in GBM, and found that 182 APA isoforms from 148 genes showed significant differential expression between normal and GBM brain tissues. We then focused on three genes with long and short APA isoforms that show inconsistent expression changes between normal and GBM brain tissues. These were myocyte enhancer factor 2D, heat shock factor binding protein 1, and polyhomeotic homolog 1 (Drosophila). Using the RNAelements program, we found that RBP binding sites were enriched in the alternative regions between the first and the last polyadenylation sites, which would result in the short APA forms escaping regulation from those RNA binding proteins. To the best of our knowledge, this report is the first comprehensive APA isoform dataset for GBM and normal brain tissues. Additionally, we demonstrated a putative novel APA-mediated mechanism for controlling RNA stability and translation for APA isoforms. These observations collectively lay a foundation for novel diagnostics and molecular mechanisms that can inform future therapeutic interventions for GBM. PMID:23421905

Brain antibodies in the cortex and blood of people with schizophrenia and controls

PubMed Central

Glass, L J; Sinclair, D; Boerrigter, D; Naude, K; Fung, S J; Brown, D; Catts, V S; Tooney, P; O'Donnell, M; Lenroot, R; Galletly, C; Liu, D; Weickert, T W; Shannon Weickert, C

2017-01-01

The immune system is implicated in the pathogenesis of schizophrenia, with elevated proinflammatory cytokine mRNAs found in the brains of ~40% of individuals with the disorder. However, it is not clear if antibodies (specifically immunoglobulin-γ (IgG)) can be found in the brain of people with schizophrenia and if their abundance relates to brain inflammatory cytokine mRNA levels. Therefore, we investigated the localization and abundance of IgG in the frontal cortex of people with schizophrenia and controls, and the impact of proinflammatory cytokine status on IgG abundance in these groups. Brain IgGs were detected surrounding blood vessels in the human and non-human primate frontal cortex by immunohistochemistry. IgG levels did not differ significantly between schizophrenia cases and controls, or between schizophrenia cases in ‘high’ and ‘low’ proinflammatory cytokine subgroups. Consistent with the existence of IgG in the parenchyma of human brain, mRNA and protein of the IgG transporter (FcGRT) were present in the brain, and did not differ according to diagnosis or inflammatory status. Finally, brain-reactive antibody presence and abundance was investigated in the blood of living people. The plasma of living schizophrenia patients and healthy controls contained antibodies that displayed positive binding to Rhesus macaque cerebellar tissue, and the abundance of these antibodies was significantly lower in patients than controls. These findings suggest that antibodies in the brain and brain-reactive antibodies in the blood are present under normal circumstances. PMID:28786974

Brain antibodies in the cortex and blood of people with schizophrenia and controls.

PubMed

Glass, L J; Sinclair, D; Boerrigter, D; Naude, K; Fung, S J; Brown, D; Catts, V S; Tooney, P; O'Donnell, M; Lenroot, R; Galletly, C; Liu, D; Weickert, T W; Shannon Weickert, C

2017-08-08

The immune system is implicated in the pathogenesis of schizophrenia, with elevated proinflammatory cytokine mRNAs found in the brains of ~40% of individuals with the disorder. However, it is not clear if antibodies (specifically immunoglobulin-γ (IgG)) can be found in the brain of people with schizophrenia and if their abundance relates to brain inflammatory cytokine mRNA levels. Therefore, we investigated the localization and abundance of IgG in the frontal cortex of people with schizophrenia and controls, and the impact of proinflammatory cytokine status on IgG abundance in these groups. Brain IgGs were detected surrounding blood vessels in the human and non-human primate frontal cortex by immunohistochemistry. IgG levels did not differ significantly between schizophrenia cases and controls, or between schizophrenia cases in 'high' and 'low' proinflammatory cytokine subgroups. Consistent with the existence of IgG in the parenchyma of human brain, mRNA and protein of the IgG transporter (FcGRT) were present in the brain, and did not differ according to diagnosis or inflammatory status. Finally, brain-reactive antibody presence and abundance was investigated in the blood of living people. The plasma of living schizophrenia patients and healthy controls contained antibodies that displayed positive binding to Rhesus macaque cerebellar tissue, and the abundance of these antibodies was significantly lower in patients than controls. These findings suggest that antibodies in the brain and brain-reactive antibodies in the blood are present under normal circumstances.

The effect of ingested sulfite on visual evoked potentials, lipid peroxidation, and antioxidant status of brain in normal and sulfite oxidase-deficient aged rats.

PubMed

Ozsoy, Ozlem; Aras, Sinem; Ozkan, Ayse; Parlak, Hande; Aslan, Mutay; Yargicoglu, Piraye; Agar, Aysel

2016-07-01

Sulfite, commonly used as a preservative in foods, beverages, and pharmaceuticals, is a very reactive and potentially toxic molecule which is detoxified by sulfite oxidase (SOX). Changes induced by aging may be exacerbated by exogenous chemicals like sulfite. The aim of this study was to investigate the effects of ingested sulfite on visual evoked potentials (VEPs) and brain antioxidant statuses by measuring superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities. Brain lipid oxidation status was also determined via thiobarbituric acid reactive substances (TBARS) in normal- and SOX-deficient aged rats. Rats do not mimic the sulfite responses seen in humans because of their relatively high SOX activity level. Therefore this study used SOX-deficient rats since they are more appropriate models for studying sulfite toxicity. Forty male Wistar rats aged 24 months were randomly assigned to four groups: control (C), sulfite (S), SOX-deficient (D) and SOX-deficient + sulfite (DS). SOX deficiency was established by feeding rats with low molybdenum (Mo) diet and adding 200 ppm tungsten (W) to their drinking water. Sulfite in the form of sodium metabisulfite (25 mg kg(-1) day(-1)) was given by gavage. Treatment continued for 6 weeks. At the end of the experimental period, flash VEPs were recorded. Hepatic SOX activity was measured to confirm SOX deficiency. SOX-deficient rats had an approximately 10-fold decrease in hepatic SOX activity compared with the normal rats. The activity of SOX in deficient rats was thus in the range of humans. There was no significant difference between control and treated groups in either latence or amplitude of VEP components. Brain SOD, CAT, and GPx activities and brain TBARS levels were similar in all experimental groups compared with the control group. Our results indicate that exogenous administration of sulfite does not affect VEP components and the antioxidant/oxidant status of aged rat brains. © The Author(s) 2014.

Physical Activity Protects the Human Brain against Metabolic Stress Induced by a Postprandial and Chronic Inflammation

PubMed Central

Pruimboom, Leo; Raison, Charles L.; Muskiet, Frits A. J.

2015-01-01

In recent years, it has become clear that chronic systemic low-grade inflammation is at the root of many, if not all, typically Western diseases associated with the metabolic syndrome. While much focus has been given to sedentary lifestyle as a cause of chronic inflammation, it is less often appreciated that chronic inflammation may also promote a sedentary lifestyle, which in turn causes chronic inflammation. Given that even minor increases in chronic inflammation reduce brain volume in otherwise healthy individuals, the bidirectional relationship between inflammation and sedentary behaviour may explain why humans have lost brain volume in the last 30,000 years and also intelligence in the last 30 years. We review evidence that lack of physical activity induces chronic low-grade inflammation and, consequently, an energy conflict between the selfish immune system and the selfish brain. Although the notion that increased physical activity would improve health in the modern world is widespread, here we provide a novel perspective on this truism by providing evidence that recovery of normal human behaviour, such as spontaneous physical activity, would calm proinflammatory activity, thereby allocating more energy to the brain and other organs, and by doing so would improve human health. PMID:26074674

PET evaluation of the dopamine system of the human brain

DOE Office of Scientific and Technical Information (OSTI.GOV)

Volkow, N.D.; Fowler, J.S.; Gatley, S.

1996-07-01

Dopamine plays a pivotal role in the regulation and control of movement, motivation and cognition. It also is closely linked to reward, reinforcement and addiction. Abnormalities in brain dopamine are associated with many neurological and psychiatric disorders including Parkinson`s disease, schizophrenia and substance abuse. This close association between dopamine and neurological and psychiatric diseases and with substance abuse make it an important topic in research in the neurosciences and an important molecular target in drug development. PET enables the direct measurement of components of the dopamine system in the living human brain. It relies on radiotracers which label dopamine receptors,more » dopamine transporters, precursors of dopamine or compounds which have specificity for the enzymes which degrade dopamine. Additionally, by using tracers that provide information on regional brain metabolism or blood flow as well as neurochemically specific pharmacological interventions, PET can be used to assess the functional consequences of change in brain dopamine activity. PET dopamine measurements have been used to investigate the normal human brain and its involvement in psychiatric and neurological diseases. It has also been used in psychopharmacological research to investigate dopamine drugs used in the treatment of Parkinson`s disease and of schizophrenia as well as to investigate the effects of drugs of abuse on the dopamine system. Since various functional and neurochemical parameters can be studied in the same subject, PET enables investigation of the functional integrity of the dopamine system in the human brain and investigation of the interactions of dopamine with other neurotransmitters. This paper summarizes the different tracers and experimental strategies developed to evaluate the various elements of the dopamine system in the human brain with PET and their applications to clinical research. 254 refs., 7 figs., 3 tabs.« less

Physiological neuronal decline in healthy aging human brain - An in vivo study with MRI and short echo-time whole-brain (1)H MR spectroscopic imaging.

PubMed

Ding, Xiao-Qi; Maudsley, Andrew A; Sabati, Mohammad; Sheriff, Sulaiman; Schmitz, Birte; Schütze, Martin; Bronzlik, Paul; Kahl, Kai G; Lanfermann, Heinrich

2016-08-15

Knowledge of physiological aging in healthy human brain is increasingly important for neuroscientific research and clinical diagnosis. To investigate neuronal decline in normal aging brain eighty-one healthy subjects aged between 20 and 70years were studied with MRI and whole-brain (1)H MR spectroscopic imaging. Concentrations of brain metabolites N-acetyl-aspartate (NAA), choline (Cho), total creatine (tCr), myo-inositol (mI), and glutamine+glutamate (Glx) in ratios to internal water, and the fractional volumes of brain tissue were estimated simultaneously in eight cerebral lobes and in cerebellum. Results demonstrated that an age-related decrease in gray matter volume was the largest contribution to changes in brain volume. Both lobar NAA and the fractional volume of gray matter (FVGM) decreased with age in all cerebral lobes, indicating that the decreased NAA was predominantly associated with decreased gray matter volume and neuronal density or metabolic activity. In cerebral white matter Cho, tCr, and mI increased with age in association with increased fractional volume, showing altered cellular membrane turn-over, energy metabolism, and glial activity in human aging white matter. In cerebellum tCr increased while brain tissue volume decreased with age, showing difference to cerebral aging. The observed age-related metabolic and microstructural variations suggest that physiological neuronal decline in aging human brain is associated with a reduction of gray matter volume and neuronal density, in combination with cellular aging in white matter indicated by microstructural alterations and altered energy metabolism in the cerebellum. Copyright © 2016 Elsevier Inc. All rights reserved.

Ageing and brain white matter structure in 3,513 UK Biobank participants

PubMed Central

Cox, Simon R.; Ritchie, Stuart J.; Tucker-Drob, Elliot M.; Liewald, David C.; Hagenaars, Saskia P.; Davies, Gail; Wardlaw, Joanna M.; Gale, Catharine R.; Bastin, Mark E.; Deary, Ian J.

2016-01-01

Quantifying the microstructural properties of the human brain's connections is necessary for understanding normal ageing and disease. Here we examine brain white matter magnetic resonance imaging (MRI) data in 3,513 generally healthy people aged 44.64–77.12 years from the UK Biobank. Using conventional water diffusion measures and newer, rarely studied indices from neurite orientation dispersion and density imaging, we document large age associations with white matter microstructure. Mean diffusivity is the most age-sensitive measure, with negative age associations strongest in the thalamic radiation and association fibres. White matter microstructure across brain tracts becomes increasingly correlated in older age. This may reflect an age-related aggregation of systemic detrimental effects. We report several other novel results, including age associations with hemisphere and sex, and comparative volumetric MRI analyses. Results from this unusually large, single-scanner sample provide one of the most extensive characterizations of age associations with major white matter tracts in the human brain. PMID:27976682

Influence of Dexamethasone on O-(2-[18F]-Fluoroethyl)-L-Tyrosine Uptake in the Human Brain and Quantification of Tumor Uptake.

PubMed

Stegmayr, Carina; Stoffels, Gabriele; Kops, Elena Rota; Lohmann, Philipp; Galldiks, Norbert; Shah, Nadim J; Neumaier, Bernd; Langen, Karl-Josef

2018-05-29

O-(2-[ 18 F]fluoroethyl)-L-tyrosine ([ 18 F]FET) is an established positron emission tomography (PET) tracer for brain tumor imaging. This study explores the influence of dexamethasone therapy on [ 18 F]FET uptake in the normal brain and its influence on the maximum and mean tumor-to-brain ratio (TBR). [ 18 F]FET PET scans of 160 brain tumor patients were evaluated (80 dexamethasone treated, 80 untreated; each group with 40 men/40 women). The standardized uptake value of [ 18 F]FET uptake in the normal brain (SUV brain ) in the different groups was compared. Nine patients were examined repeatedly with and without dexamethasone therapy. SUV brain of [ 18 F]FET uptake was significantly higher in dexamethasone-treated patients than in untreated patients (SUV brain 1.33 ± 0.1 versus 1.06 ± 0.16 in male and 1.45 ± 0.25 versus 1.31 ± 0.28 in female patients). Similar results were observed in patients with serial PET scans. Furthermore, compared to men, a significantly higher SUV brain was found in women, both with and without dexamethasone treatment. There were no significant differences between the different groups for TBR max and TBR mean , which could have been masked by the high standard deviation. In a patient with a stable brain metastasis investigated twice with and without dexamethasone, the TBR max and the biological tumor volume (BTV) decreased considerably after dexamethasone due to an increased SUV brain . Dexamethasone treatment appears to increase the [ 18 F]FET uptake in the normal brain. An effect on TBR max , TBR mean , and BTV cannot be excluded which should be considered especially for treatment monitoring and the estimation of BTV using [ 18 F]FET PET.

Morphology, morphometry and probability mapping of the pars opercularis of the inferior frontal gyrus: an in vivo MRI analysis.

PubMed

Tomaiuolo, F; MacDonald, J D; Caramanos, Z; Posner, G; Chiavaras, M; Evans, A C; Petrides, M

1999-09-01

The pars opercularis occupies the posterior part of the inferior frontal gyrus. Electrical stimulation or damage of this region interferes with language production. The present study investigated the morphology and morphometry of the pars opercularis in 108 normal adult human cerebral hemispheres by means of magnetic resonance imaging. The brain images were transformed into a standardized proportional steoreotaxic space (i.e. that of Talairach and Tournoux) in order to minimize interindividual brain size variability. There was considerable variability in the shape and location of the pars opercularis across brains and between cerebral hemispheres. There was no significant difference or correlation between left and right hemisphere grey matter volumes. There was also no significant difference between sex and side of asymmetry of the pars opercularis. A probability map of the pars opercularis was constructed by averaging its location and extent in each individual normalized brain into Talairach space to aid in localization of activity changes in functional neuroimaging studies.

The “Visual Shock” of Francis Bacon: an essay in neuroesthetics

PubMed Central

Zeki, Semir; Ishizu, Tomohiro

2013-01-01

In this paper we discuss the work of Francis Bacon in the context of his declared aim of giving a “visual shock.”We explore what this means in terms of brain activity and what insights into the brain's visual perceptive system his work gives. We do so especially with reference to the representation of faces and bodies in the human visual brain. We discuss the evidence that shows that both these categories of stimuli have a very privileged status in visual perception, compared to the perception of other stimuli, including man-made artifacts such as houses, chairs, and cars. We show that viewing stimuli that depart significantly from a normal representation of faces and bodies entails a significant difference in the pattern of brain activation. We argue that Bacon succeeded in delivering his “visual shock” because he subverted the normal neural representation of faces and bodies, without at the same time subverting the representation of man-made artifacts. PMID:24339812

The "Visual Shock" of Francis Bacon: an essay in neuroesthetics.

PubMed

Zeki, Semir; Ishizu, Tomohiro

2013-01-01

In this paper we discuss the work of Francis Bacon in the context of his declared aim of giving a "visual shock."We explore what this means in terms of brain activity and what insights into the brain's visual perceptive system his work gives. We do so especially with reference to the representation of faces and bodies in the human visual brain. We discuss the evidence that shows that both these categories of stimuli have a very privileged status in visual perception, compared to the perception of other stimuli, including man-made artifacts such as houses, chairs, and cars. We show that viewing stimuli that depart significantly from a normal representation of faces and bodies entails a significant difference in the pattern of brain activation. We argue that Bacon succeeded in delivering his "visual shock" because he subverted the normal neural representation of faces and bodies, without at the same time subverting the representation of man-made artifacts.

Histogram-based normalization technique on human brain magnetic resonance images from different acquisitions.

PubMed

Sun, Xiaofei; Shi, Lin; Luo, Yishan; Yang, Wei; Li, Hongpeng; Liang, Peipeng; Li, Kuncheng; Mok, Vincent C T; Chu, Winnie C W; Wang, Defeng

2015-07-28

Intensity normalization is an important preprocessing step in brain magnetic resonance image (MRI) analysis. During MR image acquisition, different scanners or parameters would be used for scanning different subjects or the same subject at a different time, which may result in large intensity variations. This intensity variation will greatly undermine the performance of subsequent MRI processing and population analysis, such as image registration, segmentation, and tissue volume measurement. In this work, we proposed a new histogram normalization method to reduce the intensity variation between MRIs obtained from different acquisitions. In our experiment, we scanned each subject twice on two different scanners using different imaging parameters. With noise estimation, the image with lower noise level was determined and treated as the high-quality reference image. Then the histogram of the low-quality image was normalized to the histogram of the high-quality image. The normalization algorithm includes two main steps: (1) intensity scaling (IS), where, for the high-quality reference image, the intensities of the image are first rescaled to a range between the low intensity region (LIR) value and the high intensity region (HIR) value; and (2) histogram normalization (HN),where the histogram of low-quality image as input image is stretched to match the histogram of the reference image, so that the intensity range in the normalized image will also lie between LIR and HIR. We performed three sets of experiments to evaluate the proposed method, i.e., image registration, segmentation, and tissue volume measurement, and compared this with the existing intensity normalization method. It is then possible to validate that our histogram normalization framework can achieve better results in all the experiments. It is also demonstrated that the brain template with normalization preprocessing is of higher quality than the template with no normalization processing. We have proposed a histogram-based MRI intensity normalization method. The method can normalize scans which were acquired on different MRI units. We have validated that the method can greatly improve the image analysis performance. Furthermore, it is demonstrated that with the help of our normalization method, we can create a higher quality Chinese brain template.

Effects of chromosomal sex and hormonal influences on shaping sex differences in brain and behavior: Lessons from cases of disorders of sex development.

PubMed

Bramble, Matthew S; Lipson, Allen; Vashist, Neerja; Vilain, Eric

2017-01-02

Sex differences in brain development and postnatal behavior are determined largely by genetic sex and in utero gonadal hormone secretions. In humans however, determining the weight that each of these factors contributes remains a challenge because social influences should also be considered. Cases of disorders of sex development (DSD) provide unique insight into how mutations in genes responsible for gonadal formation can perturb the subsequent developmental hormonal milieu and elicit changes in normal human brain maturation. Specific forms of DSDs such as complete androgen insensitivity syndrome (CAIS), congenital adrenal hyperplasia (CAH), and 5α-reductase deficiency syndrome have variable effects between males and females, and the developmental outcomes of such conditions are largely dependent on sex chromosome composition. Medical and psychological works focused on CAH, CAIS, and 5α-reductase deficiency have helped form the foundation for understanding the roles of genetic and hormonal factors necessary for guiding human brain development. Here we highlight how the three aforementioned DSDs contribute to brain and behavioral phenotypes that can uniquely affect 46,XY and 46,XX individuals in dramatically different fashions. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

An anatomically comprehensive atlas of the adult human brain transcriptome

PubMed Central

Guillozet-Bongaarts, Angela L.; Shen, Elaine H.; Ng, Lydia; Miller, Jeremy A.; van de Lagemaat, Louie N.; Smith, Kimberly A.; Ebbert, Amanda; Riley, Zackery L.; Abajian, Chris; Beckmann, Christian F.; Bernard, Amy; Bertagnolli, Darren; Boe, Andrew F.; Cartagena, Preston M.; Chakravarty, M. Mallar; Chapin, Mike; Chong, Jimmy; Dalley, Rachel A.; David Daly, Barry; Dang, Chinh; Datta, Suvro; Dee, Nick; Dolbeare, Tim A.; Faber, Vance; Feng, David; Fowler, David R.; Goldy, Jeff; Gregor, Benjamin W.; Haradon, Zeb; Haynor, David R.; Hohmann, John G.; Horvath, Steve; Howard, Robert E.; Jeromin, Andreas; Jochim, Jayson M.; Kinnunen, Marty; Lau, Christopher; Lazarz, Evan T.; Lee, Changkyu; Lemon, Tracy A.; Li, Ling; Li, Yang; Morris, John A.; Overly, Caroline C.; Parker, Patrick D.; Parry, Sheana E.; Reding, Melissa; Royall, Joshua J.; Schulkin, Jay; Sequeira, Pedro Adolfo; Slaughterbeck, Clifford R.; Smith, Simon C.; Sodt, Andy J.; Sunkin, Susan M.; Swanson, Beryl E.; Vawter, Marquis P.; Williams, Derric; Wohnoutka, Paul; Zielke, H. Ronald; Geschwind, Daniel H.; Hof, Patrick R.; Smith, Stephen M.; Koch, Christof; Grant, Seth G. N.; Jones, Allan R.

2014-01-01

Neuroanatomically precise, genome-wide maps of transcript distributions are critical resources to complement genomic sequence data and to correlate functional and genetic brain architecture. Here we describe the generation and analysis of a transcriptional atlas of the adult human brain, comprising extensive histological analysis and comprehensive microarray profiling of ~900 neuroanatomically precise subdivisions in two individuals. Transcriptional regulation varies enormously by anatomical location, with different regions and their constituent cell types displaying robust molecular signatures that are highly conserved between individuals. Analysis of differential gene expression and gene co-expression relationships demonstrates that brain-wide variation strongly reflects the distributions of major cell classes such as neurons, oligodendrocytes, astrocytes and microglia. Local neighbourhood relationships between fine anatomical subdivisions are associated with discrete neuronal subtypes and genes involved with synaptic transmission. The neocortex displays a relatively homogeneous transcriptional pattern, but with distinct features associated selectively with primary sensorimotor cortices and with enriched frontal lobe expression. Notably, the spatial topography of the neocortex is strongly reflected in its molecular topography— the closer two cortical regions, the more similar their transcriptomes. This freely accessible online data resource forms a high-resolution transcriptional baseline for neurogenetic studies of normal and abnormal human brain function. PMID:22996553

Early life stress-induced alterations in rat brain structures measured with high resolution MRI.

PubMed

Sarabdjitsingh, R Angela; Loi, Manila; Joëls, Marian; Dijkhuizen, Rick M; van der Toorn, Annette

2017-01-01

Adverse experiences early in life impair cognitive function both in rodents and humans. In humans this increases the vulnerability to develop mental illnesses while in the rodent brain early life stress (ELS) abnormalities are associated with changes in synaptic plasticity, excitability and microstructure. Detailed information on the effects of ELS on rodent brain structural integrity at large and connectivity within the brain is currently lacking; this information is highly relevant for understanding the mechanism by which early life stress predisposes to mental illnesses. Here, we exposed rats to 24 hours of maternal deprivation (MD) at postnatal day 3, a paradigm known to increase corticosterone levels and thereby activate glucocorticoid receptors in the brain. Using structural magnetic resonance imaging we examined: i) volumetric changes and white/grey matter properties of the whole cerebrum and of specific brain areas; and ii) whether potential alterations could be normalized by blocking glucocorticoid receptors with mifepristone during the critical developmental window of early adolescence, i.e. between postnatal days 26 and 28. The results show that MD caused a volumetric reduction of the prefrontal cortex, particularly the ventromedial part, and the orbitofrontal cortex. Within the whole cerebrum, white (relative to grey) matter volume was decreased and region-specifically in prefrontal cortex and dorsomedial striatum following MD. A trend was found for the hippocampus. Grey matter fractions were not affected. Treatment with mifepristone did not normalize these changes. This study indicates that early life stress in rodents has long lasting consequences for the volume and structural integrity of the brain. However, changes were relatively modest and-unlike behavior- not mitigated by blockade of glucocorticoid receptors during a critical developmental period.

WINCS Harmoni: Closed-loop dynamic neurochemical control of therapeutic interventions

NASA Astrophysics Data System (ADS)

Lee, Kendall H.; Lujan, J. Luis; Trevathan, James K.; Ross, Erika K.; Bartoletta, John J.; Park, Hyung Ook; Paek, Seungleal Brian; Nicolai, Evan N.; Lee, Jannifer H.; Min, Hoon-Ki; Kimble, Christopher J.; Blaha, Charles D.; Bennet, Kevin E.

2017-04-01

There has been significant progress in understanding the role of neurotransmitters in normal and pathologic brain function. However, preclinical trials aimed at improving therapeutic interventions do not take advantage of real-time in vivo neurochemical changes in dynamic brain processes such as disease progression and response to pharmacologic, cognitive, behavioral, and neuromodulation therapies. This is due in part to a lack of flexible research tools that allow in vivo measurement of the dynamic changes in brain chemistry. Here, we present a research platform, WINCS Harmoni, which can measure in vivo neurochemical activity simultaneously across multiple anatomical targets to study normal and pathologic brain function. In addition, WINCS Harmoni can provide real-time neurochemical feedback for closed-loop control of neurochemical levels via its synchronized stimulation and neurochemical sensing capabilities. We demonstrate these and other key features of this platform in non-human primate, swine, and rodent models of deep brain stimulation (DBS). Ultimately, systems like the one described here will improve our understanding of the dynamics of brain physiology in the context of neurologic disease and therapeutic interventions, which may lead to the development of precision medicine and personalized therapies for optimal therapeutic efficacy.

Vascular targeting of LIGHT normalizes blood vessels in primary brain cancer and induces intratumoural high endothelial venules.

PubMed

He, Bo; Jabouille, Arnaud; Steri, Veronica; Johansson-Percival, Anna; Michael, Iacovos P; Kotamraju, Venkata Ramana; Junckerstorff, Reimar; Nowak, Anna K; Hamzah, Juliana; Lee, Gabriel; Bergers, Gabriele; Ganss, Ruth

2018-06-01

High-grade brain cancer such as glioblastoma (GBM) remains an incurable disease. A common feature of GBM is the angiogenic vasculature, which can be targeted with selected peptides for payload delivery. We assessed the ability of micelle-tagged, vascular homing peptides RGR, CGKRK and NGR to specifically bind to blood vessels in syngeneic orthotopic GBM models. By using the peptide CGKRK to deliver the tumour necrosis factor (TNF) superfamily member LIGHT (also known as TNF superfamily member 14; TNFSF14) to angiogenic tumour vessels, we have generated a reagent that normalizes the brain cancer vasculature by inducing pericyte contractility and re-establishing endothelial barrier integrity. LIGHT-mediated vascular remodelling also activates endothelia and induces intratumoural high endothelial venules (HEVs), which are specialized blood vessels for lymphocyte infiltration. Combining CGKRK-LIGHT with anti-vascular endothelial growth factor and checkpoint blockade amplified HEV frequency and T-cell accumulation in GBM, which is often sparsely infiltrated by immune effector cells, and reduced tumour burden. Furthermore, CGKRK and RGR peptides strongly bound to blood vessels in freshly resected human GBM, demonstrating shared peptide-binding activities in mouse and human primary brain tumour vessels. Thus, peptide-mediated LIGHT targeting is a highly translatable approach in primary brain cancer to reduce vascular leakiness and enhance immunotherapy. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Redox proteomics and the dynamic molecular landscape of the aging brain.

PubMed

Perluigi, Marzia; Swomley, Aaron M; Butterfield, D Allan

2014-01-01

It is well established that the risk to develop neurodegenerative disorders increases with chronological aging. Accumulating studies contributed to characterize the age-dependent changes either at gene and protein expression level which, taken together, show that aging of the human brain results from the combination of the normal decline of multiple biological functions with environmental factors that contribute to defining disease risk of late-life brain disorders. Finding the "way out" of the labyrinth of such complex molecular interactions may help to fill the gap between "normal" brain aging and development of age-dependent diseases. To this purpose, proteomics studies are a powerful tool to better understand where to set the boundary line of healthy aging and age-related disease by analyzing the variation of protein expression levels and the major post translational modifications that determine "protein" physio/pathological fate. Increasing attention has been focused on oxidative modifications due to the crucial role of oxidative stress in aging, in addition to the fact that this type of modification is irreversible and may alter protein function. Redox proteomics studies contributed to decipher the complexity of brain aging by identifying the proteins that were increasingly oxidized and eventually dysfunctional as a function of age. The purpose of this review is to summarize the most important findings obtained by applying proteomics approaches to murine models of aging with also a brief overview of some human studies, in particular those related to dementia. Copyright © 2014. Published by Elsevier B.V.

Improved Determination of the Myelin Water Fraction in Human Brain using Magnetic Resonance Imaging through Bayesian Analysis of mcDESPOT

PubMed Central

Bouhrara, Mustapha; Spencer, Richard G.

2015-01-01

Myelin water fraction (MWF) mapping with magnetic resonance imaging has led to the ability to directly observe myelination and demyelination in both the developing brain and in disease. Multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) has been proposed as a rapid approach for multicomponent relaxometry and has been applied to map MWF in human brain. However, even for the simplest two-pool signal model consisting of MWF and non-myelin-associated water, the dimensionality of the parameter space for obtaining MWF estimates remains high. This renders parameter estimation difficult, especially at low-to-moderate signal-to-noise ratios (SNR), due to the presence of local minima and the flatness of the fit residual energy surface used for parameter determination using conventional nonlinear least squares (NLLS)-based algorithms. In this study, we introduce three Bayesian approaches for analysis of the mcDESPOT signal model to determine MWF. Given the high dimensional nature of mcDESPOT signal model, and, thereby, the high dimensional marginalizations over nuisance parameters needed to derive the posterior probability distribution of MWF parameter, the introduced Bayesian analyses use different approaches to reduce the dimensionality of the parameter space. The first approach uses normalization by average signal amplitude, and assumes that noise can be accurately estimated from signal-free regions of the image. The second approach likewise uses average amplitude normalization, but incorporates a full treatment of noise as an unknown variable through marginalization. The third approach does not use amplitude normalization and incorporates marginalization over both noise and signal amplitude. Through extensive Monte Carlo numerical simulations and analysis of in-vivo human brain datasets exhibiting a range of SNR and spatial resolution, we demonstrated the markedly improved accuracy and precision in the estimation of MWF using these Bayesian methods as compared to the stochastic region contraction (SRC) implementation of NLLS. PMID:26499810

Sex dependence of brain size and shape in bipolar disorder: an exploratory study.

PubMed

Mackay, Clare E; Roddick, Elina; Barrick, Thomas R; Lloyd, Adrian J; Roberts, Neil; Crow, Tim J; Young, Allan H; Ferrier, I Nicol

2010-05-01

Anomalies of asymmetry and sex differences in brain structure have frequently been described in schizophrenic illnesses but have seldom been explored in bipolar disorder. We measured volumes of the left and right frontal, temporal, parietal, and occipital lobes and computed the magnitude of brain torque (i.e., rightward frontal and leftward occipital asymmetry) for 49 patients with bipolar disorder and 47 healthy controls and performed an exploratory analysis of sex differences in patients and controls. Patients had significantly greater cerebrospinal fluid volume than controls, but no difference in total brain volume. There were no main effects of diagnosis in gray matter lobe volume or brain torque, but when analyses were performed separately for male and female subjects, significant sex-by-diagnosis interactions were found in the volume of the left frontal, left temporal, right parietal, and right occipital lobes, such that male patients with bipolar disorder tend toward larger, more symmetric brains than male controls, whereas female patients tend toward smaller, more asymmetric brains than female controls. The lateralised nature of these interactions was such that the normal sex difference in volume was significantly accentuated, whilst the normal sex difference in asymmetry tended to be diminished in patients with bipolar disorder. We conclude that bipolar disorder in part reflects an interaction between brain growth and sex along the anterior-posterior axis of the human brain.

Morphofunctional study of the therapeutic efficacy of human mesenchymal and neural stem cells in rats with diffuse brain injury.

PubMed

Tsyb, A F; Yuzhakov, V V; Roshal', L M; Sukhikh, G T; Konoplyannikov, A G; Sushkevich, G N; Yakovleva, N D; Ingel', I E; Bandurko, L N; Sevan'kaeva, L E; Mikhina, L N; Fomina, N K; Marei, M V; Semenova, Zh B; Konoplyannikova, O A; Kal'sina, S Sh; Lepekhina, L A; Semenkova, I V; Agaeva, E V; Shevchuk, A S; Pavlova, L N; Tokarev, O Yu; Karaseva, O V; Chernyshova, T A

2009-01-01

We studied the effect of transplantation of human stem cells from various tissues on reparative processes in the brain of rats with closed craniocerebral injury. Combined treatment with standard drugs and systemic administration of xenogeneic stem cells had a neuroprotective effect. The morphology of neurons rapidly returned to normal after administration of fetal neural stem cells. Fetal mesenchymal stem cells produced a prolonged effect on proliferative activity of progenitor cells in the subventricular zone of neurogenesis. Adult mesenchymal stem cells had a strong effect on recovery of the vascular bed in ischemic regions.

Pig brain stereotaxic standard space: mapping of cerebral blood flow normative values and effect of MPTP-lesioning.

PubMed

Andersen, Flemming; Watanabe, Hideaki; Bjarkam, Carsten; Danielsen, Erik H; Cumming, Paul

2005-07-15

The analysis of physiological processes in brain by position emission tomography (PET) is facilitated when images are spatially normalized to a standard coordinate system. Thus, PET activation studies of human brain frequently employ the common stereotaxic coordinates of Talairach. We have developed an analogous stereotaxic coordinate system for the brain of the Gottingen miniature pig, based on automatic co-registration of magnetic resonance (MR) images obtained in 22 male pigs. The origin of the pig brain stereotaxic space (0, 0, 0) was arbitrarily placed in the centroid of the pineal gland as identified on the average MRI template. The orthogonal planes were imposed using the line between stereotaxic zero and the optic chiasm. A series of mean MR images in the coronal, sagittal and horizontal planes were generated. To test the utility of the common coordinate system for functional imaging studies of minipig brain, we calculated cerebral blood flow (CBF) maps from normal minipigs and from minipigs with a syndrome of parkisonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-poisoning. These maps were transformed from the native space into the common stereotaxic space. After global normalization of these maps, an undirected search for differences between the groups was then performed using statistical parametric mapping. Using this method, we detected a statistically significant focal increase in CBF in the left cerebellum of the MPTP-lesioned group. We expect the present approach to be of general use in the statistical parametric mapping of CBF and other physiological parameters in living pig brain.

Protein Kinase CK2 Content in GL261 Mouse Glioblastoma.

PubMed

Ferrer-Font, Laura; Alcaraz, Estefania; Plana, Maria; Candiota, Ana Paula; Itarte, Emilio; Arús, Carles

2016-07-01

Glioblastoma (GBM) is the most prevalent and aggressive human glial tumour with a median survival of 14-15 months. Temozolomide (TMZ) is the standard chemotherapeutic choice for GBM treatment. Unfortunately, chemoresistence always ensues with concomitant tumour regrowth. Protein kinase CK2 (CK2) contributes to tumour development, proliferation, and suppression of apoptosis in cancer and it is overexpressed in human GBM. Targeting CK2 in GBM treatment may benefit patients. With this translational perspective in mind, we have studied the CK2 expression level by Western blot analysis in a preclinical model of GBM: GL261 cells growing orthotopically in C57BL/6 mice. The expression level of the CK2 catalytic subunit (CK2α) was higher in tumour (about 4-fold) and in contralateral brain parenchyma (more than 2-fold) than in normal brain parenchyma (p < 0.05). In contrast, no significant changes were found in CK2 regulatory subunit (CK2β) expression, suggesting an increased unbalance of CK2α/CK2β in GL261 tumours with respect to normal brain parenchyma, in agreement with a differential role of these two subunits in tumours.

Methylation, expression, and mutation analysis of the cell cycle control genes in human brain tumors.

PubMed

Yin, Dong; Xie, Dong; Hofmann, Wolf-Karsten; Miller, Carl W; Black, Keith L; Koeffler, H Phillip

2002-11-28

Methylation status of the p15(INK4B), p16(INK4A), p14(ARF) and retinoblastoma (RB) genes was studied using methylation specific polymerase chain reaction (MSP) in 85 human brain tumors of various subtypes and four normal brain samples. These genes play an important role in the control of the cell cycle. Twenty-four out of 85 cases (28%) had at least one of these genes methylated. The frequency of p14(ARF) methylation was 15 out of 85 (18%) cases, and the expression of p14(ARF) in methylated gliomas was significantly lower than in unmethylated gliomas. The incidence of methylation of p15(INK4B), p16(INK4A) and RB gene was 4%, 7%, and 4%, respectively. Samples with p14(ARF) methylation did not have p16(INK4A) methylation even though both genes physically overlap. None of the target genes was methylated in the normal brain samples. In addition, the p53 gene was mutated in 19 out of 85 (22%) samples as determined by single strand conformation polymorphism (SSCP) analysis and DNA sequencing. Thirty out of 85 (35%) brain tumors had either a p53 mutation or methylation of p14(ARF). Also, the p14(ARF) expression in p53 wild-type gliomas was lower than levels in p53 mutated gliomas. This finding is consistent with wild-type p53 being able to autoregulate its levels by down-regulating expression of p14(ARF). In summary, inactivation of the apoptosis pathway that included the p14(ARF) and p53 genes by hypermethylation and mutation, respectively, occurred frequently in human brain tumors. Down-regulation of p14(ARF) in gliomas was associated with hypermethylation of its promoter and the presence of a wild-type p53 in these samples.

Immunopathological Changes in the Brain of Immunosuppressed Mice Experimentally Infected with Toxocara canis

PubMed Central

Eid, Mohamed M.; El-Kowrany, Samy I.; Othman, Ahmad A.; Gendy, Dina I. El; Saied, Eman M.

2015-01-01

Toxocariasis is a soil-transmitted helminthozoonosis due to infection of humans by larvae of Toxocara canis. The disease could produce cognitive and behavioral disturbances especially in children. Meanwhile, in our modern era, the incidence of immunosuppression has been progressively increasing due to increased incidence of malignancy as well as increased use of immunosuppressive agents. The present study aimed at comparing some of the pathological and immunological alterations in the brain of normal and immunosuppressed mice experimentally infected with T. canis. Therefore, 180 Swiss albino mice were divided into 4 groups including normal (control) group, immunocompetent T. canis-infected group, immunosuppressed group (control), and immunosuppressed infected group. Infected mice were subjected to larval counts in the brain, and the brains from all mice were assessed for histopathological changes, astrogliosis, and IL-5 mRNA expression levels in brain tissues. The results showed that under immunosuppression, there were significant increase in brain larval counts, significant enhancement of reactive gliosis, and significant reduction in IL-5 mRNA expression. All these changes were maximal in the chronic stage of infection. In conclusion, the immunopathological alterations in the brains of infected animals were progressive over time, and were exaggerated under the effect of immunosuppression as did the intensity of cerebral infection. PMID:25748709

The Anatomical Distance of Functional Connections Predicts Brain Network Topology in Health and Schizophrenia

PubMed Central

Vértes, Petra E.; Stidd, Reva; Lalonde, François; Clasen, Liv; Rapoport, Judith; Giedd, Jay; Bullmore, Edward T.; Gogtay, Nitin

2013-01-01

The human brain is a topologically complex network embedded in anatomical space. Here, we systematically explored relationships between functional connectivity, complex network topology, and anatomical (Euclidean) distance between connected brain regions, in the resting-state functional magnetic resonance imaging brain networks of 20 healthy volunteers and 19 patients with childhood-onset schizophrenia (COS). Normal between-subject differences in average distance of connected edges in brain graphs were strongly associated with variation in topological properties of functional networks. In addition, a club or subset of connector hubs was identified, in lateral temporal, parietal, dorsal prefrontal, and medial prefrontal/cingulate cortical regions. In COS, there was reduced strength of functional connectivity over short distances especially, and therefore, global mean connection distance of thresholded graphs was significantly greater than normal. As predicted from relationships between spatial and topological properties of normal networks, this disorder-related proportional increase in connection distance was associated with reduced clustering and modularity and increased global efficiency of COS networks. Between-group differences in connection distance were localized specifically to connector hubs of multimodal association cortex. In relation to the neurodevelopmental pathogenesis of schizophrenia, we argue that the data are consistent with the interpretation that spatial and topological disturbances of functional network organization could arise from excessive “pruning” of short-distance functional connections in schizophrenia. PMID:22275481

Holoprosencephaly: from Homer to Hedgehog.

PubMed

Ming, J E; Muenke, M

1998-03-01

Holoprosencephaly (HPE), a common developmental defect affecting the forebrain and face, is etiologically heterogeneous and exhibits wide phenotypic variation. Graded degrees of severity of the brain malformation are also reflected in the highly variable craniofacial malformations associated with HPE. In addition, individuals with microforms of HPE, who usually have normal cognition and normal brain imaging, are at risk for having children with HPE. Some obligate carriers for HPE may not have any phenotypic abnormalities. Recurrent chromosomal rearrangements in individuals with HPE suggest loci containing genes important for brain development, and abnormalities in these genes may result in HPE. Recently, Sonic Hedgehog (SHH) was the first gene identified as causing HPE in humans. Proper function of SHH depends on cholesterol modification. Other candidate genes that may be involved in HPE include components of the SHH pathway, elements involved in cholesterol metabolism, and genes expressed in the developing forebrain.

Dynamic Bayesian network modeling for longitudinal brain morphometry

PubMed Central

Chen, Rong; Resnick, Susan M; Davatzikos, Christos; Herskovits, Edward H

2011-01-01

Identifying interactions among brain regions from structural magnetic-resonance images presents one of the major challenges in computational neuroanatomy. We propose a Bayesian data-mining approach to the detection of longitudinal morphological changes in the human brain. Our method uses a dynamic Bayesian network to represent evolving inter-regional dependencies. The major advantage of dynamic Bayesian network modeling is that it can represent complicated interactions among temporal processes. We validated our approach by analyzing a simulated atrophy study, and found that this approach requires only a small number of samples to detect the ground-truth temporal model. We further applied dynamic Bayesian network modeling to a longitudinal study of normal aging and mild cognitive impairment — the Baltimore Longitudinal Study of Aging. We found that interactions among regional volume-change rates for the mild cognitive impairment group are different from those for the normal-aging group. PMID:21963916

The INIA19 Template and NeuroMaps Atlas for Primate Brain Image Parcellation and Spatial Normalization

PubMed Central

Rohlfing, Torsten; Kroenke, Christopher D.; Sullivan, Edith V.; Dubach, Mark F.; Bowden, Douglas M.; Grant, Kathleen A.; Pfefferbaum, Adolf

2012-01-01

The INIA19 is a new, high-quality template for imaging-based studies of non-human primate brains, created from high-resolution, T1-weighted magnetic resonance (MR) images of 19 rhesus macaque (Macaca mulatta) animals. Combined with the comprehensive cortical and sub-cortical label map of the NeuroMaps atlas, the INIA19 is equally suitable for studies requiring both spatial normalization and atlas label propagation. Population-averaged template images are provided for both the brain and the whole head, to allow alignment of the atlas with both skull-stripped and unstripped data, and thus to facilitate its use for skull stripping of new images. This article describes the construction of the template using freely available software tools, as well as the template itself, which is being made available to the scientific community (http://nitrc.org/projects/inia19/). PMID:23230398

Brain Biochemistry and Personality: A Magnetic Resonance Spectroscopy Study

PubMed Central

Ryman, Sephira G.; Gasparovic, Chuck; Bedrick, Edward J.; Flores, Ranee A.; Marshall, Alison N.; Jung, Rex E.

2011-01-01

To investigate the biochemical correlates of normal personality we utilized proton magnetic resonance spectroscopy (1H-MRS). Our sample consisted of 60 subjects ranging in age from 18 to 32 (27 females). Personality was assessed with the NEO Five-Factor Inventory (NEO-FFI). We measured brain biochemistry within the precuneus, the cingulate cortex, and underlying white matter. We hypothesized that brain biochemistry within these regions would predict individual differences across major domains of personality functioning. Biochemical models were fit for all personality domains including Neuroticism, Extraversion, Openness, Agreeableness, and Conscientiousness. Our findings involved differing concentrations of Choline (Cho), Creatine (Cre), and N-acetylaspartate (NAA) in regions both within (i.e., posterior cingulate cortex) and white matter underlying (i.e., precuneus) the Default Mode Network (DMN). These results add to an emerging literature regarding personality neuroscience, and implicate biochemical integrity within the default mode network as constraining major personality domains within normal human subjects. PMID:22073190

A PML/Slit Axis Controls Physiological Cell Migration and Cancer Invasion in the CNS.

PubMed

Amodeo, Valeria; A, Deli; Betts, Joanne; Bartesaghi, Stefano; Zhang, Ying; Richard-Londt, Angela; Ellis, Matthew; Roshani, Rozita; Vouri, Mikaella; Galavotti, Sara; Oberndorfer, Sarah; Leite, Ana Paula; Mackay, Alan; Lampada, Aikaterini; Stratford, Eva Wessel; Li, Ningning; Dinsdale, David; Grimwade, David; Jones, Chris; Nicotera, Pierluigi; Michod, David; Brandner, Sebastian; Salomoni, Paolo

2017-07-11

Cell migration through the brain parenchyma underpins neurogenesis and glioblastoma (GBM) development. Since GBM cells and neuroblasts use the same migratory routes, mechanisms underlying migration during neurogenesis and brain cancer pathogenesis may be similar. Here, we identify a common pathway controlling cell migration in normal and neoplastic cells in the CNS. The nuclear scaffold protein promyelocytic leukemia (PML), a regulator of forebrain development, promotes neural progenitor/stem cell (NPC) and neuroblast migration in the adult mouse brain. The PML pro-migratory role is active also in transformed mouse NPCs and in human primary GBM cells. In both normal and neoplastic settings, PML controls cell migration via Polycomb repressive complex 2 (PRC2)-mediated repression of Slits, key regulators of axon guidance. Finally, a PML/SLIT1 axis regulates sensitivity to the PML-targeting drug arsenic trioxide in primary GBM cells. Taken together, these findings uncover a drug-targetable molecular axis controlling cell migration in both normal and neoplastic cells. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Organotypic distribution of stem cell markers in formalin-fixed brain harboring glioblastoma multiforme.

PubMed

Schrot, Rudolph J; Ma, Joyce H; Greco, Claudia M; Arias, Angelo D; Angelastro, James M

2007-11-01

The role of stem cells in the origin, growth patterns, and infiltration of glioblastoma multiforme is a subject of intense investigation. One possibility is that glioblastoma may arise from transformed stem cells in the ventricular zone. To explore this hypothesis, we examined the distribution of two stem cell markers, activating transcription factor 5 (ATF5) and CD133, in an autopsy brain specimen from an individual with glioblastoma multiforme. A 41-year-old male with a right posterior temporal glioblastoma had undergone surgery, radiation, and chemotherapy. The brain was harvested within several hours after death. After formalin fixation, sectioning, and mapping of tumor location in the gross specimen, histologic specimens were prepared from tumor-bearing and grossly normal hemispheres. Fluorescence immunohistochemistry and colorimetric staining were performed for ATF5 and CD133. Both markers co-localized to the ependymal and subependymal zones on the side of the tumor, but not in the normal hemisphere or more rostrally in the affected hemisphere. ATF5 staining was especially robust within the diseased hemisphere in histologically normal ependyma. To our knowledge, this is the first in situ demonstration of stem cell markers in whole human brain. These preliminary results support the hypothesis that some glioblastomas may arise from the neurogenic zone of the lateral ventricle. The robust staining for ATF5 and CD133 in histologically normal ventricular zone suggests that an increase in periventricular stem cell activity occurred in this patient on the side of the tumor, either as a localized response to brain injury or as an integral component of oncogenesis and tumor recurrence.

Proteomics analyses for the global proteins in the brain tissues of different human prion diseases.

PubMed

Shi, Qi; Chen, Li-Na; Zhang, Bao-Yun; Xiao, Kang; Zhou, Wei; Chen, Cao; Zhang, Xiao-Mei; Tian, Chan; Gao, Chen; Wang, Jing; Han, Jun; Dong, Xiao-Ping

2015-04-01

Proteomics changes of brain tissues have been described in different neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. However, the brain proteomics of human prion disease remains less understood. In the study, the proteomics patterns of cortex and cerebellum of brain tissues of sporadic Creutzfeldt-Jakob disease, fatal familial insomnia, and G114V genetic CJD were analyzed with isobaric tags for relative and absolute quantitation combined with multidimensional liquid chromatography and MS analysis, with the brains from three normal individuals as controls. Global protein profiling, significant pathway, and functional categories were analyzed. In total, 2287 proteins were identified with quantitative information both in cortex and cerebellum regions. Cerebellum tissues appeared to contain more up- and down-regulated proteins (727 proteins) than cortex regions (312 proteins) of Creutzfeldt-Jakob disease, fatal familial insomnia, and G114V genetic CJD. Viral myocarditis, Parkinson's disease, Alzheimer's disease, lysosome, oxidative phosphorylation, protein export, and drug metabolism-cytochrome P450 were the most commonly affected pathways of the three kinds of diseases. Almost coincident biological functions were identified in the brain tissues of the three diseases. In all, data here demonstrate that the brain tissues of Creutzfeldt-Jakob disease, fatal familial insomnia, and G114V genetic CJD have obvious proteomics changes at their terminal stages, which show the similarities not only among human prion diseases but also with other neurodegeneration diseases. This is the first study to provide a reference proteome map for human prion diseases and will be helpful for future studies focused on potential biomarkers for the diagnosis and therapy of human prion diseases. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

1H Spectroscopic Imaging of Human Brain at 3T: Comparison of Fast 3D-MRSI Techniques

PubMed Central

Zierhut, Matthew L.; Ozturk-Isik, Esin; Chen, Albert P.; Park, Ilwoo; Vigneron, Daniel B.; Nelson, Sarah J.

2011-01-01

Purpose To investigate the signal-to-noise-ratio (SNR) and data quality of time-reduced 1H 3D-MRSI techniques in the human brain at 3T. Materials and Methods Techniques that were investigated included ellipsoidal k-space sampling, parallel imaging, and EPSI. The SNR values for NAA, Cho, Cre, and lactate or lipid peaks were compared after correcting for effective spatial resolution and acquisition time in a phantom and in the brains of human volunteers. Other factors considered were linewidths, metabolite ratios, partial volume effects, and subcutaneous lipid contamination. Results In volunteers, the median normalized SNR for parallel imaging data decreased by 34–42%, but could be significantly improved using regularization. The normalized signal to noise loss in flyback EPSI data was 11–18%. The effective spatial resolutions of the traditional, ellipsoidal, SENSE, and EPSI data were 1.02, 2.43, 1.03, and 1.01cm3, respectively. As expected, lipid contamination was variable between subjects but was highest for the SENSE data. Patient data obtained using the flyback EPSI method were of excellent quality. Conclusions Data from all 1H 3D-MRSI techniques were qualitatively acceptable, based upon SNR, linewidths, and metabolite ratios. The larger FOV obtained with the EPSI methods showed negligible lipid aliasing with acceptable SNR values in less than 9.5 minutes without compromising the PSF. PMID:19711396

Novel immunolocalization of alpha-synuclein in human muscle of inclusion-body myositis, regenerating and necrotic muscle fibers, and at neuromuscular junctions.

PubMed

Askanas, V; Engel, W K; Alvarez, R B; McFerrin, J; Broccolini, A

2000-07-01

Alpha-synuclein (alpha-syn) is an important component of neuronal and glial inclusions in brains of patients with several neurodegenerative disorders. Sporadic inclusion-body myositis (s-IBM) is the most common progressive muscle disease of older patients. Its muscle phenotype shows several similarities with Alzheimer disease brain. A distinct feature of s-IBM pathology is specific vacuolar degeneration of muscle fibers characterized by intracellular amyloid inclusions formed by both amyloid-beta (Abeta) and paired-helical filaments composed of phosphorylated tau. We immunostained alpha-syn in muscle biopsies of s-IBM, disease-control, and normal patients. Approximately 60% of Abeta-positive vacuolated muscle fibers (VMF) contained well-defined inclusions immunoreactive with antibodies against alpha-syn. In those fibers. alpha-syn co-localized with Abeta, both by light microscopy, and ultrastructurally. Paired-helical filaments did not contain alpha-syn immunoreactivity. In all muscle biopsies, alpha-syn was strongly immunoreactive at the postsynaptic region of the neuromuscular junctions. alpha-syn immunoreactivity also occurred diffusely in regenerating and necrotic muscle fibers. In cultured human muscle fibers, alpha-syn and its mRNA were expressed by immunocytochemistry, immunoblots, and Northern blots. Our study provides the first demonstration that alpha-syn participates in normal and pathologic processes of human muscle. Therefore. its function is not exclusive to the brain and neurodegenerative diseases.

Multi-Vendor Implementation and Comparison of Volumetric Whole-Brain Echo-Planar MR Spectroscopic Imaging

PubMed Central

Sabati, Mohammad; Sheriff, Sulaiman; Gu, Meng; Wei, Juan; Zhu, Henry; Barker, Peter B.; Spielman, Daniel M.; Alger, Jeffry R.; Maudsley, Andrew A.

2014-01-01

Purpose To assess volumetric proton MR spectroscopic imaging of the human brain on multi-vendor MRI instruments. Methods Echo-planar spectroscopic imaging (EPSI) was developed on instruments from three manufacturers, with matched specifications and acquisition protocols that accounted for differences in sampling performance, RF power, and data formats. Inter-site reproducibility was evaluated for signal-normalized maps of N-acetylaspartate (NAA), Creatine (Cre) and Choline using phantom and human subject measurements. Comparative analyses included metrics for spectral quality, spatial coverage, and mean values in atlas-registered brain regions. Results Inter-site differences for phantom measurements were under 1.7% for individual metabolites and 0.2% for ratio measurements. Spatial uniformity ranged from 79% to 91%. The human studies found differences of mean values in the temporal lobe, but good agreement in other white-matter regions, with maximum differences relative to their mean of under 3.2%. For NAA/Cre, the maximum difference was 1.8%. In grey-matter a significant difference was observed for frontal lobe NAA. Primary causes of inter-site differences were attributed to shim quality, B0 drift, and accuracy of RF excitation. Correlation coefficients for measurements at each site were over 0.60, indicating good reliability. Conclusion A volumetric intensity-normalized MRSI acquisition can be implemented in a comparable manner across multi-vendor MR instruments. PMID:25354190

Multivendor implementation and comparison of volumetric whole-brain echo-planar MR spectroscopic imaging.

PubMed

Sabati, Mohammad; Sheriff, Sulaiman; Gu, Meng; Wei, Juan; Zhu, Henry; Barker, Peter B; Spielman, Daniel M; Alger, Jeffry R; Maudsley, Andrew A

2015-11-01

To assess volumetric proton MR spectroscopic imaging (MRSI) of the human brain on multivendor MRI instruments. Echo-planar spectroscopic imaging was developed on instruments from three manufacturers, with matched specifications and acquisition protocols that accounted for differences in sampling performance, radiofrequency (RF) power, and data formats. Intersite reproducibility was evaluated for signal-normalized maps of N-acetylaspartate (NAA), creatine (Cre), and choline using phantom and human subject measurements. Comparative analyses included metrics for spectral quality, spatial coverage, and mean values in atlas-registered brain regions. Intersite differences for phantom measurements were less than 1.7% for individual metabolites and less than 0.2% for ratio measurements. Spatial uniformity ranged from 79% to 91%. The human studies found differences of mean values in the temporal lobe, but good agreement in other white matter regions, with maximum differences relative to their mean of under 3.2%. For NAA/Cre, the maximum difference was 1.8%. In gray matter, a significant difference was observed for frontal lobe NAA. Primary causes of intersite differences were attributed to shim quality, B0 drift, and accuracy of RF excitation. Correlation coefficients for measurements at each site were over 0.60, indicating good reliability. A volumetric intensity-normalized MRSI acquisition can be implemented in a comparable manner across multivendor MR instruments. © 2014 Wiley Periodicals, Inc.

The ascending reticular activating system from pontine reticular formation to the thalamus in the human brain.

PubMed

Yeo, Sang Seok; Chang, Pyung Hun; Jang, Sung Ho

2013-01-01

Action of the ascending reticular activating system (ARAS) on the cerebral cortex is responsible for achievement of consciousness. In this study, we attempted to reconstruct the lower single component of the ARAS from the reticular formation (RF) to the thalamus in the normal human brain using diffusion tensor imaging (DTI). Twenty six normal healthy subjects were recruited for this study. A 1.5-T scanner was used for scanning of diffusion tensor images, and the lower single component of the ARAS was reconstructed using FMRIB software. We utilized two ROIs for reconstruction of the lower single component of the ARAS: the seed ROI - the RF of the pons at the level of the trigeminal nerve entry zone, the target ROI - the intralaminar nuclei of the thalamus at the level of the commissural plane. The reconstructed ARAS originated from the pontine RF, ascended through the mesencephalic tegmentum just posterior to the red nucleus, and then terminated on the intralaminar nuclei of the thalamus. No significant differences in fractional anisotropy, mean diffusivity, and tract number were observed between hemispheres (p > 0.05). We reconstructed the lower single component of the ARAS from the RF to the thalamus in the human brain using DTI. The results of this study might be of value for the diagnosis and prognosis of patients with impaired consciousness.

Ascorbic Acid and the Brain: Rationale for the Use against Cognitive Decline

PubMed Central

Harrison, Fiona E.; Bowman, Gene L.; Polidori, Maria Cristina

2014-01-01

This review is focused upon the role of ascorbic acid (AA, vitamin C) in the promotion of healthy brain aging. Particular attention is attributed to the biochemistry and neuronal metabolism interface, transport across tissues, animal models that are useful for this area of research, and the human studies that implicate AA in the continuum between normal cognitive aging and age-related cognitive decline up to Alzheimer’s disease. Vascular risk factors and comorbidity relationships with cognitive decline and AA are discussed to facilitate strategies for advancing AA research in the area of brain health and neurodegeneration. PMID:24763117

Normal development and growth of the human neurocranium and cranial base.

PubMed

Friede, H

1981-01-01

The literature on normal development and growth of certain areas of the human head is reviewed, starting with the early induction of the desmal neurocranium. the development of the brain capsule with its dural reinforcement bands and their connection with the basicranium is discussed, as is the primordial chondrocranium, including its bone replacement. Growth of the calvaria and the three cranial fossae is also analysed. Special interest is focused on the anterior fossa, as knowledge of the growth in this area is very important for an understanding of pathogenesis and possibilities of treating premature craniosynostosis. Finally it is stressed that close observation of the effects of treatment on this pathology may increase our knowledge of normal growth.

Fluorescent Affibody Molecule Administered In Vivo at a Microdose Level Labels EGFR Expressing Glioma Tumor Regions.

PubMed

de Souza, Ana Luiza Ribeiro; Marra, Kayla; Gunn, Jason; Samkoe, Kimberley S; Hoopes, P Jack; Feldwisch, Joachim; Paulsen, Keith D; Pogue, Brian W

2017-02-01

Fluorescence guidance in surgical oncology provides the potential to realize enhanced molecular tumor contrast with dedicated targeted tracers, potentially with a microdose injection level. For most glioma tumors, the blood brain barrier is compromised allowing some exogenous drug/molecule delivery and accumulation for imaging. The aberrant overexpression and/or activation of epidermal growth factor receptor (EGFR) is associated with many types of cancers, including glioblastoma, and so the use of a near-infrared (NIR) fluorescent molecule targeted to the EGFR receptor provides the potential for improving tumor contrast during surgery. Fluorescently labeled affibody molecule (ABY-029) has high EGFR affinity and high potential specificity with reasonably fast plasma clearance. In this study, ABY-29 was evaluated in glioma versus normal brain uptake from intravenous injection at a range of doses, down to a microdose injection level. Nude rats were inoculated with the U251 human glioma cell line in the brain. Tumors were allowed to grow for 3-4 weeks. ABY-029 fluorescence ex vivo imaging of brain slices was acquired at different time points (1-48 h) and varying injection doses from 25 to 122 μg/kg (from human protein microdose equivalent to five times microdose levels). The tumor was most clearly visualized at 1-h post-injection with 8- to 16-fold average contrast relative to normal brain. However, the tumor still could be identified after 48 h. In all cases, the ABY-029 fluorescence appeared to localize preferentially in EGFR-positive regions. Increasing the injected dose from a microdose level to five times, a microdose level increased the signal by 10-fold, and the contrast was from 8 to 16, showing that there was value in doses slightly higher than the microdose restriction. Normal tissue uptake was found to be affected by the tumor size, indicating that edema was a likely factor affecting the expected tumor to normal tissue contrast. These results suggest that the NIR-labeled affibody molecules provide an excellent potential to increase surgical visualization of EGFR-positive tumor regions.

High-resolution temporal and regional mapping of MAPT expression and splicing in human brain development.

PubMed

Hefti, Marco M; Farrell, Kurt; Kim, SoongHo; Bowles, Kathryn R; Fowkes, Mary E; Raj, Towfique; Crary, John F

2018-01-01

The microtubule associated protein tau plays a critical role in the pathogenesis of neurodegenerative disease. Recent studies suggest that tau also plays a role in disorders of neuronal connectivity, including epilepsy and post-traumatic stress disorder. Animal studies have shown that the MAPT gene, which codes for the tau protein, undergoes complex pre-mRNA alternative splicing to produce multiple isoforms during brain development. Human data, particularly on temporal and regional variation in tau splicing during development are however lacking. In this study, we present the first detailed examination of the temporal and regional sequence of MAPT alternative splicing in the developing human brain. We used a novel computational analysis of large transcriptomic datasets (total n = 502 patients), quantitative polymerase chain reaction (qPCR) and western blotting to examine tau expression and splicing in post-mortem human fetal, pediatric and adult brains. We found that MAPT exons 2 and 10 undergo abrupt shifts in expression during the perinatal period that are unique in the canonical human microtubule-associated protein family, while exon 3 showed small but significant temporal variation. Tau isoform expression may be a marker of neuronal maturation, temporally correlated with the onset of axonal growth. Immature brain regions such as the ganglionic eminence and rhombic lip had very low tau expression, but within more mature regions, there was little variation in tau expression or splicing. We thus demonstrate an abrupt, evolutionarily conserved shift in tau isoform expression during the human perinatal period that may be due to tau expression in maturing neurons. Alternative splicing of the MAPT pre-mRNA may play a vital role in normal brain development across multiple species and provides a basis for future investigations into the developmental and pathological functions of the tau protein.

Department of Defense Report on Search for Human Radiation Experiment Records, 1944 - 1994, Volume 2

DTIC Science & Technology

1997-06-01

1-66 Serial investigation of a variety of congenital deformities of the brain case and facial skeleton and the response to treatment ...subsequent treatment of cleft lip and palate defects. The original proposal called for 100 patients and a comparison group of 100 "normals." To date, no...brain case and facial skeleton and the response to treatment . Document Type: Protocol. Document Date: 12 January 1966 Authors: Guy C. Nicholson; Thomas

427th Brookhaven Lecture

ScienceCinema

Gene-Jack Wang

2017-12-09

The increasing number of obese individuals in the U.S. and other countries world-wide adds urgency to the need to understand the mechanisms underlying pathological overeating. Research by the speaker and others at Brookhaven National Laboratory and elsewhere is compiling evidence that the brain circuits disrupted in obesity are similar to those involved in drug addiction. Using positron emission tomography (PET), the speaker and his colleagues have implicated brain dopamine in the normal and the pathological intake of food by humans.

Quantitative targeted absolute proteomic analysis of transporters, receptors and junction proteins for validation of human cerebral microvascular endothelial cell line hCMEC/D3 as a human blood-brain barrier model.

PubMed

Ohtsuki, Sumio; Ikeda, Chiemi; Uchida, Yasuo; Sakamoto, Yumi; Miller, Florence; Glacial, Fabienne; Decleves, Xavier; Scherrmann, Jean-Michel; Couraud, Pierre-Olivier; Kubo, Yoshiyuki; Tachikawa, Masanori; Terasaki, Tetsuya

2013-01-07

Human cerebral microvascular endothelial cell line hCMEC/D3 is an established model of the human blood-brain barrier (BBB). The purpose of the present study was to determine, by means of quantitative targeted absolute proteomics, the protein expression levels in hCMEC/D3 cells of multiple transporters, receptors and junction proteins for comparison with our previously reported findings in isolated human brain microvessels. Among 91 target molecules, 12 transporters, 2 receptors, 1 junction protein and 1 membrane marker were present at quantifiable levels in plasma membrane fraction of hCMEC/D3 cells. ABCA2, MDR1, MRP4, BCRP, GLUT1, 4F2hc, MCT1, ENT1, transferrin and insulin receptors and claudin-5 were detected in both hCMEC/D3 cells and human brain microvessels. After normalization based on Na(+)/K(+) ATPase expression, the differences in protein expression levels between hCMEC/D3 cells and human brain microvessels were within 4-fold for these proteins, with the exceptions of ENT1, transferrin receptor and claudin-5. ABCA8, LAT1, LRP1 and γ-GTP were below the limit of quantification in the cells, but were found in human brain microvessels. ABCA3, ABCA6, MRP1 and ATA1 were found only in hCMEC/D3 cells. Furthermore, compared with human umbilical vein endothelial cells (HUVECs) as reference nonbrain endothelial cells, MDR1 was found only in hCMEC/D3 cells, and GLUT1 expression was 15-fold higher in hCMEC/D3 cells than in HUVECs. In conclusion, this is the first study to examine the suitability and limitations of the hCMEC/D3 cell line as a BBB functional model in terms of quantitative expression levels of transporters, receptors and tight junction proteins.

The Expression of DJ-1 (PARK7) in Normal Human CNS and Idiopathic Parkinson's Disease

ERIC Educational Resources Information Center

Bandopadhyay, Rina; Kingsbury, Ann E.; Cookson, Mark R.; Reid, Andrew R.; Evans, Ian M.; Hope, Andrew D.; Pittman, Alan M.; Lashley, Tammaryn; Canet-Aviles, Rosa; Miller, David W.; McLendon, Chris; Strand, Catherine; Leonard, Andrew J.; Abou-Sleiman, Patrick M.; Healy, Daniel G.; Ariga, Hiroyashi; Wood, Nicholas W.; de Silva, Rohan; Revesz, Tamas; Hardy, John A.; Lees, Andrew J.

2004-01-01

Two mutations in the DJ-1 gene on chromosome1p36 have been identified recently to cause early-onset, autosomal recessive Parkinson's disease. As no information is available regarding the distribution of DJ-1 protein in the human brain, in this study we used a monoclonal antibody for DJ-1 to map its distribution in frontal cortex and substantia…

Mapping human brain capillary water lifetime: high‐resolution metabolic neuroimaging

PubMed Central

Li, Xin; Sammi, Manoj K.; Bourdette, Dennis N.; Neuwelt, Edward A.

2015-01-01

Shutter‐speed analysis of dynamic‐contrast‐agent (CA)‐enhanced normal, multiple sclerosis (MS), and glioblastoma (GBM) human brain data gives the mean capillary water molecule lifetime (τ b) and blood volume fraction (v b; capillary density–volume product (ρ † V)) in a high‐resolution 1H2O MRI voxel (40 μL) or ROI. The equilibrium water extravasation rate constant, k po (τ b −1), averages 3.2 and 2.9 s−1 in resting‐state normal white matter (NWM) and gray matter (NGM), respectively (n = 6). The results (italicized) lead to three major conclusions. (A) k po differences are dominated by capillary water permeability (P W †), not size, differences. NWM and NGM voxel k po and vb values are independent. Quantitative analyses of concomitant population‐averaged k po, vb variations in normal and normal‐appearing MS brain ROIs confirm PW † dominance. (B) P W † is dominated (>95%) by a trans(endothelial)cellular pathway, not the P CA † paracellular route. In MS lesions and GBM tumors, PCA † increases but PW † decreases. (C) k po tracks steady‐state ATP production/consumption flux per capillary. In normal, MS, and GBM brain, regional k po correlates with literature MRSI ATP (positively) and Na + (negatively) tissue concentrations. This suggests that the PW † pathway is metabolically active. Excellent agreement of the relative NGM/NWM k po vb product ratio with the literature 31PMRSI‐MT CMRoxphos ratio confirms the flux property. We have previously shown that the cellular water molecule efflux rate constant (k io) is proportional to plasma membrane P‐type ATPase turnover, likely due to active trans‐membrane water cycling. With synaptic proximities and synergistic metabolic cooperativities, polar brain endothelial, neuroglial, and neuronal cells form “gliovascular units.” We hypothesize that a chain of water cycling processes transmits brain metabolic activity to k po, letting it report neurogliovascular unit Na+,K+‐ATPase activity. Cerebral k po maps represent metabolic (functional) neuroimages. The NGM 2.9 s−1 k po means an equilibrium unidirectional water efflux of ~1015 H2O molecules s−1 per capillary (in 1 μL tissue): consistent with the known ATP consumption rate and water co‐transporting membrane symporter stoichiometries. © 2015 The Authors NMR in Biomedicine Published by John Wiley & Sons Ltd. PMID:25914365

The emergence of mind and emotion in the evolution of neocortex.

PubMed

Freeman, Walter J

2011-01-01

The most deeply transformative concept for the growth of 21st Century psychiatry is the constellation of the chaotic dynamics of the brain. Brains are no longer seen as rational systems that are plagued with emotional disorders reflecting primitives inherited from our animal ancestors. Brains are dynamical systems that continually create patterns by acting intentionally into the environment and shaping themselves in accord with the sensory consequences of their intended actions. Emotions are now seen not as reversions to animal behaviors but as the sources of force and energy that brains require for the actions they take to understand the world and themselves. Humans are unique in experiencing consciousness of their own actions, which they experience as conscience: guilt, shame, pride and joy. Chaotic brain dynamics strives always for unity and harmony, but as a necessary condition for adaptation to a changing world, it repeatedly lapses into disorder. The successes are seen in the normal unity of consciousness; the failures are seen in the disorders that we rightly label the schizophrenias and the less severe character disorders. The foundation for healthy unity is revealed by studies in the evolution of brains, in particular the way in which neocortex of mammals emerged from the primitive allocortex of reptiles. The amazing facts of brain dynamics are now falling into several places. The power-law connectivity of cortex supports the scale-free dynamics of the global workspace in brains ranging from mouse to whale. That dynamics in humans holds the secrets of speech and symbol utilization. By recursive interactions in vast areas of human neocortex the scale-free connectivity supports our unified consciousness. Here in this dynamics are to be sought the keys to understanding and treating the disorders that uniquely plague the human mind.

Brain Microbial Populations in HIV/AIDS: α-Proteobacteria Predominate Independent of Host Immune Status

PubMed Central

Branton, William G.; Ellestad, Kristofor K.; Maingat, Ferdinand; Wheatley, B. Matt; Rud, Erling; Warren, René L.; Holt, Robert A.; Surette, Michael G.; Power, Christopher

2013-01-01

The brain is assumed to be a sterile organ in the absence of disease although the impact of immune disruption is uncertain in terms of brain microbial diversity or quantity. To investigate microbial diversity and quantity in the brain, the profile of infectious agents was examined in pathologically normal and abnormal brains from persons with HIV/AIDS [HIV] (n = 12), other disease controls [ODC] (n = 14) and in cerebral surgical resections for epilepsy [SURG] (n = 6). Deep sequencing of cerebral white matter-derived RNA from the HIV (n = 4) and ODC (n = 4) patients and SURG (n = 2) groups revealed bacterially-encoded 16 s RNA sequences in all brain specimens with α-proteobacteria representing over 70% of bacterial sequences while the other 30% of bacterial classes varied widely. Bacterial rRNA was detected in white matter glial cells by in situ hybridization and peptidoglycan immunoreactivity was also localized principally in glia in human brains. Analyses of amplified bacterial 16 s rRNA sequences disclosed that Proteobacteria was the principal bacterial phylum in all human brain samples with similar bacterial rRNA quantities in HIV and ODC groups despite increased host neuroimmune responses in the HIV group. Exogenous viruses including bacteriophage and human herpes viruses-4, -5 and -6 were detected variably in autopsied brains from both clinical groups. Brains from SIV- and SHIV-infected macaques displayed a profile of bacterial phyla also dominated by Proteobacteria but bacterial sequences were not detected in experimentally FIV-infected cat or RAG1−/− mouse brains. Intracerebral implantation of human brain homogenates into RAG1−/− mice revealed a preponderance of α-proteobacteria 16 s RNA sequences in the brains of recipient mice at 7 weeks post-implantation, which was abrogated by prior heat-treatment of the brain homogenate. Thus, α-proteobacteria represented the major bacterial component of the primate brain’s microbiome regardless of underlying immune status, which could be transferred into naïve hosts leading to microbial persistence in the brain. PMID:23355888

Automatic Brain Portion Segmentation From Magnetic Resonance Images of Head Scans Using Gray Scale Transformation and Morphological Operations.

PubMed

Somasundaram, Karuppanagounder; Ezhilarasan, Kamalanathan

2015-01-01

To develop an automatic skull stripping method for magnetic resonance imaging (MRI) of human head scans. The proposed method is based on gray scale transformation and morphological operations. The proposed method has been tested with 20 volumes of normal T1-weighted images taken from Internet Brain Segmentation Repository. Experimental results show that the proposed method gives better results than the popular skull stripping methods Brain Extraction Tool and Brain Surface Extractor. The average value of Jaccard and Dice coefficients are 0.93 and 0.962 respectively. In this article, we have proposed a novel skull stripping method using intensity transformation and morphological operations. This is a low computational complexity method but gives competitive or better results than that of the popular skull stripping methods Brain Surface Extractor and Brain Extraction Tool.

A biometric analysis of brain size in micrencephalics.

PubMed

Hofman, M A

1984-01-01

Brain weight and head circumference in micrencephalic patients were analysed as a function of age, height and sex in relation to normal human standards. A quantitative definition of micrencephaly is proposed, which is based on these analyses. Evidence is presented, furthermore, that micrencephalics have a significantly lower brain weight in adolescence than in early childhood, and that this cerebral dystrophy continues throughout adulthood, leading to death in more than 85% of the males and 78% of the females before they reach the age of 30 years. Since this decline in brain weight after approximately 3-5 years of age is not accompanied by a similar reduction in head circumference, the brains of elderly micrencephalic patients no longer occupy the entire cranial cavity. It is evident, therefore, that head circumference in the case of micrencephaly is an unsuitable parameter for estimating brain size.

Revealing pathologies in the liquid crystalline structures of the brain by polarimetric studies (Presentation Recording)

NASA Astrophysics Data System (ADS)

Bakhshetyan, Karen; Melkonyan, Gurgen G.; Galstian, Tigran V.; Saghatelyan, Armen

2015-10-01

Natural or "self" alignment of molecular complexes in living tissue represents many similarities with liquid crystals (LC), which are anisotropic liquids. The orientational characteristics of those complexes may be related to many important functional parameters and their study may reveal important pathologies. The know-how, accumulated thanks to the study of LC materials, may thus be used to this end. One of the traditionally used methods, to characterize those materials, is the polarized light imaging (PLI) that allows for label-free analysis of anisotropic structures in the brain tissue and can be used, for example, for the analysis of myelinated fiber bundles. In the current work, we first attempted to apply the PLI on the mouse histological brain sections to create a map of anisotropic structures using cross-polarizer transmission light. Then we implemented the PLI for comparative study of histological sections of human postmortem brain samples under normal and pathological conditions, such as Parkinson's disease (PD). Imaging the coronal, sagittal and horizontal sections of mouse brain allowed us to create a false color-coded fiber orientation map under polarized light. In human brain datasets for both control and PD groups we measured the pixel intensities in myelin-rich subregions of internal capsule and normalized these to non-myelinated background signal from putamen and caudate nucleus. Quantification of intensities revealed a statistically significant reduction of fiber intensity of PD compared to control subjects (2.801 +/- 0.303 and 3.724 +/- 0.07 respectively; *p < 0.05). Our study confirms the validity of PLI method for visualizing myelinated axonal fibers. This relatively simple technique can become a promising tool for study of neurodegenerative diseases where labeling-free imaging is an important benefit.

Deregulated proliferation and differentiation in brain tumors

PubMed Central

Swartling, Fredrik J; Čančer, Matko; Frantz, Aaron; Weishaupt, Holger; Persson, Anders I

2014-01-01

Neurogenesis, the generation of new neurons, is deregulated in neural stem cell (NSC)- and progenitor-derived murine models of malignant medulloblastoma and glioma, the most common brain tumors of children and adults, respectively. Molecular characterization of human malignant brain tumors, and in particular brain tumor stem cells (BTSCs), has identified neurodevelopmental transcription factors, microRNAs, and epigenetic factors known to inhibit neuronal and glial differentiation. We are starting to understand how these factors are regulated by the major oncogenic drivers in malignant brain tumors. In this review, we will focus on the molecular switches that block normal neuronal differentiation and induce brain tumor formation. Genetic or pharmacological manipulation of these switches in BTSCs has been shown to restore the ability of tumor cells to differentiate. We will discuss potential brain tumor therapies that will promote differentiation in order to reduce treatment-resistance, suppress tumor growth, and prevent recurrence in patients. PMID:25416506

3D variational brain tumor segmentation using Dirichlet priors on a clustered feature set.

PubMed

Popuri, Karteek; Cobzas, Dana; Murtha, Albert; Jägersand, Martin

2012-07-01

Brain tumor segmentation is a required step before any radiation treatment or surgery. When performed manually, segmentation is time consuming and prone to human errors. Therefore, there have been significant efforts to automate the process. But, automatic tumor segmentation from MRI data is a particularly challenging task. Tumors have a large diversity in shape and appearance with intensities overlapping the normal brain tissues. In addition, an expanding tumor can also deflect and deform nearby tissue. In our work, we propose an automatic brain tumor segmentation method that addresses these last two difficult problems. We use the available MRI modalities (T1, T1c, T2) and their texture characteristics to construct a multidimensional feature set. Then, we extract clusters which provide a compact representation of the essential information in these features. The main idea in this work is to incorporate these clustered features into the 3D variational segmentation framework. In contrast to previous variational approaches, we propose a segmentation method that evolves the contour in a supervised fashion. The segmentation boundary is driven by the learned region statistics in the cluster space. We incorporate prior knowledge about the normal brain tissue appearance during the estimation of these region statistics. In particular, we use a Dirichlet prior that discourages the clusters from the normal brain region to be in the tumor region. This leads to a better disambiguation of the tumor from brain tissue. We evaluated the performance of our automatic segmentation method on 15 real MRI scans of brain tumor patients, with tumors that are inhomogeneous in appearance, small in size and in proximity to the major structures in the brain. Validation with the expert segmentation labels yielded encouraging results: Jaccard (58%), Precision (81%), Recall (67%), Hausdorff distance (24 mm). Using priors on the brain/tumor appearance, our proposed automatic 3D variational segmentation method was able to better disambiguate the tumor from the surrounding tissue.

Herpesviruses in brain and Alzheimer's disease.

PubMed

Lin, Woan-Ru; Wozniak, Matthew A; Cooper, Robert J; Wilcock, Gordon K; Itzhaki, Ruth F

2002-07-01

It has been established, using polymerase chain reaction (PCR), that herpes simplex virus type 1 (HSV1) is present in a high proportion of brains of elderly normal subjects and Alzheimer's disease (AD) patients. It was subsequently discovered that the virus confers a strong risk of AD when in brain of carriers of the type 4 allele of the apolipoprotein E gene (apoE-epsilon4). This study has now sought, using PCR, the presence of three other herpesviruses in brain: human herpesvirus 6 (HHV6)-types A and B, herpes simplex virus type 2 (HSV2) and cytomegalovirus (CMV). HHV6 is present in a much higher proportion of the AD than of age-matched normal brains (70% vs. 40%, p=0.003) and there is extensive overlap with the presence of HSV1 in AD brains, but HHV6, unlike HSV1, is not directly associated in AD with apoE-epsilon4. In 59% of the AD patients' brains harbouring HHV6, type B is present while 38% harbour both type A and type B, and 3% type A. HSV2 is present at relatively low frequency in brains of both AD patients and normals (13% and 20%), and CMV at rather higher frequencies in the two groups (36% and 35%); in neither case is the difference between the groups statistically significant. It is suggested that the striking difference in the proportion of elderly brains harbouring HSV1 and HSV2 might reflect the lower proportion of people infected with the latter, or the difference in susceptibility of the frontotemporal regions to the two viruses. In the case of HHV6, it is not possible to exclude its presence as an opportunist, but alternatively, it might enhance the damage caused by HSV1 and apoE-epsilon4 in AD; in some viral diseases it is associated with characteristic brain lesions and it also augments the damage caused by certain viruses in cell culture and in animals. Copyright 2002 John Wiley & Sons, Ltd.

Fluid and flexible minds: Intelligence reflects synchrony in the brain’s intrinsic network architecture

PubMed Central

Ferguson, Michael A.; Anderson, Jeffrey S.; Spreng, R. Nathan

2017-01-01

Human intelligence has been conceptualized as a complex system of dissociable cognitive processes, yet studies investigating the neural basis of intelligence have typically emphasized the contributions of discrete brain regions or, more recently, of specific networks of functionally connected regions. Here we take a broader, systems perspective in order to investigate whether intelligence is an emergent property of synchrony within the brain’s intrinsic network architecture. Using a large sample of resting-state fMRI and cognitive data (n = 830), we report that the synchrony of functional interactions within and across distributed brain networks reliably predicts fluid and flexible intellectual functioning. By adopting a whole-brain, systems-level approach, we were able to reliably predict individual differences in human intelligence by characterizing features of the brain’s intrinsic network architecture. These findings hold promise for the eventual development of neural markers to predict changes in intellectual function that are associated with neurodevelopment, normal aging, and brain disease.

The neuroscience of observing consciousness & mirror neurons in therapeutic hypnosis.

PubMed

Rossi, Ernest L; Rossi, Kathryn L

2006-04-01

Neuroscience documents the activity of "mirror neurons" in the human brain as a mechanism whereby we experience empathy and recognize the intentions of others by observing their behavior and automatically matching their brain activity. This neural basis of empathy finds support in research on dysfunctions in the mirror systems of humans with autism and fMRI research on normal subjects designed to assess intentionality, emotions, and complex cognition. Such empathy research now appears to be consistent with the historical and research literature on hypnotic induction, rapport, and many of the classical phenomena of suggestion. A preliminary outline of how mirror neurons may function as a rapport zone mediating between observing consciousness, the gene expression/protein synthesis cycle, and brain plasticity in therapeutic hypnosis and psychosomatic medicine is proposed. Brain plasticity is generalized in the theory, research, and practice of utilizing mirror neurons as an explanatory framework in developing and training new skill sets for facilitating an activity-dependent approach to creative problem solving, mind-body healing, and rehabilitation with therapeutic hypnosis.

Mapping population-based structural connectomes.

PubMed

Zhang, Zhengwu; Descoteaux, Maxime; Zhang, Jingwen; Girard, Gabriel; Chamberland, Maxime; Dunson, David; Srivastava, Anuj; Zhu, Hongtu

2018-05-15

Advances in understanding the structural connectomes of human brain require improved approaches for the construction, comparison and integration of high-dimensional whole-brain tractography data from a large number of individuals. This article develops a population-based structural connectome (PSC) mapping framework to address these challenges. PSC simultaneously characterizes a large number of white matter bundles within and across different subjects by registering different subjects' brains based on coarse cortical parcellations, compressing the bundles of each connection, and extracting novel connection weights. A robust tractography algorithm and streamline post-processing techniques, including dilation of gray matter regions, streamline cutting, and outlier streamline removal are applied to improve the robustness of the extracted structural connectomes. The developed PSC framework can be used to reproducibly extract binary networks, weighted networks and streamline-based brain connectomes. We apply the PSC to Human Connectome Project data to illustrate its application in characterizing normal variations and heritability of structural connectomes in healthy subjects. Copyright © 2018 Elsevier Inc. All rights reserved.

Editorial brain malformation surveillance in the Zika era

PubMed Central

Trevathan, Edwin

2016-01-01

The current surveillance systems for congenital microcephaly are necessary to monitor the impact of Zika virus (ZIKV) on the developing human brain, as well as the ZIKV prevention efforts. However, these congenital microcephaly surveillance systems are insufficient. Abnormalities of neuronal differentiation, development and migration may occur among infants with normal head circumference who have intrauterine exposure to ZIKV. Therefore, surveillance for congenital microcephaly does not ascertain many of the infants seriously impacted by congenital ZIKV infection. Furthermore, many infants with normal head circumference and with malformations of the brain cortex do not have clinical manifestations of their congenital malformations until several months to many years after birth, when they present with clinical manifestations such as seizures/epilepsy, developmental delays with or without developmental regression, and/or motor impairment. In response to the ZIKV threat, public health surveillance systems must be enhanced to ascertain a wide variety of congenital brain malformations, as well as their clinical manifestations that lead to diagnostic brain imaging. Birth Defects Research (Part A) 106:869–874, 2016. © 2016 The Authors Birth Defects Research Part A: Clinical and Molecular Teratology Published by Wiley Periodicals, Inc. PMID:27891785

In vivo neuronal function of the fragile X mental retardation protein is regulated by phosphorylation

PubMed Central

Coffee, R. Lane; Williamson, Ashley J.; Adkins, Christopher M.; Gray, Marisa C.; Page, Terry L.; Broadie, Kendal

2012-01-01

Fragile X syndrome (FXS), caused by loss of the Fragile X Mental Retardation 1 (FMR1) gene product (FMRP), is the most common heritable cause of intellectual disability and autism spectrum disorders. It has been long hypothesized that the phosphorylation of serine 500 (S500) in human FMRP controls its function as an RNA-binding translational repressor. To test this hypothesis in vivo, we employed neuronally targeted expression of three human FMR1 transgenes, including wild-type (hFMR1), dephosphomimetic (S500A-hFMR1) and phosphomimetic (S500D-hFMR1), in the Drosophila FXS disease model to investigate phosphorylation requirements. At the molecular level, dfmr1 null mutants exhibit elevated brain protein levels due to loss of translational repressor activity. This defect is rescued for an individual target protein and across the population of brain proteins by the phosphomimetic, whereas the dephosphomimetic phenocopies the null condition. At the cellular level, dfmr1 null synapse architecture exhibits increased area, branching and bouton number. The phosphomimetic fully rescues these synaptogenesis defects, whereas the dephosphomimetic provides no rescue. The presence of Futsch-positive (microtubule-associated protein 1B) supernumerary microtubule loops is elevated in dfmr1 null synapses. The human phosphomimetic restores normal Futsch loops, whereas the dephosphomimetic provides no activity. At the behavioral level, dfmr1 null mutants exhibit strongly impaired olfactory associative learning. The human phosphomimetic targeted only to the brain-learning center restores normal learning ability, whereas the dephosphomimetic provides absolutely no rescue. We conclude that human FMRP S500 phosphorylation is necessary for its in vivo function as a neuronal translational repressor and regulator of synaptic architecture, and for the manifestation of FMRP-dependent learning behavior. PMID:22080836

A Postmortem Study of Frontal and Temporal Gyri Thickness and Cell Number in Human Obesity.

PubMed

Gómez-Apo, Erick; García-Sierra, Adrián; Silva-Pereyra, Juan; Soto-Abraham, Virgilia; Mondragón-Maya, Alejandra; Velasco-Vales, Verónica; Pescatello, Linda S

2018-01-01

This study aimed to compare cortex thickness and neuronal cell density in postmortem brain tissue from people with overweight or obesity and normal weight. The cortex thickness and neuron density of eight donors with overweight or obesity (mean = 31.6 kg/m 2 ; SD = 4.35; n = 8; 6 male) and eight donors with normal weight (mean = 21.8 kg/m 2 ; SD = 1.5; n = 8; 5 male) were compared. All participants were Mexican and lived in Mexico City. Randomly selected thickness measures of different cortex areas from the frontal and temporal lobes were analyzed based on high-resolution real-size photographs. A histological analysis of systematic-random fields was used to quantify the number of neurons in postmortem left and right of the first, second, and third gyri of frontal and temporal lobe brain samples. No statistical difference was found in cortical thickness between donors with overweight or obesity and individuals with normal weight. A smaller number of neurons was found among the donors with overweight or obesity than the donors with normal weight at different frontal and temporal areas. A lower density of neurons is associated with overweight or obesity. The morphological basis for structural brain changes in obesity requires further investigation. © 2017 The Obesity Society.

miRNA-21 is developmentally regulated in mouse brain and is co-expressed with SOX2 in glioma

PubMed Central

2012-01-01

Background MicroRNAs (miRNAs) and their role during tumor development have been studied in great detail during the last decade, albeit their expression pattern and regulation during normal development are however not so well established. Previous studies have shown that miRNAs are differentially expressed in solid human tumors. Platelet-derived growth factor (PDGF) signaling is known to be involved in normal development of the brain as well as in malignant primary brain tumors, gliomas, but the complete mechanism is still lacking. We decided to investigate the expression of the oncogenic miR-21 during normal mouse development and glioma, focusing on PDGF signaling as a potential regulator of miR-21. Methods We generated mouse glioma using the RCAS/tv-a system for driving PDGF-BB expression in a cell-specific manner. Expression of miR-21 in mouse cell cultures and mouse brain were assessed using Northern blot analysis and in situ hybridization. Immunohistochemistry and Western blot analysis were used to investigate SOX2 expression. LNA-modified siRNA was used for irreversible depletion of miR-21. For inhibition of PDGF signaling Gleevec (imatinib mesylate), Rapamycin and U0126, as well as siRNA were used. Statistical significance was calculated using double-sided unpaired Student´s t-test. Results We identified miR-21 to be highly expressed during embryonic and newborn brain development followed by a gradual decrease until undetectable at postnatal day 7 (P7), this pattern correlated with SOX2 expression. Furthermore, miR-21 and SOX2 showed up-regulation and overlapping expression pattern in RCAS/tv-a generated mouse brain tumor specimens. Upon irreversible depletion of miR-21 the expression of SOX2 was strongly diminished in both mouse primary glioma cultures and human glioma cell lines. Interestingly, in normal fibroblasts the expression of miR-21 was induced by PDGF-BB, and inhibition of PDGF signaling in mouse glioma primary cultures resulted in suppression of miR-21 suggesting that miR-21 is indeed regulated by PDGF signaling. Conclusions Our data show that miR-21 and SOX2 are tightly regulated already during embryogenesis and define a distinct population with putative tumor cell of origin characteristics. Furthermore, we believe that miR-21 is a mediator of PDGF-driven brain tumors, which suggests miR-21 as a promising target for treatment of glioma. PMID:22931209

Brain structural plasticity with spaceflight.

PubMed

Koppelmans, Vincent; Bloomberg, Jacob J; Mulavara, Ajitkumar P; Seidler, Rachael D

2016-01-01

Humans undergo extensive sensorimotor adaptation during spaceflight due to altered vestibular inputs and body unloading. No studies have yet evaluated the effects of spaceflight on human brain structure despite the fact that recently reported optic nerve structural changes are hypothesized to occur due to increased intracranial pressure occurring with microgravity. This is the first report on human brain structural changes with spaceflight. We evaluated retrospective longitudinal T2-weighted MRI scans and balance data from 27 astronauts (thirteen ~2-week shuttle crew members and fourteen ~6-month International Space Station crew members) to determine spaceflight effects on brain structure, and whether any pre to postflight brain changes are associated with balance changes. Data were obtained from the NASA Lifetime Surveillance of Astronaut Health. Brain scans were segmented into gray matter maps and normalized into MNI space using a stepwise approach through subject specific templates. Non-parametric permutation testing was used to analyze pre to postflight volumetric gray matter changes. We found extensive volumetric gray matter decreases, including large areas covering the temporal and frontal poles and around the orbits. This effect was larger in International Space Station versus shuttle crew members in some regions. There were bilateral focal gray matter increases within the medial primary somatosensory and motor cortex; i.e., the cerebral areas where the lower limbs are represented. These intriguing findings are observed in a retrospective data set; future prospective studies should probe the underlying mechanisms and behavioral consequences.

Apparent diffusion coefficient of the normal human brain for various experimental conditions

NASA Astrophysics Data System (ADS)

Moraru, Luminita; Dimitrievici, Lucian

2017-01-01

Diffusion-Weighted Magnetic Resonance Imaging (DW-MRI) is being increasingly used to assess both brain tissues and cerebrospinal fluid integrity. In this paper we study inter-site reproducibility of the apparent diffusion coefficient values for the main cerebral tissues such as gray matter, white matter and into cerebrospinal fluid and for three different stacks of slices that were spaced at L = 79.8, 84.9 and 90 mm. We assessed the impact of the attenuation factor and diffusion gradient on the results reproducibility.

Are microglia minding us? Digging up the unconscious mind-brain relationship from a neuropsychoanalytic approach

PubMed Central

Kato, Takahiro A.; Kanba, Shigenobu

2013-01-01

The unconscious mind-brain relationship remains unresolved. From the perspective of neuroscience, neuronal networks including synapses have been dominantly believed to play crucial roles in human mental activities, while glial contribution to mental activities has long been ignored. Recently, it has been suggested that microglia, glial cells with immunological/inflammatory functions, play important roles in psychiatric disorders. Newly revealed microglial roles, such as constant direct contact with synapses even in the normal brain, have defied the common traditional belief that microglia do not contribute to neuronal networks. Recent human neuroeconomic investigations with healthy volunteers using minocycline, an antibiotic with inhibitory effects on microglial activation, suggest that microglia may unconsciously modulate human social behaviors as “noise.” We herein propose a novel unconscious mind structural system in the brain centering on microglia from a neuropsychoanalytic approach. At least to some extent, microglial activation in the brain may activate unconscious drives as “psychological immune memory/reaction” in the mind, and result in various emotions, traumatic reactions, psychiatric symptoms including suicidal behaviors, and (psychoanalytic) transference during interpersonal relationships. Microglia have the potential to bridge the huge gap between neuroscience, biological psychiatry, psychology and psychoanalysis as a key player to connect the conscious and the unconscious world. PMID:23443737

Hand grips strength effect on motor function in human brain using fMRI: a pilot study

NASA Astrophysics Data System (ADS)

Ismail, S. S.; Mohamad, M.; Syazarina, S. O.; Nafisah, W. Y.

2014-11-01

Several methods of motor tasks for fMRI scanning have been evolving from simple to more complex tasks. Motor tasks on upper extremity were applied in order to excite the increscent of motor activation on contralesional and ipsilateral hemispheres in brain. The main objective of this study is to study the different conditions for motor tasks on upper extremity that affected the brain activation. Ten healthy right handed with normal vision (3 male and 7 female, age range=20-30 years, mean=24.6 years, SD=2.21) participated in this study. Prior to the scanning, participants were trained on hand grip tasks using rubber ball and pressure gauge tool outside the scanner. During fMRI session, a block design with 30-s task blocks and alternating 30-s rest periods was employed while participants viewed a computer screen via a back projection-mirror system and instructed to follow the instruction by gripping their hand with normal and strong grips using a rubber ball. Statistical Parametric mapping (SPM8) software was used to determine the brain activation. Both tasks activated the primary motor (M1), supplementary motor area (SMA), dorsal and ventral of premotor cortex area (PMA) in left hemisphere while in right hemisphere the area of primary motor (M1) somatosensory was activated. However, the comparison between both tasks revealed that the strong hand grip showed the higher activation at M1, PMA and SMA on left hemisphere and also the area of SMA on right hemisphere. Both conditions of motor tasks could provide insights the functional organization on human brain.

Could linear MRI measurements of hippocampus differentiate normal brain aging in elderly persons from Alzheimer disease?

PubMed

Tarroun, Abdullah; Bonnefoy, Marc; Bouffard-Vercelli, Juliette; Gedeon, Claire; Vallee, Bernard; Cotton, François

2007-02-01

Although mild progressive specific structural brain changes are commonly associated with normal human aging, it is unclear whether automatic or manual measurements of these structures can differentiate normal brain aging in elderly persons from patients suffering from cognitive impairment. The objective of this study was primarily to define, with a standard high resolution MRI, the range of normal linear age-specific values for the hippocampal formation (HF), and secondarily to differentiate hippocampal atrophy in normal aging from that occurring in Alzheimer disease (AD). Two MRI-based linear measurements of the hippocampal formation at the level of the head and of the tail, standardized by the cranial dimensions, were obtained from coronal and sagittal T1-weighted MR images in 25 normal elderly subjects, and 26 patients with AD. In this study, dimensions of the HF have been standardized and they revealed normal distributions for each side and each sex: the width of the hippocampal head at the level of the amygdala was 16.42 +/- 1.9 mm, and its height 7.93 +/- 1.4 mm; the width of the tail at the level of the cerebral aqueduct was 8.54 +/- 1.2 mm, and the height 5.74 +/- 0.4 mm. There were no significant differences in standardized dimensions of the HF between sides, sexes, or in comparison to head dimensions in the two groups. In addition, the median inter-observer agreement index was 93%. In contrast, the dimensions of the hippocampal formation decreased gradually with increasing age, owing to physiological atrophy, but this atrophy is more significant in the group of AD.

On the other hand: including left-handers in cognitive neuroscience and neurogenetics.

PubMed

Willems, Roel M; Van der Haegen, Lise; Fisher, Simon E; Francks, Clyde

2014-03-01

Left-handers are often excluded from study cohorts in neuroscience and neurogenetics in order to reduce variance in the data. However, recent investigations have shown that the inclusion or targeted recruitment of left-handers can be informative in studies on a range of topics, such as cerebral lateralization and the genetic underpinning of asymmetrical brain development. Left-handed individuals represent a substantial portion of the human population and therefore left-handedness falls within the normal range of human diversity; thus, it is important to account for this variation in our understanding of brain functioning. We call for neuroscientists and neurogeneticists to recognize the potential of studying this often-discarded group of research subjects.

Treating Brain Tumor with Microbeam Radiation Generated by a Compact Carbon-Nanotube-Based Irradiator: Initial Radiation Efficacy Study.

PubMed

Yuan, Hong; Zhang, Lei; Frank, Jonathan E; Inscoe, Christina R; Burk, Laurel M; Hadsell, Mike; Lee, Yueh Z; Lu, Jianping; Chang, Sha; Zhou, Otto

2015-09-01

Microbeam radiation treatment (MRT) using synchrotron radiation has shown great promise in the treatment of brain tumors, with a demonstrated ability to eradicate the tumor while sparing normal tissue in small animal models. With the goal of expediting the advancement of MRT research beyond the limited number of synchrotron facilities in the world, we recently developed a compact laboratory-scale microbeam irradiator using carbon nanotube (CNT) field emission-based X-ray source array technology. The focus of this study is to evaluate the effects of the microbeam radiation generated by this compact irradiator in terms of tumor control and normal tissue damage in a mouse brain tumor model. Mice with U87MG human glioblastoma were treated with sham irradiation, low-dose MRT, high-dose MRT or 10 Gy broad-beam radiation treatment (BRT). The microbeams were 280 μm wide and spaced at 900 μm center-to-center with peak dose at either 48 Gy (low-dose MRT) or 72 Gy (high-dose MRT). Survival studies showed that the mice treated with both MRT protocols had a significantly extended life span compared to the untreated control group (31.4 and 48.5% of life extension for low- and high-dose MRT, respectively) and had similar survival to the BRT group. Immunostaining on MRT mice demonstrated much higher DNA damage and apoptosis level in tumor tissue compared to the normal brain tissue. Apoptosis in normal tissue was significantly lower in the low-dose MRT group compared to that in the BRT group at 48 h postirradiation. Interestingly, there was a significantly higher level of cell proliferation in the MRT-treated normal tissue compared to that in the BRT-treated mice, indicating rapid normal tissue repairing process after MRT. Microbeam radiation exposure on normal brain tissue causes little apoptosis and no macrophage infiltration at 30 days after exposure. This study is the first biological assessment on MRT effects using the compact CNT-based irradiator. It provides an alternative technology that can enable widespread MRT research on mechanistic studies using a preclinical model, as well as further translational research towards clinical applications.

Neurovascular coupling and energy metabolism in the developing brain

PubMed Central

Kozberg, M.; Hillman, E.

2016-01-01

In the adult brain, increases in local neural activity are almost always accompanied by increases in local blood flow. However, many functional imaging studies of the newborn and developing human brain have observed patterns of hemodynamic responses that differ from adult responses. Among the proposed mechanisms for the observed variations is that neurovascular coupling itself is still developing in the perinatal brain. Many of the components thought to be involved in actuating and propagating this hemodynamic response are known to still be developing postnatally, including perivascular cells such as astrocytes and pericytes. Both neural and vascular networks expand and are then selectively pruned over the first year of human life. Additionally, the metabolic demands of the newborn brain are still evolving. These changes are highly likely to affect early postnatal neurovascular coupling, and thus may affect functional imaging signals in this age group. This chapter will discuss the literature relating to neurovascular development. Potential effects of normal and aberrant development of neurovascular coupling on the newborn brain will also be explored, as well as ways to effectively utilize imaging techniques that rely on hemodynamic modulation such as fMRI and NIRS in younger populations. PMID:27130418

Translational neurophysiology in sheep: measuring sleep and neurological dysfunction in CLN5 Batten disease affected sheep

PubMed Central

Perentos, Nicholas; Martins, Amadeu Q.; Watson, Thomas C.; Bartsch, Ullrich; Mitchell, Nadia L.; Palmer, David N.; Jones, Matthew W.

2015-01-01

Creating valid mouse models of slowly progressing human neurological diseases is challenging, not least because the short lifespan of rodents confounds realistic modelling of disease time course. With their large brains and long lives, sheep offer significant advantages for translational studies of human disease. Here we used normal and CLN5 Batten disease affected sheep to demonstrate the use of the species for studying neurological function in a model of human disease. We show that electroencephalography can be used in sheep, and that longitudinal recordings spanning many months are possible. This is the first time such an electroencephalography study has been performed in sheep. We characterized sleep in sheep, quantifying characteristic vigilance states and neurophysiological hallmarks such as sleep spindles. Mild sleep abnormalities and abnormal epileptiform waveforms were found in the electroencephalographies of Batten disease affected sheep. These abnormalities resemble the epileptiform activity seen in children with Batten disease and demonstrate the translational relevance of both the technique and the model. Given that both spontaneous and engineered sheep models of human neurodegenerative diseases already exist, sheep constitute a powerful species in which longitudinal in vivo studies can be conducted. This will advance our understanding of normal brain function and improve our capacity for translational research into neurological disorders. PMID:25724202

Language systems in normal and aphasic human subjects: functional imaging studies and inferences from animal studies.

PubMed

Wise, Richard J S

2003-01-01

The old neurological model of language, based on the writings of Broca, Wernicke and Lichtheim in the 19th century, is now undergoing major modifications. Observations on the anatomy and physiology of auditory processing in non-human primates are giving strong indicators as to how speech perception is organised in the human brain. In the light of this knowledge, functional activation studies with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) are achieving a new level of precision in the investigation of language organisation in the human brain, in a manner not possible with observations on patients with aphasic stroke. Although the use of functional imaging to inform methods of improving aphasia rehabilitation remains underdeveloped, there are strong indicators that this methodology will provide the means to research a very imperfectly developed area of therapy.

Sex steroids and human behavior: prenatal androgen exposure and sex-typical play behavior in children.

PubMed

Hines, Melissa

2003-12-01

Gonadal hormones, particularly androgens, direct certain aspects of brain development and exert permanent influences on sex-typical behavior in nonhuman mammals. Androgens also influence human behavioral development, with the most convincing evidence coming from studies of sex-typical play. Girls exposed to unusually high levels of androgens prenatally, because they have the genetic disorder, congenital adrenal hyperplasia (CAH), show increased preferences for toys and activities usually preferred by boys, and for male playmates, and decreased preferences for toys and activities usually preferred by girls. Normal variability in androgen prenatally also has been related to subsequent sex-typed play behavior in girls, and nonhuman primates have been observed to show sex-typed preferences for human toys. These findings suggest that androgen during early development influences childhood play behavior in humans at least in part by altering brain development.

Clinical NOE 13C MRS for neuropsychiatric disorders of the frontal lobe

NASA Astrophysics Data System (ADS)

Sailasuta, Napapon; Robertson, Larry W.; Harris, Kent C.; Gropman, Andrea L.; Allen, Peter S.; Ross, Brian D.

2008-12-01

In this communication, a scheme is described whereby in vivo 13C MRS can safely be performed in the frontal lobe, a human brain region hitherto precluded on grounds of SAR, but important in being the seat of impaired cognitive function in many neuropsychiatric and developmental disorders. By combining two well known features of 13C NMR—the use of low power NOE and the focus on 13C carbon atoms which are only minimally coupled to protons, we are able to overcome the obstacle of SAR and develop means of monitoring the 13C fluxes of critically important metabolic pathways in frontal brain structures of normal volunteers and patients. Using a combination of low-power WALTZ decoupling, variants of random noise for nuclear overhauser effect enhancement it was possible to reduce power deposition to 20% of the advised maximum specific absorption rate (SAR). In model solutions 13C signal enhancement achieved with this scheme were comparable to that obtained with WALTZ-4. In human brain, the low power procedure effectively determined glutamine, glutamate and bicarbonate in the posterior parietal brain after [1- 13C] glucose infusion. The same 13C enriched metabolites were defined in frontal brain of human volunteers after administration of [1- 13C] acetate, a recognized probe of glial metabolism. Time courses of incorporation of 13C into cerebral glutamate, glutamine and bicarbonate were constructed. The results suggest efficacy for measurement of in vivo cerebral metabolic rates of the glutamate-glutamine and tricarboxylic acid cycles in 20 min MR scans in previously inaccessible brain regions in humans at 1.5T. We predict these will be clinically useful biomarkers in many human neuropsychiatric and genetic conditions.

Broca's arrow: evolution, prediction, and language in the brain.

PubMed

Cooper, David L

2006-01-01

Brodmann's areas 44 and 45 in the human brain, also known as Broca's area, have long been associated with language functions, especially in the left hemisphere. However, the precise role Broca's area plays in human language has not been established with certainty. Broca's area has homologs in the great apes and in area F5 in monkeys, which suggests that its original function was not linguistic at all. In fact, great ape and hominid brains show very similar left-over-right asymmetries in Broca's area homologs as well as in other areas, such as homologs to Wernicke's area, that are normally associated with language in modern humans. Moreover, the so-called mirror neurons are located in Broca's area in great apes and area F5 in monkeys, which seem to provide a representation of cause and effect in a primate's environment, particularly its social environment. Humans appear to have these mirror neurons in Broca's area as well. Similarly, genetic evidence related to the FOXP2 gene implicates Broca's area in linguistic function and dysfunction, but the gene itself is a highly conserved developmental gene in vertebrates and is shared with only two or three differences between humans and great apes, five between humans and mice, and eight between humans and songbirds. Taking neurons and portions of the brain as discrete computational segments in the sense of constituting specific Turing machines, this evidence points to a predictive motor and conceptual function for Broca's area in primates, especially for social concepts. In human language, this is consistent with evidence from typological and cognitive linguistics. (c) 2006 Wiley-Liss, Inc.

Dynamic glucose enhanced (DGE) MRI for combined imaging of blood-brain barrier break down and increased blood volume in brain cancer.

PubMed

Xu, Xiang; Chan, Kannie W Y; Knutsson, Linda; Artemov, Dmitri; Xu, Jiadi; Liu, Guanshu; Kato, Yoshinori; Lal, Bachchu; Laterra, John; McMahon, Michael T; van Zijl, Peter C M

2015-12-01

Recently, natural d-glucose was suggested as a potential biodegradable contrast agent. The feasibility of using d-glucose for dynamic perfusion imaging was explored to detect malignant brain tumors based on blood brain barrier breakdown. Mice were inoculated orthotopically with human U87-EGFRvIII glioma cells. Time-resolved glucose signal changes were detected using chemical exchange saturation transfer (glucoCEST) MRI. Dynamic glucose enhanced (DGE) MRI was used to measure tissue response to an intravenous bolus of d-glucose. DGE images of mouse brains bearing human glioma showed two times higher and persistent changes in tumor compared with contralateral brain. Area-under-curve (AUC) analysis of DGE delineated blood vessels and tumor and had contrast comparable to the AUC determined using dynamic contrast enhanced (DCE) MRI with GdDTPA, both showing a significantly higher AUC in tumor than in brain (P < 0.005). Both CEST and relaxation effects contribute to the signal change. DGE MRI is a feasible technique for studying brain tumor enhancement reflecting differences in tumor blood volume and permeability with respect to normal brain. We expect DGE will provide a low-risk and less expensive alternative to DCE MRI for imaging cancer in vulnerable populations, such as children and patients with renal impairment. © 2015 Wiley Periodicals, Inc.

Dynamic Glucose Enhanced (DGE) MRI for Combined Imaging of Blood Brain Barrier Break Down and Increased Blood Volume in Brain Cancer

PubMed Central

Xu, Xiang; Chan, Kannie WY; Knutsson, Linda; Artemov, Dmitri; Xu, Jiadi; Liu, Guanshu; Kato, Yoshinori; Lal, Bachchu; Laterra, John; McMahon, Michael T.; van Zijl, Peter C.M.

2015-01-01

Purpose Recently, natural d-glucose was suggested as a potential biodegradable contrast agent. The feasibility of using d-glucose for dynamic perfusion imaging was explored to detect malignant brain tumors based on blood brain barrier breakdown. Methods Mice were inoculated orthotopically with human U87-EGFRvIII glioma cells. Time-resolved glucose signal changes were detected using chemical exchange saturation transfer (glucoCEST) MRI. Dynamic glucose enhanced (DGE) MRI was used to measure tissue response to an intravenous bolus of d-glucose. Results DGE images of mouse brains bearing human glioma showed two times higher and persistent changes in tumor compared to contralateral brain. Area-under-curve (AUC) analysis of DGE delineated blood vessels and tumor and had contrast comparable to the AUC determined using dynamic contrast enhanced (DCE) MRI with GdDTPA, both showing a significantly higher AUC in tumor than in brain (p<0.005). Both CEST and relaxation effects contribute to the signal change. Conclusion DGE MRI is a feasible technique for studying brain tumor enhancement reflecting differences in tumor blood volume and permeability with respect to normal brain. We expect DGE will provide a low-risk and less expensive alternative to DCE MRI for imaging cancer in vulnerable populations, such as children and patients with renal impairment. PMID:26404120

Magnetic resonance spectroscopy of the human brain

NASA Astrophysics Data System (ADS)

Strózik-Kotlorz, D.

2014-01-01

I give a brief description of the magnetic resonance spectroscopy (MRS) in the human brain examinations. MRS allows a noninvasive chemical analysis of the brain using a standard high field MR system. Nowadays, the dominant form of MR brain spectroscopy is proton spectroscopy. Two main techniques of MRS, which utilize the chemical shift of metabolites in the external magnetic field, are SVS (single voxel) and CSI (single slice). The major peaks in the spectrum of a normal brain include NAA, Cr, Cho and m-Ins, which are neuronal, energetic, membrane turnover and glial markers, respectively. In disease, two pathological metabolites can be found in the brain spectra: Lac, which is end product of anaerobic glycolysis and Lip, which is a marker of membrane breakdown, occurring in necrosis. The common way to analyze clinical spectra is to determine metabolite ratios, e.g. NAA/Cr, Cho/Cr, Cho/NAA. This analysis permits a safe and noninvasive examination of the brain tissue as each disease state has its own characteristic spectroscopic image. MRS is a valuable diagnostic tool in such clinical applications as detecting brain tumors and differentiating tumors from inflammatory and infectious processes. Proton MRS is also very helpful in diagnostic of ischemic lesions, Alzheimer's disease and hepatic encephalopathy. The MRS brain spectra should always be correlated with the Magnetic Resonance Imaging (MRI) results and alone cannot make neurological diagnosis.

The entropic brain: a theory of conscious states informed by neuroimaging research with psychedelic drugs

PubMed Central

Carhart-Harris, Robin L.; Leech, Robert; Hellyer, Peter J.; Shanahan, Murray; Feilding, Amanda; Tagliazucchi, Enzo; Chialvo, Dante R.; Nutt, David

2014-01-01

Entropy is a dimensionless quantity that is used for measuring uncertainty about the state of a system but it can also imply physical qualities, where high entropy is synonymous with high disorder. Entropy is applied here in the context of states of consciousness and their associated neurodynamics, with a particular focus on the psychedelic state. The psychedelic state is considered an exemplar of a primitive or primary state of consciousness that preceded the development of modern, adult, human, normal waking consciousness. Based on neuroimaging data with psilocybin, a classic psychedelic drug, it is argued that the defining feature of “primary states” is elevated entropy in certain aspects of brain function, such as the repertoire of functional connectivity motifs that form and fragment across time. Indeed, since there is a greater repertoire of connectivity motifs in the psychedelic state than in normal waking consciousness, this implies that primary states may exhibit “criticality,” i.e., the property of being poised at a “critical” point in a transition zone between order and disorder where certain phenomena such as power-law scaling appear. Moreover, if primary states are critical, then this suggests that entropy is suppressed in normal waking consciousness, meaning that the brain operates just below criticality. It is argued that this entropy suppression furnishes normal waking consciousness with a constrained quality and associated metacognitive functions, including reality-testing and self-awareness. It is also proposed that entry into primary states depends on a collapse of the normally highly organized activity within the default-mode network (DMN) and a decoupling between the DMN and the medial temporal lobes (which are normally significantly coupled). These hypotheses can be tested by examining brain activity and associated cognition in other candidate primary states such as rapid eye movement (REM) sleep and early psychosis and comparing these with non-primary states such as normal waking consciousness and the anaesthetized state. PMID:24550805

The entropic brain: a theory of conscious states informed by neuroimaging research with psychedelic drugs.

PubMed

Carhart-Harris, Robin L; Leech, Robert; Hellyer, Peter J; Shanahan, Murray; Feilding, Amanda; Tagliazucchi, Enzo; Chialvo, Dante R; Nutt, David

2014-01-01

Entropy is a dimensionless quantity that is used for measuring uncertainty about the state of a system but it can also imply physical qualities, where high entropy is synonymous with high disorder. Entropy is applied here in the context of states of consciousness and their associated neurodynamics, with a particular focus on the psychedelic state. The psychedelic state is considered an exemplar of a primitive or primary state of consciousness that preceded the development of modern, adult, human, normal waking consciousness. Based on neuroimaging data with psilocybin, a classic psychedelic drug, it is argued that the defining feature of "primary states" is elevated entropy in certain aspects of brain function, such as the repertoire of functional connectivity motifs that form and fragment across time. Indeed, since there is a greater repertoire of connectivity motifs in the psychedelic state than in normal waking consciousness, this implies that primary states may exhibit "criticality," i.e., the property of being poised at a "critical" point in a transition zone between order and disorder where certain phenomena such as power-law scaling appear. Moreover, if primary states are critical, then this suggests that entropy is suppressed in normal waking consciousness, meaning that the brain operates just below criticality. It is argued that this entropy suppression furnishes normal waking consciousness with a constrained quality and associated metacognitive functions, including reality-testing and self-awareness. It is also proposed that entry into primary states depends on a collapse of the normally highly organized activity within the default-mode network (DMN) and a decoupling between the DMN and the medial temporal lobes (which are normally significantly coupled). These hypotheses can be tested by examining brain activity and associated cognition in other candidate primary states such as rapid eye movement (REM) sleep and early psychosis and comparing these with non-primary states such as normal waking consciousness and the anaesthetized state.

Intrinsic connectivity of neural networks in the awake rabbit.

PubMed

Schroeder, Matthew P; Weiss, Craig; Procissi, Daniel; Disterhoft, John F; Wang, Lei

2016-04-01

The way in which the brain is functionally connected into different networks has emerged as an important research topic in order to understand normal neural processing and signaling. Since some experimental manipulations are difficult or unethical to perform in humans, animal models are better suited to investigate this topic. Rabbits are a species that can undergo MRI scanning in an awake and conscious state with minimal preparation and habituation. In this study, we characterized the intrinsic functional networks of the resting New Zealand White rabbit brain using BOLD fMRI data. Group independent component analysis revealed seven networks similar to those previously found in humans, non-human primates and/or rodents including the hippocampus, default mode, cerebellum, thalamus, and visual, somatosensory, and parietal cortices. For the first time, the intrinsic functional networks of the resting rabbit brain have been elucidated demonstrating the rabbit's applicability as a translational animal model. Without the confounding effects of anesthetics or sedatives, future experiments may employ rabbits to understand changes in neural connectivity and brain functioning as a result of experimental manipulation (e.g., temporary or permanent network disruption, learning-related changes, and drug administration). Copyright © 2016 Elsevier Inc. All rights reserved.

The macro-structural variability of the human neocortex.

PubMed

Kruggel, Frithjof

2018-05-15

The human neocortex shows a considerable individual structural variability. While primary gyri and sulci are found in all normally developed brains and bear clear-cut gross structural descriptions, secondary structures are highly variable and not present in all brains. The blend of common and individual structures poses challenges when comparing structural and functional results from quantitative neuroimaging studies across individuals, and sets limits on the precision of location information much above the spatial resolution of current neuroimaging methods. This work aimed at quantifying structural variability on the neocortex, and at assessing the spatial relationship between regions common to all brains and their individual structural variants. Based on structural MRI data provided as the "900 Subjects Release" of the Human Connectome Project, a data-driven analytic approach was employed here from which the definition of seven cortical "communities" emerged. Apparently, these communities comprise common regions of structural features, while the individual variability is confined within a community. Similarities between the community structure and the state of the brain development at gestation week 32 lead suggest that communities are segregated early. Subdividing the neocortex into communities is suggested as anatomically more meaningful than the traditional lobar structure. Copyright © 2018 Elsevier Inc. All rights reserved.

Recurrent genomic instability of chromosome 1q in neural derivatives of human embryonic stem cells

PubMed Central

Varela, Christine; Denis, Jérôme Alexandre; Polentes, Jérôme; Feyeux, Maxime; Aubert, Sophie; Champon, Benoite; Piétu, Geneviève; Peschanski, Marc; Lefort, Nathalie

2012-01-01

Human pluripotent stem cells offer a limitless source of cells for regenerative medicine. Neural derivatives of human embryonic stem cells (hESCs) are currently being used for cell therapy in 3 clinical trials. However, hESCs are prone to genomic instability, which could limit their clinical utility. Here, we report that neural differentiation of hESCs systematically produced a neural stem cell population that could be propagated for more than 50 passages without entering senescence; this was true for all 6 hESC lines tested. The apparent spontaneous loss of evolution toward normal senescence of somatic cells was associated with a jumping translocation of chromosome 1q. This chromosomal defect has previously been associated with hematologic malignancies and pediatric brain tumors with poor clinical outcome. Neural stem cells carrying the 1q defect implanted into the brains of rats failed to integrate and expand, whereas normal cells engrafted. Our results call for additional quality controls to be implemented to ensure genomic integrity not only of undifferentiated pluripotent stem cells, but also of hESC derivatives that form cell therapy end products, particularly neural lines. PMID:22269325

Expression of the Murine Duchenne Muscular Dystrophy Gene in Muscle and Brain

NASA Astrophysics Data System (ADS)

Chamberlain, Jeffrey S.; Pearlman, Joel A.; Muzny, Donna M.; Gibbs, Richard A.; Ranier, Joel E.; Reeves, Alice A.; Caskey, C. Thomas

1988-03-01

Complementary DNA clones were isolated that represent the 5' terminal 2.5 kilobases of the murine Duchenne muscular dystrophy (Dmd) messenger RNA (mRNA). Mouse Dmd mRNA was detectable in skeletal and cardiac muscle and at a level approximately 90 percent lower in brain. Dmd mRNA is also present, but at much lower than normal levels, in both the muscle and brain of three different strains of dystrophic mdx mice. The identification of Dmd mRNA in brain raises the possibility of a relation between human Duchenne muscular dystrophy (DMD) gene expression and the mental retardation found in some DMD males. These results also provide evidence that the mdx mutations are allelic variants of mouse Dmd gene mutations.

Factors Influencing Cerebral Plasticity in the Normal and Injured Brain

PubMed Central

Kolb, Bryan; Teskey, G. Campbell; Gibb, Robbin

2010-01-01

An important development in behavioral neuroscience in the past 20 years has been the demonstration that it is possible to stimulate functional recovery after cerebral injury in laboratory animals. Rodent models of cerebral injury provide an important tool for developing such rehabilitation programs. The models include analysis at different levels including detailed behavioral paradigms, electrophysiology, neuronal morphology, protein chemistry, and epigenetics. A significant challenge for the next 20 years will be the translation of this work to improve the outcome from brain injury and disease in humans. Our goal in the article will be to synthesize the multidisciplinary laboratory work on brain plasticity and behavior in the injured brain to inform the development of rehabilitation programs. PMID:21120136

Novel Biomarkers of Human GM1 Gangliosidosis Reflect the Clinical Efficacy of Gene Therapy in a Feline Model.

PubMed

Gray-Edwards, Heather L; Regier, Debra S; Shirley, Jamie L; Randle, Ashley N; Salibi, Nouha; Thomas, Sarah E; Latour, Yvonne L; Johnston, Jean; Golas, Gretchen; Maguire, Annie S; Taylor, Amanda R; Sorjonen, Donald C; McCurdy, Victoria J; Christopherson, Peter W; Bradbury, Allison M; Beyers, Ronald J; Johnson, Aime K; Brunson, Brandon L; Cox, Nancy R; Baker, Henry J; Denney, Thomas S; Sena-Esteves, Miguel; Tifft, Cynthia J; Martin, Douglas R

2017-04-05

GM1 gangliosidosis is a fatal neurodegenerative disease that affects individuals of all ages. Favorable outcomes using adeno-associated viral (AAV) gene therapy in GM1 mice and cats have prompted consideration of human clinical trials, yet there remains a paucity of objective biomarkers to track disease status. We developed a panel of biomarkers using blood, urine, cerebrospinal fluid (CSF), electrodiagnostics, 7 T MRI, and magnetic resonance spectroscopy in GM1 cats-either untreated or AAV treated for more than 5 years-and compared them to markers in human GM1 patients where possible. Significant alterations were noted in CSF and blood of GM1 humans and cats, with partial or full normalization after gene therapy in cats. Gene therapy improved the rhythmic slowing of electroencephalograms (EEGs) in GM1 cats, a phenomenon present also in GM1 patients, but nonetheless the epileptiform activity persisted. After gene therapy, MR-based analyses revealed remarkable preservation of brain architecture and correction of brain metabolites associated with microgliosis, neuroaxonal loss, and demyelination. Therapeutic benefit of AAV gene therapy in GM1 cats, many of which maintain near-normal function >5 years post-treatment, supports the strong consideration of human clinical trials, for which the biomarkers described herein will be essential for outcome assessment. Copyright © 2017 The American Society of Gene and Cell Therapy. All rights reserved.

Molecular Barriers to Zoonotic Transmission of Prions

PubMed Central

Barria, Marcelo A.; Balachandran, Aru; Morita, Masanori; Kitamoto, Tetsuyuki; Barron, Rona; Manson, Jean; Knight, Richard; Ironside, James W.

2014-01-01

The risks posed to human health by individual animal prion diseases cannot be determined a priori and are difficult to address empirically. The fundamental event in prion disease pathogenesis is thought to be the seeded conversion of normal prion protein to its pathologic isoform. We used a rapid molecular conversion assay (protein misfolding cyclic amplification) to test whether brain homogenates from specimens of classical bovine spongiform encephalopathy (BSE), atypical BSE (H-type BSE and L-type BSE), classical scrapie, atypical scrapie, and chronic wasting disease can convert normal human prion protein to the abnormal disease-associated form. None of the tested prion isolates from diseased animals were as efficient as classical BSE in converting human prion protein. However, in the case of chronic wasting disease, there was no absolute barrier to conversion of the human prion protein. PMID:24377702

The Structural Connectome of the Human Central Homeostatic Network.

PubMed

Edlow, Brian L; McNab, Jennifer A; Witzel, Thomas; Kinney, Hannah C

2016-04-01

Homeostatic adaptations to stress are regulated by interactions between the brainstem and regions of the forebrain, including limbic sites related to respiratory, autonomic, affective, and cognitive processing. Neuroanatomic connections between these homeostatic regions, however, have not been thoroughly identified in the human brain. In this study, we perform diffusion spectrum imaging tractography using the MGH-USC Connectome MRI scanner to visualize structural connections in the human brain linking autonomic and cardiorespiratory nuclei in the midbrain, pons, and medulla oblongata with forebrain sites critical to homeostatic control. Probabilistic tractography analyses in six healthy adults revealed connections between six brainstem nuclei and seven forebrain regions, several over long distances between the caudal medulla and cerebral cortex. The strongest evidence for brainstem-homeostatic forebrain connectivity in this study was between the brainstem midline raphe and the medial temporal lobe. The subiculum and amygdala were the sampled forebrain nodes with the most extensive brainstem connections. Within the human brainstem-homeostatic forebrain connectome, we observed that a lateral forebrain bundle, whose connectivity is distinct from that of rodents and nonhuman primates, is the primary conduit for connections between the brainstem and medial temporal lobe. This study supports the concept that interconnected brainstem and forebrain nodes form an integrated central homeostatic network (CHN) in the human brain. Our findings provide an initial foundation for elucidating the neuroanatomic basis of homeostasis in the normal human brain, as well as for mapping CHN disconnections in patients with disorders of homeostasis, including sudden and unexpected death, and epilepsy.

Possible psycho-physiological consequences of human long-term space missions

NASA Astrophysics Data System (ADS)

Belisheva, N. K.; Lammer, H.; Biernat, H. K.; Kachanova, T. L.; Kalashnikova, I. V.

Experiments carried out on the Earth s surface during different years and under contrast periods of solar activity have shown that the functional state of biosystems including the human organisms are controlled by global and local geocosmical agents Our finding have a close relation to space research because they demonstrate the reactions of biosystems on variations of global and local geocosmical agents and the mechanisms of modulations of biosystems state by geocosmical agents We revealed the role of variations of the geomagnetic field for the stimulation of immune systems functional state of peripheral blood human brain growth of microflora skin covers and pathogenic microorganisms The study of the psycho-physiological state of the human organism has demonstrated that an increase of the neutron intensity near the Earth s surface is associated with anxiety decrease of normal and increase of paradox reactions of examinees The analysis of the human brain functional state in dependent on the geomagnetic variation structure dose under exposure to the variations of geomagnetic field in a certain amplitude-frequency range and also the intensity of the nucleon component of secondary cosmic rays showed that the stable and unstable states of the human brain are determined by geomagnetic field variations and the intensity of the nucleon component The stable state of the brain manifested under the periodic oscillations of the geomagnetic field in a certain amplitude-frequency range The low level of geomagnetic activity associated with an

Consequences of Traumatic Brain Injury for Human Vergence Dynamics

PubMed Central

Tyler, Christopher W.; Likova, Lora T.; Mineff, Kristyo N.; Elsaid, Anas M.; Nicholas, Spero C.

2015-01-01

Purpose: Traumatic brain injury involving loss of consciousness has focal effects in the human brainstem, suggesting that it may have particular consequences for eye movement control. This hypothesis was investigated by measurements of vergence eye movement parameters. Methods: Disparity vergence eye movements were measured for a population of 123 normally sighted individuals, 26 of whom had suffered diffuse traumatic brain injury (dTBI) in the past, while the remainder served as controls. Vergence tracking responses were measured to sinusoidal disparity modulation of a random-dot field. Disparity vergence step responses were characterized in terms of their dynamic parameters separately for the convergence and divergence directions. Results: The control group showed notable differences between convergence and divergence dynamics. The dTBI group showed significantly abnormal vergence behavior on many of the dynamic parameters. Conclusion: The results support the hypothesis that occult injury to the oculomotor control system is a common residual outcome of dTBI. PMID:25691880

Brain dopamine neurone 'damage': methamphetamine users vs. Parkinson's disease - a critical assessment of the evidence.

PubMed

Kish, Stephen J; Boileau, Isabelle; Callaghan, Russell C; Tong, Junchao

2017-01-01

The objective of this review is to evaluate the evidence that recreational methamphetamine exposure might damage dopamine neurones in human brain, as predicted by experimental animal findings. Brain dopamine marker data in methamphetamine users can now be compared with those in Parkinson's disease, for which the Oleh Hornykiewicz discovery in Vienna of a brain dopamine deficiency is established. Whereas all examined striatal (caudate and putamen) dopamine neuronal markers are decreased in Parkinson's disease, levels of only some (dopamine, dopamine transporter) but not others (dopamine metabolites, synthetic enzymes, vesicular monoamine transporter 2) are below normal in methamphetamine users. This suggests that loss of dopamine neurones might not be characteristic of methamphetamine exposure in at least some human drug users. In methamphetamine users, dopamine loss was more marked in caudate than in putamen, whereas in Parkinson's disease, the putamen is distinctly more affected. Substantia nigra loss of dopamine-containing cell bodies is characteristic of Parkinson's disease, but similar neuropathological studies have yet to be conducted in methamphetamine users. Similarly, it is uncertain whether brain gliosis, a common feature of brain damage, occurs after methamphetamine exposure in humans. Preliminary epidemiological findings suggest that methamphetamine use might increase risk of subsequent development of Parkinson's disease. We conclude that the available literature is insufficient to indicate that recreational methamphetamine exposure likely causes loss of dopamine neurones in humans but does suggest presence of a striatal dopamine deficiency that, in principle, could be corrected by dopamine substitution medication if safety and subject selection considerations can be resolved. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Hemisphere- and gender-related differences in small-world brain networks: a resting-state functional MRI study.

PubMed

Tian, Lixia; Wang, Jinhui; Yan, Chaogan; He, Yong

2011-01-01

We employed resting-state functional MRI (R-fMRI) to investigate hemisphere- and gender-related differences in the topological organization of human brain functional networks. Brain networks were first constructed by measuring inter-regional temporal correlations of R-fMRI data within each hemisphere in 86 young, healthy, right-handed adults (38 males and 48 females) followed by a graph-theory analysis. The hemispheric networks exhibit small-world attributes (high clustering and short paths) that are compatible with previous results in the whole-brain functional networks. Furthermore, we found that compared with females, males have a higher normalized clustering coefficient in the right hemispheric network but a lower clustering coefficient in the left hemispheric network, suggesting a gender-hemisphere interaction. Moreover, we observed significant hemisphere-related differences in the regional nodal characteristics in various brain regions, such as the frontal and occipital regions (leftward asymmetry) and the temporal regions (rightward asymmetry), findings that are consistent with previous studies of brain structural and functional asymmetries. Together, our results suggest that the topological organization of human brain functional networks is associated with gender and hemispheres, and they provide insights into the understanding of functional substrates underlying individual differences in behaviors and cognition. Copyright © 2010 Elsevier Inc. All rights reserved.

Toward the holistic, reference, and extendable atlas of the human brain, head, and neck.

PubMed

Nowinski, Wieslaw L

2015-06-01

Despite numerous efforts, a fairly complete (holistic) anatomical model of the whole, normal, adult human brain, which is required as the reference in brain studies and clinical applications, has not yet been constructed. Our ultimate objective is to build this kind of atlas from advanced in vivo imaging. This work presents the taxonomy of our currently developed brain atlases and addresses the design, content, functionality, and current results in the holistic atlas development as well as atlas usefulness and future directions. We have developed to date 35 commercial brain atlases (along with numerous research prototypes), licensed to 63 companies and institutions, and made available to medical societies, organizations, medical schools, and individuals. These atlases have been applied in education, research, and clinical applications. Hundreds of thousands of patients have been treated by using our atlases. Based on this experience, the first version of the holistic and reference atlas of the brain, head, and neck has been developed and made available. The atlas has been created from multispectral 3 and 7 Tesla and high-resolution CT in vivo scans. It is fully 3D, scalable, interactive, and highly detailed with about 3,000 labeled components. This atlas forms a foundation for the development of a multi-level molecular, cellular, anatomical, physiological, and behavioral brain atlas platform.

Genetic Causes of Microcephaly and Lessons for Neuronal Development

PubMed Central

Gilmore, Edward C.; Walsh, Christopher A.

2012-01-01

The study of human developmental microcephaly is providing important insights into brain development. It has become clear that developmental microcephalies are associated with abnormalities in cellular production, and that the pathophysiology of microcephaly provides remarkable insights into how the brain generates the proper number of neurons that determine brain size. Most of the genetic causes of ‘primary’ developmental microcephaly (i.e., not associated with other syndromic features) are associated with centrosomal abnormalities. In addition to other functions, centrosomal proteins control the mitotic spindle, which is essential for normal cell proliferation during mitosis. However, the brain is often uniquely affected when microcephaly genes are mutated implying special centrosomal related functions in neuronal production. Although models explaining how this could occur have some compelling data, they are not without controversy. Interestingly, some of the microcephaly genes show evidence that they were targets of evolutionary selection in primates and human ancestors, suggesting potential evolutionary roles in controlling neuronal number and brain volume across species. Mutations in DNA repair pathway genes also lead to microcephaly. Double stranded DNA breaks appear to be a prominent type of damage that needs to be repaired during brain development, yet why defects in DNA repair affect the brain preferentially and if DNA repair relates to centrosome function, are not clearly understood. PMID:24014418

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lowe, Xiu R; Bhattacharya, Sanchita; Marchetti, Francesco

Understanding the cognitive and behavioral consequences of brain exposures to low-dose ionizing radiation has broad relevance for health risks from medical radiation diagnostic procedures, radiotherapy, environmental nuclear contamination, as well as earth orbit and space missions. Analyses of transcriptome profiles of murine brain tissue after whole-body radiation showed that low-dose exposures (10 cGy) induced genes not affected by high dose (2 Gy), and low-dose genes were associated with unique pathways and functions. The low-dose response had two major components: pathways that are consistently seen across tissues, and pathways that were brain tissue specific. Low-dose genes clustered into a saturated networkmore » (p < 10{sup -53}) containing mostly down-regulated genes involving ion channels, long-term potentiation and depression, vascular damage, etc. We identified 9 neural signaling pathways that showed a high degree of concordance in their transcriptional response in mouse brain tissue after low-dose radiation, in the aging human brain (unirradiated), and in brain tissue from patients with Alzheimer's disease. Mice exposed to high-dose radiation did not show these effects and associations. Our findings indicate that the molecular response of the mouse brain within a few hours after low-dose irradiation involves the down-regulation of neural pathways associated with cognitive dysfunctions that are also down regulated in normal human aging and Alzheimer's disease.« less

The SRI24 multichannel brain atlas: construction and applications

NASA Astrophysics Data System (ADS)

Rohlfing, Torsten; Zahr, Natalie M.; Sullivan, Edith V.; Pfefferbaum, Adolf

2008-03-01

We present a new standard atlas of the human brain based on magnetic resonance images. The atlas was generated using unbiased population registration from high-resolution images obtained by multichannel-coil acquisition at 3T in a group of 24 normal subjects. The final atlas comprises three anatomical channels (T I-weighted, early and late spin echo), three diffusion-related channels (fractional anisotropy, mean diffusivity, diffusion-weighted image), and three tissue probability maps (CSF, gray matter, white matter). The atlas is dynamic in that it is implicitly represented by nonrigid transformations between the 24 subject images, as well as distortion-correction alignments between the image channels in each subject. The atlas can, therefore, be generated at essentially arbitrary image resolutions and orientations (e.g., AC/PC aligned), without compounding interpolation artifacts. We demonstrate in this paper two different applications of the atlas: (a) region definition by label propagation in a fiber tracking study is enabled by the increased sharpness of our atlas compared with other available atlases, and (b) spatial normalization is enabled by its average shape property. In summary, our atlas has unique features and will be made available to the scientific community as a resource and reference system for future imaging-based studies of the human brain.

A case report describing detection of Rhodoturola minuta fungemia in an ewe lamb

USDA-ARS?s Scientific Manuscript database

An eight-month-old crossbred ewe that was normal upon physical examination was humanely euthanized for tissue collection. Prior to euthanasia, whole blood was collected via jugular venipuncture into 60-ml syringes containing EDTA anticoagulant. After sacrifice, the brain was removed and the choroi...

Daily supplementation with mushroom (Agaricus bisporus) improves balance and working memory in aged rats

USDA-ARS?s Scientific Manuscript database

Animals and humans show decrements in motor control, cognition, and brain function during normal aging, partly due to the long-term effects of oxidative stress and inflammation. Recent studies have identified a number of fruits and vegetables, whose phytochemical make-up contains potent antioxidant ...

Dietary Precursors of Serotonin and Newborn State Behavior.

ERIC Educational Resources Information Center

Yogman, Michael W.; Zeisel, Steven

Although previous research with adult humans and nonhumans has suggested a relationship between sleep behavior and brain serotonin levels, no studies have been made of the relationship of normal children's or infants' sleep patterns to serotonin levels, tryptophan metabolism, or diet. This study investigates the relationship between dietary…

Abnormal brain chemistry in chronic back pain: an in vivo proton magnetic resonance spectroscopy study.

PubMed

Grachev, I D; Fredrickson, B E; Apkarian, A V

2000-12-15

The neurobiology of chronic pain, including chronic back pain, is unknown. Structural imaging studies of the spine cannot explain all cases of chronic back pain. Functional brain imaging studies indicate that the brain activation patterns are different between chronic pain patients and normal subjects, and the thalamus, and prefrontal and cingulate cortices are involved in some types of chronic pain. Animal models of chronic pain suggest abnormal spinal cord chemistry. Does chronic pain cause brain chemistry changes? We examined brain chemistry changes in patients with chronic back pain using in vivo single- voxel proton magnetic resonance spectroscopy ((1)H-MRS). In vivo (1)H-MRS was used to measure relative concentrations of N-acetyl aspartate, creatine, choline, glutamate, glutamine, gamma-aminobutyric acid, inositol, glucose and lactate in relation to the concentration of creatine. These measurements were performed in six brain regions of nine chronic low back pain patients and 11 normal volunteers. All chronic back pain subjects underwent clinical evaluation and perceptual measures of pain and anxiety. We show that chronic back pain alters the human brain chemistry. Reductions of N-acetyl aspartate and glucose were demonstrated in the dorsolateral prefrontal cortex. Cingulate, sensorimotor, and other brain regions showed no chemical concentration differences. In chronic back pain, the interrelationship between chemicals within and across brain regions was abnormal, and there was a specific relationship between regional chemicals and perceptual measures of pain and anxiety. These findings provide direct evidence of abnormal brain chemistry in chronic back pain, which may be useful in diagnosis and future development of more effective pharmacological treatments.

Logical Interactions in AN Expanded Space

NASA Astrophysics Data System (ADS)

Tadić, Bosiljka

Understanding the emergent behavior in many complex systems in the physical world and society requires a detailed study of dynamical phenomena occurring and mutually coupled at different scales. The brain processes underlying the social conduct of each, and the emergent social behavior of interacting individuals on a larger scale, represent striking examples of the multiscale complexity. Studies of the human brain, a paradigm of a complex functional system, are enabled by a wealth of brain imaging data that provide clues of how we comprehend space, time, languages, numbers, and differentiate normal from diseased individuals, for example. The social brain, a neural basis for social cognition, represents a dynamically organized part of the brain which is involved in the inference of thoughts, feelings, and intentions going on in the brains of others. Research in this currently unexplored area opens a new perspective on the genesis of the societal organization at different levels and the associated social values...

Language Impairments in ASD Resulting from a Failed Domestication of the Human Brain

PubMed Central

Benítez-Burraco, Antonio; Lattanzi, Wanda; Murphy, Elliot

2016-01-01

Autism spectrum disorders (ASD) are pervasive neurodevelopmental disorders entailing social and cognitive deficits, including marked problems with language. Numerous genes have been associated with ASD, but it is unclear how language deficits arise from gene mutation or dysregulation. It is also unclear why ASD shows such high prevalence within human populations. Interestingly, the emergence of a modern faculty of language has been hypothesized to be linked to changes in the human brain/skull, but also to the process of self-domestication of the human species. It is our intention to show that people with ASD exhibit less marked domesticated traits at the morphological, physiological, and behavioral levels. We also discuss many ASD candidates represented among the genes known to be involved in the “domestication syndrome” (the constellation of traits exhibited by domesticated mammals, which seemingly results from the hypofunction of the neural crest) and among the set of genes involved in language function closely connected to them. Moreover, many of these genes show altered expression profiles in the brain of autists. In addition, some candidates for domestication and language-readiness show the same expression profile in people with ASD and chimps in different brain areas involved in language processing. Similarities regarding the brain oscillatory behavior of these areas can be expected too. We conclude that ASD may represent an abnormal ontogenetic itinerary for the human faculty of language resulting in part from changes in genes important for the “domestication syndrome” and, ultimately, from the normal functioning of the neural crest. PMID:27621700

Comparison of 4'-[methyl-(11)C]thiothymidine ((11)C-4DST) and 3'-deoxy-3'-[(18)F]fluorothymidine ((18)F-FLT) PET/CT in human brain glioma imaging.

PubMed

Toyota, Yasunori; Miyake, Keisuke; Kawai, Nobuyuki; Hatakeyama, Tetsuhiro; Yamamoto, Yuka; Toyohara, Jun; Nishiyama, Yoshihiro; Tamiya, Takashi

2015-01-01

3'-deoxy-3'-[(18)F]fluorothymidine ((18)F-FLT) has been used to evaluate tumor malignancy and cell proliferation in human brain gliomas. However, (18)F-FLT has several limitations in clinical use. Recently, (11)C-labeled thymidine analogue, 4'-[methyl-(11)C]thiothymidine ((11)C-4DST), became available as an in vivo cell proliferation positron emission tomography (PET) tracer. The present study was conducted to evaluate the usefulness of (11)C-4DST PET in the diagnosis of human brain gliomas by comparing with the images of (18)F-FLT PET. Twenty patients with primary and recurrent brain gliomas underwent (18)F-FLT and (11)C-4DST PET scans. The uptake values in the tumors were evaluated using the maximum standardized uptake value (SUVmax), the tumor-to-normal tissue uptake (T/N) ratio, and the tumor-to-blood uptake (T/B) ratio. These values were compared among different glioma grades. Correlation between the Ki-67 labeling index and the uptake values of (11)C-4DST and (18)F-FLT in the tumor was evaluated using linear regression analysis. The relationship between the individual (18)F-FLT and (11)C-4DST uptake values in the tumors was also examined. (11)C-4DST uptake was significantly higher than that of (18)F-FLT in the normal brain. The uptake values of (11)C-4DST in the tumor were similar to those of (18)F-FLT resulting in better visualization with (18)F-FLT. No significant differences in the uptake values of (18)F-FLT and (11)C-4DST were noted among different glioma grades. Linear regression analysis showed a significant correlation between the Ki-67 labeling index and the T/N ratio of (11)C-4DST (r = 0.50, P < 0.05) and (18)F-FLT (r = 0.50, P < 0.05). Significant correlations were also found between the Ki-67 labeling index and the T/B ratio of (11)C-4DST (r = 0.52, P < 0.05) and (18)F-FLT (r = 0.55, P < 0.05). A highly significant correlation was observed between the individual T/N ratio of (11)C-4DST and (18)F-FLT in the tumor (r = 0.79, P = 0.0001). The present study demonstrates that (11)C-4DST is useful for the imaging of human brain gliomas with PET. A relatively higher background uptake of (11)C-4DST in the normal brain compared to (18)F-FLT limits the detection of low-tracer-uptake tumors. Moreover, no superiority was found in (11)C-4DST over (18)F-FLT in the evaluation of cell proliferation.

Signals that regulate the oncogenic fate of neural stem cells and progenitors

PubMed Central

Swartling, Fredrik J.; Bolin, Sara; Phillips, Joanna J.; Persson, Anders I.

2013-01-01

Brain tumors have frequently been associated with a neural stem cell (NSC) origin and contain stem-like tumor cells, so-called brain tumor stem cells (BTSCs) that share many features with normal NSCs. A stem cell state of BTSCs confers resistance to radiotherapy and treatment with alkylating agents. It is also a hallmark of aggressive brain tumors and is maintained by transcriptional networks that are also active in embryonic stem cells. Advances in reprogramming of somatic cells into induced pluripotent stem (iPS) cells have further identified genes that drive stemness. In this review, we will highlight the possible drivers of stemness in medulloblastoma and glioma, the most frequent types of primary malignant brain cancer in children and adults, respectively. Signals that drive expansion of developmentally defined neural precursor cells are also active in corresponding brain tumors. Transcriptomal subgroups of human medulloblastoma and glioma match features of NSCs but also more restricted progenitors. Lessons from genetically-engineered mouse (GEM) models show that temporally and regionally defined NSCs can give rise to distinct subgroups of medulloblastoma and glioma. We will further discuss how acquisition of stem cell features may drive brain tumorigenesis from a non-NSC origin. Genetic alterations, signaling pathways, and therapy-induced changes in the tumor microenvironment can drive reprogramming networks and induce stemness in brain tumors. Finally, we propose a model where dysregulation of microRNAs (miRNAs) that normally provide barriers against reprogramming plays an integral role in promoting stemness in brain tumors. PMID:23376224

Perturbation of Brain Oscillations after Ischemic Stroke: A Potential Biomarker for Post-Stroke Function and Therapy

PubMed Central

Rabiller, Gratianne; He, Ji-Wei; Nishijima, Yasuo; Wong, Aaron; Liu, Jialing

2015-01-01

Brain waves resonate from the generators of electrical current and propagate across brain regions with oscillation frequencies ranging from 0.05 to 500 Hz. The commonly observed oscillatory waves recorded by an electroencephalogram (EEG) in normal adult humans can be grouped into five main categories according to the frequency and amplitude, namely δ (1–4 Hz, 20–200 μV), θ (4–8 Hz, 10 μV), α (8–12 Hz, 20–200 μV), β (12–30 Hz, 5–10 μV), and γ (30–80 Hz, low amplitude). Emerging evidence from experimental and human studies suggests that groups of function and behavior seem to be specifically associated with the presence of each oscillation band, although the complex relationship between oscillation frequency and function, as well as the interaction between brain oscillations, are far from clear. Changes of brain oscillation patterns have long been implicated in the diseases of the central nervous system including ischemic stroke, in which the reduction of cerebral blood flow as well as the progression of tissue damage have direct spatiotemporal effects on the power of several oscillatory bands and their interactions. This review summarizes the current knowledge in behavior and function associated with each brain oscillation, and also in the specific changes in brain electrical activities that correspond to the molecular events and functional alterations observed after experimental and human stroke. We provide the basis of the generations of brain oscillations and potential cellular and molecular mechanisms underlying stroke-induced perturbation. We will also discuss the implications of using brain oscillation patterns as biomarkers for the prediction of stroke outcome and therapeutic efficacy. PMID:26516838

Cerebral ketone body metabolism.

PubMed

Morris, A A M

2005-01-01

Ketone bodies (KBs) are an important source of energy for the brain. During the neonatal period, they are also precursors for the synthesis of lipids (especially cholesterol) and amino acids. The rate of cerebral KB metabolism depends primarily on the concentration in blood; high concentrations occur during fasting and on a high-fat diet. Cerebral KB metabolism is also regulated by the permeability of the blood-brain barrier (BBB), which depends on the abundance of monocarboxylic acid transporters (MCT1). The BBB's permeability to KBs increases with fasting in humans. In rats, permeability increases during the suckling period, but human neonates have not been studied. Monocarboxylic acid transporters are also present in the plasma membranes of neurons and glia but their role in regulating KB metabolism is uncertain. Finally, the rate of cerebral KB metabolism depends on the activities of the relevant enzymes in brain. The activities vary with age in rats, but reliable results are not available for humans. Cerebral KB metabolism in humans differs from that in the rat in several respects. During fasting, for example, KBs supply more of the brain's energy in humans than in the rat. Conversely, KBs are probably used more extensively in the brain of suckling rats than in human neonates. These differences complicate the interpretation of rodent studies. Most patients with inborn errors of ketogenesis develop normally, suggesting that the only essential role for KBs is as an alternative fuel during illness or prolonged fasting. On the other hand, in HMG-CoA lyase deficiency, imaging generally shows asymptomatic white-matter abnormalities. The ability of KBs to act as an alternative fuel explains the effectiveness of the ketogenic diet in GLUT1 deficiency, but its effectiveness in epilepsy remains unexplained.

Evaluation of Raman spectra of human brain tumor tissue using the learning vector quantization neural network

NASA Astrophysics Data System (ADS)

Liu, Tuo; Chen, Changshui; Shi, Xingzhe; Liu, Chengyong

2016-05-01

The Raman spectra of tissue of 20 brain tumor patients was recorded using a confocal microlaser Raman spectroscope with 785 nm excitation in vitro. A total of 133 spectra were investigated. Spectra peaks from normal white matter tissue and tumor tissue were analyzed. Algorithms, such as principal component analysis, linear discriminant analysis, and the support vector machine, are commonly used to analyze spectral data. However, in this study, we employed the learning vector quantization (LVQ) neural network, which is typically used for pattern recognition. By applying the proposed method, a normal diagnosis accuracy of 85.7% and a glioma diagnosis accuracy of 89.5% were achieved. The LVQ neural network is a recent approach to excavating Raman spectra information. Moreover, it is fast and convenient, does not require the spectra peak counterpart, and achieves a relatively high accuracy. It can be used in brain tumor prognostics and in helping to optimize the cutting margins of gliomas.

The human brain and face: mechanisms of cranial, neurological and facial development revealed through malformations of holoprosencephaly, cyclopia and aberrations in chromosome 18

PubMed Central

Gondré-Lewis, Marjorie C; Gboluaje, Temitayo; Reid, Shaina N; Lin, Stephen; Wang, Paul; Green, William; Diogo, Rui; Fidélia-Lambert, Marie N; Herman, Mary M

2015-01-01

The study of inborn genetic errors can lend insight into mechanisms of normal human development and congenital malformations. Here, we present the first detailed comparison of cranial and neuro pathology in two exceedingly rare human individuals with cyclopia and alobar holoprosencephaly (HPE) in the presence and absence of aberrant chromosome 18 (aCh18). The aCh18 fetus contained one normal Ch18 and one with a pseudo-isodicentric duplication of chromosome 18q and partial deletion of 18p from 18p11.31 where the HPE gene, TGIF, resides, to the p terminus. In addition to synophthalmia, the aCh18 cyclopic malformations included a failure of induction of most of the telencephalon – closely approximating anencephaly, unchecked development of brain stem structures, near absence of the sphenoid bone and a malformed neurocranium and viscerocranium that constitute the median face. Although there was complete erasure of the olfactory and superior nasal structures, rudiments of nasal structures derived from the maxillary bone were evident, but with absent pharyngeal structures. The second non-aCh18 cyclopic fetus was initially classified as a true Cyclops, as it appeared to have a proboscis and one median eye with a single iris, but further analysis revealed two eye globes as expected for synophthalmic cyclopia. Furthermore, the proboscis was associated with the medial ethmoid ridge, consistent with an incomplete induction of these nasal structures, even as the nasal septum and paranasal sinuses were apparently developed. An important conclusion of this study is that it is the brain that predicts the overall configuration of the face, due to its influence on the development of surrounding skeletal structures. The present data using a combination of macroscopic, computed tomography (CT) and magnetic resonance imaging (MRI) techniques provide an unparalleled analysis on the extent of the effects of median defects, and insight into normal development and patterning of the brain, face and their skeletal support. PMID:26278930

The human brain and face: mechanisms of cranial, neurological and facial development revealed through malformations of holoprosencephaly, cyclopia and aberrations in chromosome 18.

PubMed

Gondré-Lewis, Marjorie C; Gboluaje, Temitayo; Reid, Shaina N; Lin, Stephen; Wang, Paul; Green, William; Diogo, Rui; Fidélia-Lambert, Marie N; Herman, Mary M

2015-09-01

The study of inborn genetic errors can lend insight into mechanisms of normal human development and congenital malformations. Here, we present the first detailed comparison of cranial and neuro pathology in two exceedingly rare human individuals with cyclopia and alobar holoprosencephaly (HPE) in the presence and absence of aberrant chromosome 18 (aCh18). The aCh18 fetus contained one normal Ch18 and one with a pseudo-isodicentric duplication of chromosome 18q and partial deletion of 18p from 18p11.31 where the HPE gene, TGIF, resides, to the p terminus. In addition to synophthalmia, the aCh18 cyclopic malformations included a failure of induction of most of the telencephalon - closely approximating anencephaly, unchecked development of brain stem structures, near absence of the sphenoid bone and a malformed neurocranium and viscerocranium that constitute the median face. Although there was complete erasure of the olfactory and superior nasal structures, rudiments of nasal structures derived from the maxillary bone were evident, but with absent pharyngeal structures. The second non-aCh18 cyclopic fetus was initially classified as a true Cyclops, as it appeared to have a proboscis and one median eye with a single iris, but further analysis revealed two eye globes as expected for synophthalmic cyclopia. Furthermore, the proboscis was associated with the medial ethmoid ridge, consistent with an incomplete induction of these nasal structures, even as the nasal septum and paranasal sinuses were apparently developed. An important conclusion of this study is that it is the brain that predicts the overall configuration of the face, due to its influence on the development of surrounding skeletal structures. The present data using a combination of macroscopic, computed tomography (CT) and magnetic resonance imaging (MRI) techniques provide an unparalleled analysis on the extent of the effects of median defects, and insight into normal development and patterning of the brain, face and their skeletal support. © 2015 Anatomical Society.

S100 B: A new concept in neurocritical care

PubMed Central

Rezaei, Omidvar; Pakdaman, Hossein; Gharehgozli, Kurosh; Simani, Leila; Vahedian-Azimi, Amir; Asaadi, Sina; Sahraei, Zahra; Hajiesmaeili, Mohammadreza

2017-01-01

After brain injuries, concentrations of some brain markers such as S100B protein in serum and cerebrospinal fluid (CSF) are correlated with the severity and outcome of brain damage. To perform an updated review of S100B roles in human neurocritical care domain, an electronic literature search was carried among articles published in English prior to March 2017. They were retrieved from PubMed, Scopus, EMBSCO, CINAHL, ISC and the Cochrane Library using keywords including “brain”, “neurobiochemical marker”, “neurocritical care”, and “S100B protein”. The integrative review included 48 studies until March 2017. S100B protein can be considered as a marker for blood brain barrier damage. The marker has an important role in the development and recovery of normal central nervous system (CNS) after injury. In addition to extra cerebral sources of S100B, the marker is principally built in the astroglial and Schwann cells. The neurobiochemical marker, S100B, has a pathognomonic role in the diagnosis of a broad spectrum of brain damage including traumatic brain injury (TBI), brain tumor, and stroke. Moreover, a potential predicting role for the neurobiochemical marker has been presumed in the efficiency of brain damage treatment and prognosis. However further animal and human studies are required before widespread routine clinical introduction of S100 protein. PMID:28761630

Half brain irradiation in a murine model of breast cancer brain metastasis: magnetic resonance imaging and histological assessments of dose-response.

PubMed

Zarghami, Niloufar; Murrell, Donna H; Jensen, Michael D; Dick, Frederick A; Chambers, Ann F; Foster, Paula J; Wong, Eugene

2018-06-01

Brain metastasis is becoming increasingly prevalent in breast cancer due to improved extra-cranial disease control. With emerging availability of modern image-guided radiation platforms, mouse models of brain metastases and small animal magnetic resonance imaging (MRI), we examined brain metastases' responses from radiotherapy in the pre-clinical setting. In this study, we employed half brain irradiation to reduce inter-subject variability in metastases dose-response evaluations. Half brain irradiation was performed on a micro-CT/RT system in a human breast cancer (MDA-MB-231-BR) brain metastasis mouse model. Radiation induced DNA double stranded breaks in tumors and normal mouse brain tissue were quantified using γ-H2AX immunohistochemistry at 30 min (acute) and 11 days (longitudinal) after half-brain treatment for doses of 8, 16 and 24 Gy. In addition, tumor responses were assessed volumetrically with in-vivo longitudinal MRI and histologically for tumor cell density and nuclear size. In the acute setting, γ-H2AX staining in tumors saturated at higher doses while normal mouse brain tissue continued to increase linearly in the phosphorylation of H2AX. While γ-H2AX fluorescence intensities returned to the background level in the brain 11 days after treatment, the residual γ-H2AX phosphorylation in the radiated tumors remained elevated compared to un-irradiated contralateral tumors. With radiation, MRI-derived relative tumor growth was significantly reduced compared to the un-irradiated side. While there was no difference in MRI tumor volume growth between 16 and 24 Gy, there was a significant reduction in tumor cell density from histology with increasing dose. In the longitudinal study, nuclear size in the residual tumor cells increased significantly as the radiation dose was increased. Radiation damages to the DNAs in the normal brain parenchyma are resolved over time, but remain unrepaired in the treated tumors. Furthermore, there is a radiation dose response in nuclear size of surviving tumor cells. Increase in nuclear size together with unrepaired DNA damage indicated that the surviving tumor cells post radiation had continued to progress in the cell cycle with DNA replication, but failed cytokinesis. Half brain irradiation provides efficient evaluation of dose-response for cancer cell lines, a pre-requisite to perform experiments to understand radio-resistance in brain metastases.

Expression of cellular prion protein in the frontal and occipital lobe in Alzheimer's disease, diffuse Lewy body disease, and in normal brain: an immunohistochemical study.

PubMed

Rezaie, Payam; Pontikis, Charlie C; Hudson, Lance; Cairns, Nigel J; Lantos, Peter L

2005-08-01

Cellular prion protein (PrP(c)) is a glycoprotein expressed at low to moderate levels within the nervous system. Recent studies suggest that PrP(c) may possess neuroprotective functions and that its expression is upregulated in certain neurodegenerative disorders. We investigated whether PrP(c) expression is altered in the frontal and occipital cortex in two well-characterized neurodegenerative disorders--Alzheimer's disease (AD) and diffuse Lewy body disease (DLBD)--compared with that in normal human brain using immunohistochemistry and computerized image analysis. The distribution of PrP(c) was further tested for correlation with glial reactivity. We found that PrP(c) was localized mainly in the gray matter (predominantly in neurons) and expressed at higher levels within the occipital cortex in the normal human brain. Image analysis revealed no significant variability in PrP(c) expression between DLBD and control cases. However, blood vessels within the white matter of DLBD cases showed immunoreactivity to PrP(c). By contrast, this protein was differentially expressed in the frontal and occipital cortex of AD cases; it was markedly overexpressed in the former and significantly reduced in the latter. Epitope specificity of antibodies appeared important when detecting PrP(c). The distribution of PrP(c) did not correlate with glial immunoreactivity. In conclusion, this study supports the proposal that regional changes in expression of PrP(c) may occur in certain neurodegenerative disorders such as AD, but not in other disorders such as DLBD.

Perineuronal satellite neuroglia in the telencephalon of New Caledonian crows and other Passeriformes: evidence of satellite glial cells in the central nervous system of healthy birds?

PubMed Central

Medina, Felipe S.; Hunt, Gavin R.; Gray, Russell D.; Wild, J. Martin

2013-01-01

Glia have been implicated in a variety of functions in the central nervous system, including the control of the neuronal extracellular space, synaptic plasticity and transmission, development and adult neurogenesis. Perineuronal glia forming groups around neurons are associated with both normal and pathological nervous tissue. Recent studies have linked reduction in the number of perineuronal oligodendrocytes in the prefrontal cortex with human schizophrenia and other psychiatric disorders. Therefore, perineuronal glia may play a decisive role in homeostasis and normal activity of the human nervous system. Here we report on the discovery of novel cell clusters in the telencephala of five healthy Passeriforme, one Psittaciform and one Charadriiforme bird species, which we refer to as Perineuronal Glial Clusters (PGCs). The aim of this study is to describe the structure and distribution of the PGCs in a number of avian species. PGCs were identified with the use of standard histological procedures. Heterochromatin masses visible inside the nuclei of these satellite glia suggest that they may correspond to oligodendrocytes. PGCs were found in the brains of nine New Caledonian crows, two Japanese jungle crows, two Australian magpies, two Indian mynah, three zebra finches (all Passeriformes), one Southern lapwing (Charadriiformes) and one monk parakeet (Psittaciformes). Microscopic survey of the brain tissue suggests that the largest PGCs are located in the hyperpallium densocellulare and mesopallium. No clusters were found in brain sections from one Gruiform (purple swamphen), one Strigiform (barn owl), one Trochiliform (green-backed firecrown), one Falconiform (chimango caracara), one Columbiform (pigeon) and one Galliform (chick). Our observations suggest that PGCs in Aves are brain region- and taxon-specific and that the presence of perineuronal glia in healthy human brains and the similar PGCs in avian gray matter is the result of convergent evolution. The discovery of PGCs in the zebra finch is of great importance because this species has the potential to become a robust animal model in which to study the function of neuron-glia interactions in healthy and diseased adult brains. PMID:23904989

The cysteine protease inhibitor, E64d, reduces brain amyloid-β and improves memory deficits in Alzheimer’s disease animal models by inhibiting cathepsin B, but not BACE1, β-secretase activity

PubMed Central

Hook, Gregory; Hook, Vivian; Kindy, Mark

2015-01-01

The cysteine protease cathepsin B is a potential drug target for reducing brain amyloid-β peptides (Aβ) and improving memory in Alzheimer’s disease (AD), because reduction of cathepsin B in transgenic mice expressing human wild-type amyloid-β protein precursor (AβPP) results in significantly decreased brain Aβ. Cathepsin B cleaves the wild-type β-secretase site sequence in AβPP to produce Aβ and cathepsin B inhibitors administered to animal models expressing AβPP containing the wild-type β-secretase site sequence reduce brain Aβ in a manner consistent with β-secretase inhibition. But such inhibitors could act either by direct inhibition of cathepsin B β-secretase activity or by off-target inhibition of the other β-secretase, the aspartyl protease BACE1. To evaluate that issue, we orally administered a cysteine protease inhibitor, E64d, to normal guinea pigs or transgenic mice expressing human AβPP, both of which express the human wild-type β-secretase site sequence. In guinea pigs, oral E64d administration caused a dose-dependent reduction of up to 92% in brain, CSF and plasma of Aβ(40) and Aβ(42), a reduction of up to 50% in the C-terminal β-secretase fragment (CTFβ), and a 91% reduction in brain cathepsin B activity but increased brain BACE1 activity by 20%. In transgenic AD mice, oral E64d administration improved memory deficits and reduced brain Aβ(40) and Aβ(42), amyloid plaque, brain CTFβ, and brain cathepsin B activity but increased brain BACE1 activity. We conclude that E64d likely reduces brain Aβ by inhibiting cathepsin B and not BACE1 β-secretase activity and that E64d therefore may have potential for treating AD patients. PMID:21613740

Data-driven identification of intensity normalization region based on longitudinal coherency of 18F-FDG metabolism in the healthy brain.

PubMed

Zhang, Huiwei; Wu, Ping; Ziegler, Sibylle I; Guan, Yihui; Wang, Yuetao; Ge, Jingjie; Schwaiger, Markus; Huang, Sung-Cheng; Zuo, Chuantao; Förster, Stefan; Shi, Kuangyu

2017-02-01

In brain 18 F-FDG PET data intensity normalization is usually applied to control for unwanted factors confounding brain metabolism. However, it can be difficult to determine a proper intensity normalization region as a reference for the identification of abnormal metabolism in diseased brains. In neurodegenerative disorders, differentiating disease-related changes in brain metabolism from age-associated natural changes remains challenging. This study proposes a new data-driven method to identify proper intensity normalization regions in order to improve separation of age-associated natural changes from disease related changes in brain metabolism. 127 female and 128 male healthy subjects (age: 20 to 79) with brain 18 F-FDG PET/CT in the course of a whole body cancer screening were included. Brain PET images were processed using SPM8 and were parcellated into 116 anatomical regions according to the AAL template. It is assumed that normal brain 18 F-FDG metabolism has longitudinal coherency and this coherency leads to better model fitting. The coefficient of determination R 2 was proposed as the coherence coefficient, and the total coherence coefficient (overall fitting quality) was employed as an index to assess proper intensity normalization strategies on single subjects and age-cohort averaged data. Age-associated longitudinal changes of normal subjects were derived using the identified intensity normalization method correspondingly. In addition, 15 subjects with clinically diagnosed Parkinson's disease were assessed to evaluate the clinical potential of the proposed new method. Intensity normalizations by paracentral lobule and cerebellar tonsil, both regions derived from the new data-driven coherency method, showed significantly better coherence coefficients than other intensity normalization regions, and especially better than the most widely used global mean normalization. Intensity normalization by paracentral lobule was the most consistent method within both analysis strategies (subject-based and age-cohort averaging). In addition, the proposed new intensity normalization method using the paracentral lobule generates significantly higher differentiation from the age-associated changes than other intensity normalization methods. Proper intensity normalization can enhance the longitudinal coherency of normal brain glucose metabolism. The paracentral lobule followed by the cerebellar tonsil are shown to be the two most stable intensity normalization regions concerning age-dependent brain metabolism. This may provide the potential to better differentiate disease-related changes from age-related changes in brain metabolism, which is of relevance in the diagnosis of neurodegenerative disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

Hypertonic Lactate to Improve Cerebral Perfusion and Glucose Availability After Acute Brain Injury.

PubMed

Carteron, Laurent; Solari, Daria; Patet, Camille; Quintard, Hervé; Miroz, John-Paul; Bloch, Jocelyne; Daniel, Roy T; Hirt, Lorenz; Eckert, Philippe; Magistretti, Pierre J; Oddo, Mauro

2018-06-19

Lactate promotes cerebral blood flow and is an efficient substrate for the brain, particularly at times of glucose shortage. Hypertonic lactate is neuroprotective after experimental brain injury; however, human data are limited. Prospective study (clinicaltrials.gov NCT01573507). Academic ICU. Twenty-three brain-injured subjects (13 traumatic brain injury/10 subarachnoid hemorrhage; median age, 59 yr [41-65 yr]; median Glasgow Coma Scale, 6 [3-7]). Three-hour IV infusion of hypertonic lactate (sodium lactate, 1,000 mmol/L; concentration, 30 µmol/kg/min) administered 39 hours (26-49 hr) from injury. We examined the effect of hypertonic lactate on cerebral perfusion (using transcranial Doppler) and brain energy metabolism (using cerebral microdialysis). The majority of subjects (13/23 = 57%) had reduced brain glucose availability (baseline pretreatment cerebral microdialysis glucose, < 1 mmol/L) despite normal baseline intracranial pressure (10 [7-15] mm Hg). Hypertonic lactate was associated with increased cerebral microdialysis lactate (+55% [31-80%]) that was paralleled by an increase in middle cerebral artery mean cerebral blood flow velocities (+36% [21-66%]) and a decrease in pulsatility index (-21% [13-26%]; all p < 0.001). Cerebral microdialysis glucose increased above normal range during hypertonic lactate (+42% [30-78%]; p < 0.05); reduced brain glucose availability correlated with a greater improvement of cerebral microdialysis glucose (Spearman r = -0.53; p = 0.009). No significant changes in cerebral perfusion pressure, mean arterial pressure, systemic carbon dioxide, and blood glucose were observed during hypertonic lactate (all p > 0.1). This is the first clinical demonstration that hypertonic lactate resuscitation improves both cerebral perfusion and brain glucose availability after brain injury. These cerebral vascular and metabolic effects appeared related to brain lactate supplementation rather than to systemic effects.

Computational Modeling of Resting-State Activity Demonstrates Markers of Normalcy in Children with Prenatal or Perinatal Stroke

PubMed Central

Raja Beharelle, Anjali; Griffa, Alessandra; Hagmann, Patric; Solodkin, Ana; McIntosh, Anthony R.; Small, Steven L.; Deco, Gustavo

2015-01-01

Children who sustain a prenatal or perinatal brain injury in the form of a stroke develop remarkably normal cognitive functions in certain areas, with a particular strength in language skills. A dominant explanation for this is that brain regions from the contralesional hemisphere “take over” their functions, whereas the damaged areas and other ipsilesional regions play much less of a role. However, it is difficult to tease apart whether changes in neural activity after early brain injury are due to damage caused by the lesion or by processes related to postinjury reorganization. We sought to differentiate between these two causes by investigating the functional connectivity (FC) of brain areas during the resting state in human children with early brain injury using a computational model. We simulated a large-scale network consisting of realistic models of local brain areas coupled through anatomical connectivity information of healthy and injured participants. We then compared the resulting simulated FC values of healthy and injured participants with the empirical ones. We found that the empirical connectivity values, especially of the damaged areas, correlated better with simulated values of a healthy brain than those of an injured brain. This result indicates that the structural damage caused by an early brain injury is unlikely to have an adverse and sustained impact on the functional connections, albeit during the resting state, of damaged areas. Therefore, these areas could continue to play a role in the development of near-normal function in certain domains such as language in these children. PMID:26063923

Raman spectroscopy for diagnosis of glioblastoma multiforme

NASA Astrophysics Data System (ADS)

Clary, Candace Elise

Glioblastoma multiforme (GBM), the most common and most fatal malignant brain tumor, is highly infiltrative and incurable. Although improved prognosis has been demonstrated by surgically resecting the bulk tumor, a lack of clear borders at the tumor margins complicates the selection decision during surgery. This dissertation investigates the potential of Raman spectroscopy for distinguishing between normal and malignant brain tissue and sets the groundwork for a surgical diagnostic guide for resection of gross malignant gliomas. These studies revealed that Raman spectroscopy was capable of discriminating between normal scid mouse brain tissue and human xenograft tumors induced in those mice. The spectra of normal and malignant tissue were normalized by dividing by the respective magnitudes of the peaks near 1440 cm -1. Spectral differences include the shape of the broad peaks near 1440 cm-1 and 1660 cm-1 and the relative magnitudes of the peaks at 1264 cm-1, 1287 cm-1, 1297 cm-1, 1556 cm -1, 1586 cm-1, 1614 cm-1, and 1683 cm-1. From these studies emerged questions regarding how to objectively normalize and compare spectra for future automation. Some differences in the Raman spectra were shown to be inherent in the disease states of the cells themselves via differences in the Raman spectra of normal human astrocytes in culture and cultured cells derived from GBM tumors. The spectra of astrocytes and glioma cells were normalized by dividing by the respective magnitudes of the peaks near 1450 cm-1. The differences between the Raman spectra of normal and transformed cells include the ratio of the 1450 cm-1/1650 cm-1 peaks and the relative magnitudes of the peaks at 1181 cm-1, 1191 cm-1, 1225 cm-1, 1263 cm -1, 1300 cm-1, 1336 cm-1, 1477 cm-1, 1494 cm-1, and 1695 cm -1. Previous Raman spectroscopic studies of biological cells have shown that the magnitude of the Raman signal decreases over time, indicating sample damage. Cells exposed to laser excitation at similar power densities were evaluated in terms of mitochondrial oxidative/reductive activity as well as protein, RNA, and DNA syntheses. Although cell death was not significant, the cells' abilities to synthesize DNA, RNA, and protein were profoundly affected by the laser irradiation.

Analysis of dual tree M-band wavelet transform based features for brain image classification.

PubMed

Ayalapogu, Ratna Raju; Pabboju, Suresh; Ramisetty, Rajeswara Rao

2018-04-29

The most complex organ in the human body is the brain. The unrestrained growth of cells in the brain is called a brain tumor. The cause of a brain tumor is still unknown and the survival rate is lower than other types of cancers. Hence, early detection is very important for proper treatment. In this study, an efficient computer-aided diagnosis (CAD) system is presented for brain image classification by analyzing MRI of the brain. At first, the MRI brain images of normal and abnormal categories are modeled by using the statistical features of dual tree m-band wavelet transform (DTMBWT). A maximum margin classifier, support vector machine (SVM) is then used for the classification and validated with k-fold approach. Results show that the system provides promising results on a repository of molecular brain neoplasia data (REMBRANDT) with 97.5% accuracy using 4 th level statistical features of DTMBWT. Viewing the experimental results, we conclude that the system gives a satisfactory performance for the brain image classification. © 2018 International Society for Magnetic Resonance in Medicine.

Brain Stimulation in Addiction

PubMed Central

Salling, Michael C; Martinez, Diana

2016-01-01

Localized stimulation of the human brain to treat neuropsychiatric disorders has been in place for over 20 years. Although these methods have been used to a greater extent for mood and movement disorders, recent work has explored brain stimulation methods as potential treatments for addiction. The rationale behind stimulation therapy in addiction involves reestablishing normal brain function in target regions in an effort to dampen addictive behaviors. In this review, we present the rationale and studies investigating brain stimulation in addiction, including transcranial magnetic stimulation, transcranial direct current stimulation, and deep brain stimulation. Overall, these studies indicate that brain stimulation has an acute effect on craving for drugs and alcohol, but few studies have investigated the effect of brain stimulation on actual drug and alcohol use or relapse. Stimulation therapies may achieve their effect through direct or indirect modulation of brain regions involved in addiction, either acutely or through plastic changes in neuronal transmission. Although these mechanisms are not well understood, further identification of the underlying neurobiology of addiction and rigorous evaluation of brain stimulation methods has the potential for unlocking an effective, long-term treatment of addiction. PMID:27240657

Monoamine oxidase: Radiotracer chemistry and human studies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fowler, Joanna S.; Logan, Jean; Shumay, Elena

Monoamine oxidase (MAO) oxidizes amines from both endogenous and exogenous sources thereby regulating the concentration of neurotransmitter amines such as serot onin, norepinephrine and dopamine as well as many xenobiotics. MAO inhibitor drugs are used in the treatment of Parkinson’s disease and in depression stimulating the development of radiotracer tools to probe the role of MAO in normal human biology and in disease. Over the past 30 since the first radiotracers were developed and the first PET images of MAO in humans were carried out, PET studies of brain MAO in healthy volunteers and in patients have identified different variablesmore » which have contributed to different MAO levels in brain and in peripheral organs. MAO radiotracers and PET have also been used to study the current and developing MAO inhibitor drugs including the selection of doses for clinical trials. In this article, we describe (1) the development of MAO radiotracers; (2) human studies including the relationship of brain MAO levels to genotype, personality, neurological and psychiatric disorders; (3) examples of the use of MAO radiotracers in drug research and development. We will conclude with outstanding needs to improve the radiotracers which are currently used and possible new applications.« less

Monoamine oxidase: Radiotracer chemistry and human studies

DOE PAGES

Fowler, Joanna S.; Logan, Jean; Shumay, Elena; ...

2015-03-01

Monoamine oxidase (MAO) oxidizes amines from both endogenous and exogenous sources thereby regulating the concentration of neurotransmitter amines such as serot onin, norepinephrine and dopamine as well as many xenobiotics. MAO inhibitor drugs are used in the treatment of Parkinson’s disease and in depression stimulating the development of radiotracer tools to probe the role of MAO in normal human biology and in disease. Over the past 30 since the first radiotracers were developed and the first PET images of MAO in humans were carried out, PET studies of brain MAO in healthy volunteers and in patients have identified different variablesmore » which have contributed to different MAO levels in brain and in peripheral organs. MAO radiotracers and PET have also been used to study the current and developing MAO inhibitor drugs including the selection of doses for clinical trials. In this article, we describe (1) the development of MAO radiotracers; (2) human studies including the relationship of brain MAO levels to genotype, personality, neurological and psychiatric disorders; (3) examples of the use of MAO radiotracers in drug research and development. We will conclude with outstanding needs to improve the radiotracers which are currently used and possible new applications.« less

Magnetic resonance spectroscopy of the human brain.

PubMed

Ross, B; Bluml, S

2001-04-01

Magnetic resonance (MR; synonymous with NMR = nuclear magnetic resonance) is a universal physical technique best known for non-invasive detection and anatomical mapping of water protons (H). MR-spectroscopy (MRS) records protons from tissue chemicals other than water, intrinsic phosphorus containing metabolites, sodium, potassium, carbon, nitrogen, and fluorine. MRS is therefore an imaging technique with the potential to record human and animal biochemistry in vivo. As a result of wide availability of MRI equipment in research laboratories and hospitals, MRS is a serious competitor with PET to define normal body composition and its perturbation by pharmacological and pathological events. This article describes practical aspects of in vivo MRS with particular emphasis on the brain, where novel metabolites have been described. A survey of these new aspects of neurochemistry emphasize their practical utility as neuronal and axonal markers, measures of energy status, membrane constituents, and osmolytes, as well as some xenobiotics, such as alcohol. The concept of multinuclear in vivo MRS is illustrated by diagnosis and therapeutic monitoring of several human brain disorders. Although these methods are currently most frequently encountered in human studies, as well as with transgenic and knockout mouse models, MRS adds a new dimension to anatomic and histopathologic descriptions. Copyright 2001 Wiley-Liss, Inc.

The Whole-Brain “Global” Signal from Resting State fMRI as a Potential Biomarker of Quantitative State Changes in Glucose Metabolism

PubMed Central

Thompson, Garth J.; Grimmer, Timo; Drzezga, Alexander; Herman, Peter

2016-01-01

Abstract The evolution of functional magnetic resonance imaging to resting state (R-fMRI) allows measurement of changes in brain networks attributed to state changes, such as in neuropsychiatric diseases versus healthy controls. Since these networks are observed by comparing normalized R-fMRI signals, it is difficult to determine the metabolic basis of such group differences. To investigate the metabolic basis of R-fMRI network differences within a normal range, eyes open versus eyes closed in healthy human subjects was used. R-fMRI was recorded simultaneously with fluoro-deoxyglucose positron emission tomography (FDG-PET). Higher baseline FDG was observed in the eyes open state. Variance-based metrics calculated from R-fMRI did not match the baseline shift in FDG. Functional connectivity density (FCD)-based metrics showed a shift similar to the baseline shift of FDG, however, this was lost if R-fMRI “nuisance signals” were regressed before FCD calculation. Average correlation with the mean R-fMRI signal across the whole brain, generally regarded as a “nuisance signal,” also showed a shift similar to the baseline of FDG. Thus, despite lacking a baseline itself, changes in whole-brain correlation may reflect changes in baseline brain metabolism. Conversely, variance-based metrics may remain similar between states due to inherent region-to-region differences overwhelming the differences between normal physiological states. As most previous studies have excluded the spatial means of R-fMRI metrics from their analysis, this work presents the first evidence of a potential R-fMRI biomarker for baseline shifts in quantifiable metabolism between brain states. PMID:27029438

The Whole-Brain "Global" Signal from Resting State fMRI as a Potential Biomarker of Quantitative State Changes in Glucose Metabolism.

PubMed

Thompson, Garth J; Riedl, Valentin; Grimmer, Timo; Drzezga, Alexander; Herman, Peter; Hyder, Fahmeed

2016-07-01

The evolution of functional magnetic resonance imaging to resting state (R-fMRI) allows measurement of changes in brain networks attributed to state changes, such as in neuropsychiatric diseases versus healthy controls. Since these networks are observed by comparing normalized R-fMRI signals, it is difficult to determine the metabolic basis of such group differences. To investigate the metabolic basis of R-fMRI network differences within a normal range, eyes open versus eyes closed in healthy human subjects was used. R-fMRI was recorded simultaneously with fluoro-deoxyglucose positron emission tomography (FDG-PET). Higher baseline FDG was observed in the eyes open state. Variance-based metrics calculated from R-fMRI did not match the baseline shift in FDG. Functional connectivity density (FCD)-based metrics showed a shift similar to the baseline shift of FDG, however, this was lost if R-fMRI "nuisance signals" were regressed before FCD calculation. Average correlation with the mean R-fMRI signal across the whole brain, generally regarded as a "nuisance signal," also showed a shift similar to the baseline of FDG. Thus, despite lacking a baseline itself, changes in whole-brain correlation may reflect changes in baseline brain metabolism. Conversely, variance-based metrics may remain similar between states due to inherent region-to-region differences overwhelming the differences between normal physiological states. As most previous studies have excluded the spatial means of R-fMRI metrics from their analysis, this work presents the first evidence of a potential R-fMRI biomarker for baseline shifts in quantifiable metabolism between brain states.

Thalamic Massa Intermedia Duplication in a Dysmorphic 14 month-old Toddler.

PubMed

Whitehead, Matthew T

2015-06-01

The massa intermedia is an inconstant parenchymal band connecting the medial thalami. It may be thickened in various disease processes such as Chiari II malformation or absent in other disease states. However, the massa intermedia may also be absent in up to 30% of normal human brains. To the best of my knowledge, detailed imaging findings of massa intermedia duplication have only been described in a single case report. An additional case of thalamic massa intermedia duplication discovered on a routine brain MR performed for dysmorphic facial features is reported herein.

No-carrier-added (18F)-N-methylspiroperidol

DOEpatents

Shiue, Chyng-Yann; Fowler, Joanna S.; Wolf, Alfred P.

1993-01-01

There is disclosed a radioligand labeled with a positron emitting radionuclide suitable for dynamic study in living humans with positron emission transaxial tomography. [.sup.18 F]-N-methylspiroperidol, exhibiting extremely high affinity for the dopamine receptors, provides enhanced uptake and retention in the brain concomitant with reduced radiation burden. These characteristics all combine to provide [.sup.18 F]-N-methylspiroperidol as a radioligand superior to known radioligands for mapping dopamine receptors in normal and disease states in the living brain. Additionally, a new synthetic procedure for this material is disclosed.

No-carrier-added (18F)-N-methylspiroperidol

DOEpatents

Shiue, Chyng-Yann; Fowler, Joanna S.; Wolf, Alfred P.

1993-07-06

There is disclosed a radioligand labeled with a positron emitting radionuclide suitable for dynamic study in living humans with positron emission transaxial tomography. [.sup.18 F]-N-methylspiroperidol, exhibiting extremely high affinity for the dopamine receptors, provides enhanced uptake and retention in the brain concomitant with reduced radiation burden. These characteristics all combine to provide [.sup.18 F]-N-methylspiroperidol as a radioligand superior to known radioligands for mapping dopamine receptors in normal and disease states in the living brain. Additionally, a new synthetic procedure for this material is disclosed.

A novel behavioral paradigm for assessing concept of nests in mice

PubMed Central

Kuang, Hui; Mei, Bing; Cui, Zhenzhong; Lin, Longnian; Tsien, Joe Z.

2013-01-01

Abstract concepts in the brain enable humans to efficiently and correctly recognize and categorize a seemingly infinite amount of objects and daily events. Such abstract generalization abilities are traditionally considered to be unique to humans and perhaps non-human primates. However, emerging neurophysiological recordings indicate the existence of neural correlates for the abstract concept of nests in the mouse brain. To facilitate the molecular and genetic analyses of concepts in the mouse model, we have developed a nest generalization test based on mice’s natural behavior. We show that inducible and forebrain-specific NMDA receptor knockout results in pronounced impairment in this test. Interestingly, this generalization deficit could be gradually compensated for over time by repeated experiences even in face of the continued deficit in object recognition memory. On the contrast, the forebrain-specific presenilin-1 knockout mice, which have subtle phenotypes, were normal in performing this test. Therefore, our study not only establishes a quantitative method for assessing the nest concept in mice, but also demonstrates its great potential in combining powerful mouse genetics for dissecting the molecular basis of concept formation in the brain. PMID:20350568

Aluminum interaction with human brain tau protein phosphorylation by various kinases

DOE Office of Scientific and Technical Information (OSTI.GOV)

El-Sebae; Abou Zeid, M.M.; Saleh, M.A.

1993-01-01

Phosphorylation is an indispensable process for energy and signal transduction in biological systems. AlCl[sub 3] at 10 nM to 10 [mu]M range activated in-vitro [[gamma][sup [minus]32]P]ATP phosphorylation of the brain ([tau]) [Gamma] protein in both normal human or E.coli expressed [Gamma] forms; in the presence of the kinases P34,PKP, and PKC. However, higher concentrations of AlCl[sub 3] inhibited the [Gamma] phosphorylation with P34, PKP, and PKC to a maximum at 1 mM level. AlCl[sub 3] at 100 [mu]M to 500 [mu]M range induced non-enzymatic phosphorylation of [Gamma] with [gamma]-ATP, [gamma]-GTP, and [alpha]-GRP. AlCl[sub 3] activated histone phosphorylation by P34 inmore » a similar pattern. The hyperphosphorylation of [Gamma] by Al[sup 3+] was accompanied in molecular shift and mobility retardation in SDS-PAGE. This may demonstrate the mechanism of the long term neurological effect of Al[sub 3+] in human brain leading to the formation of the neutrofibrillary tangles related to Alzeheimer's disease.« less

Activated forms of astrocytes with higher GLT-1 expression are associated with cognitive normal subjects with Alzheimer pathology in human brain.

PubMed

Kobayashi, Eiji; Nakano, Masako; Kubota, Kenta; Himuro, Nobuaki; Mizoguchi, Shougo; Chikenji, Takako; Otani, Miho; Mizue, Yuka; Nagaishi, Kanna; Fujimiya, Mineko

2018-01-26

Although the cognitive impairment in Alzheimer's disease (AD) is believed to be caused by amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs), several postmortem studies have reported cognitive normal subjects with AD brain pathology. As the mechanism underlying these discrepancies has not been clarified, we focused the neuroprotective role of astrocytes. After examining 47 donated brains, we classified brains into 3 groups, no AD pathology with no dementia (N-N), AD pathology with no dementia (AD-N), and AD pathology with dementia (AD-D), which represented 41%, 21%, and 38% of brains, respectively. No differences were found in the accumulation of Aβ plaques or NFTs in the entorhinal cortex (EC) between AD-N and AD-D. Number of neurons and synaptic density were increased in AD-N compared to those in AD-D. The astrocytes in AD-N possessed longer or thicker processes, while those in AD-D possessed shorter or thinner processes in layer I/II of the EC. Astrocytes in all layers of the EC in AD-N showed enhanced GLT-1 expression in comparison to those in AD-D. Therefore these activated forms of astrocytes with increased GLT-1 expression may exert beneficial roles in preserving cognitive function, even in the presence of Aβ and NFTs.

Regional gray matter growth, sexual dimorphism, and cerebral asymmetry in the neonatal brain.

PubMed

Gilmore, John H; Lin, Weili; Prastawa, Marcel W; Looney, Christopher B; Vetsa, Y Sampath K; Knickmeyer, Rebecca C; Evans, Dianne D; Smith, J Keith; Hamer, Robert M; Lieberman, Jeffrey A; Gerig, Guido

2007-02-07

Although there has been recent interest in the study of childhood and adolescent brain development, very little is known about normal brain development in the first few months of life. In older children, there are regional differences in cortical gray matter development, whereas cortical gray and white matter growth after birth has not been studied to a great extent. The adult human brain is also characterized by cerebral asymmetries and sexual dimorphisms, although very little is known about how these asymmetries and dimorphisms develop. We used magnetic resonance imaging and an automatic segmentation methodology to study brain structure in 74 neonates in the first few weeks after birth. We found robust cortical gray matter growth compared with white matter growth, with occipital regions growing much faster than prefrontal regions. Sexual dimorphism is present at birth, with males having larger total brain cortical gray and white matter volumes than females. In contrast to adults and older children, the left hemisphere is larger than the right hemisphere, and the normal pattern of fronto-occipital asymmetry described in older children and adults is not present. Regional differences in cortical gray matter growth are likely related to differential maturation of sensory and motor systems compared with prefrontal executive function after birth. These findings also indicate that whereas some adult patterns of sexual dimorphism and cerebral asymmetries are present at birth, others develop after birth.

Multimodality Instrument for Tissue Characterization

NASA Technical Reports Server (NTRS)

Mah, Robert W. (Inventor); Andrews, Russell J. (Inventor)

2000-01-01

A system with multimodality instrument for tissue identification includes a computer-controlled motor driven heuristic probe with a multisensory tip is discussed. For neurosurgical applications, the instrument is mounted on a stereotactic frame for the probe to penetrate the brain in a precisely controlled fashion. The resistance of the brain tissue being penetrated is continually monitored by a miniaturized strain gauge attached to the probe tip. Other modality sensors may be mounted near the probe tip to provide real-time tissue characterizations and the ability to detect the proximity of blood vessels, thus eliminating errors normally associated with registration of pre-operative scans, tissue swelling, elastic tissue deformation, human judgement, etc., and rendering surgical procedures safer, more accurate, and efficient. A neural network, program adaptively learns the information on resistance and other characteristic features of normal brain tissue during the surgery and provides near real-time modeling. A fuzzy logic interface to the neural network program incorporates expert medical knowledge in the learning process. Identification of abnormal brain tissue is determined by the detection of change and comparison with previously learned models of abnormal brain tissues. The operation of the instrument is controlled through a user friendly graphical interface. Patient data is presented in a 3D stereographics display. Acoustic feedback of selected information may optionally be provided. Upon detection of the close proximity to blood vessels or abnormal brain tissue, the computer-controlled motor immediately stops probe penetration.

The Reorganization of Human Brain Networks Modulated by Driving Mental Fatigue.

PubMed

Chunlin Zhao; Min Zhao; Yong Yang; Junfeng Gao; Nini Rao; Pan Lin

2017-05-01

The organization of the brain functional network is associated with mental fatigue, but little is known about the brain network topology that is modulated by the mental fatigue. In this study, we used the graph theory approach to investigate reconfiguration changes in functional networks of different electroen-cephalography (EEG) bands from 16 subjects performing a simulated driving task. Behavior and brain functional networks were compared between the normal and driving mental fatigue states. The scores of subjective self-reports indicated that 90 min of simulated driving-induced mental fatigue. We observed that coherence was significantly increased in the frontal, central, and temporal brain regions. Furthermore, in the brain network topology metric, significant increases were observed in the clustering coefficient (Cp) for beta, alpha, and delta bands and the character path length (Lp) for all EEG bands. The normalized measures γ showed significant increases in beta, alpha, and delta bands, and λ showed similar patterns in beta and theta bands. These results indicate that functional network topology can shift the network topology structure toward a more economic but less efficient configuration, which suggests low wiring costs in functional networks and disruption of the effective interactions between and across cortical regions during mental fatigue states. Graph theory analysis might be a useful tool for further understanding the neural mechanisms of driving mental fatigue.

Human brain cancer studied by resonance Raman spectroscopy

NASA Astrophysics Data System (ADS)

Zhou, Yan; Liu, Cheng-Hui; Sun, Yi; Pu, Yang; Boydston-White, Susie; Liu, Yulong; Alfano, Robert R.

2012-11-01

The resonance Raman (RR) spectra of six types of human brain tissues are examined using a confocal micro-Raman system with 532-nm excitation in vitro. Forty-three RR spectra from seven subjects are investigated. The spectral peaks from malignant meningioma, stage III (cancer), benign meningioma (benign), normal meningeal tissues (normal), glioblastoma multiforme grade IV (cancer), acoustic neuroma (benign), and pituitary adenoma (benign) are analyzed. Using a 532-nm excitation, the resonance-enhanced peak at 1548 cm-1 (amide II) is observed in all of the tissue specimens, but is not observed in the spectra collected using the nonresonance Raman system. An increase in the intensity ratio of 1587 to 1605 cm-1 is observed in the RR spectra collected from meningeal cancer tissue as compared with the spectra collected from the benign and normal meningeal tissue. The peak around 1732 cm-1 attributed to fatty acids (lipids) are diminished in the spectra collected from the meningeal cancer tumors as compared with the spectra from normal and benign tissues. The characteristic band of spectral peaks observed between 2800 and 3100 cm-1 are attributed to the vibrations of methyl (-CH3) and methylene (-CH2-) groups. The ratio of the intensities of the spectral peaks of 2935 to 2880 cm-1 from the meningeal cancer tissues is found to be lower in comparison with that of the spectral peaks from normal, and benign tissues, which may be used as a distinct marker for distinguishing cancerous tissues from normal meningeal tissues. The statistical methods of principal component analysis and the support vector machine are used to analyze the RR spectral data collected from meningeal tissues, yielding a diagnostic sensitivity of 90.9% and specificity of 100% when two principal components are used.

Neuroprotection: Lessons from hibernators

PubMed Central

Dave, Kunjan R.; Christian, Sherri L.; Perez-Pinzon, Miguel A.; Drew, Kelly L.

2012-01-01

Mammals that hibernate experience extreme metabolic states and body temperatures as they transition between euthermia, a state resembling typical warm blooded mammals, and prolonged torpor, a state of suspended animation where the brain receives as low as 10% of normal cerebral blood flow. Transitions into and out of torpor are more physiologically challenging than the extreme metabolic suppression and cold body temperatures of torpor per se. Mammals that hibernate show unprecedented capacities to tolerate cerebral ischemia, a decrease in blood flow to the brain caused by stroke, cardiac arrest or brain trauma. While cerebral ischemia often leads to death or disability in humans and most other mammals, hibernating mammals suffer no ill effects when blood flow to the brain is dramatically decreased during torpor or experimentally induced during euthermia. These animals, as adults, also display rapid and pronounced synaptic flexibility where synapses retract during torpor and rapidly re-emerge upon arousal. A variety of coordinated adaptations contribute to tolerance of cerebral ischemia in these animals. In this review we discuss adaptations in heterothermic mammals that may suggest novel therapeutic targets and strategies to protect the human brain against cerebral ischemic damage and neurodegenerative disease. PMID:22326449

The Neurobiology of Moral Behavior: Review and Neuropsychiatric Implications

PubMed Central

Mendez, Mario F.

2011-01-01

Morality may be innate to the human brain. This review examines the neurobiological evidence from research involving functional magnetic resonance imaging of normal subjects, developmental sociopathy, acquired sociopathy from brain lesions, and frontotemporal dementia. These studies indicate a “neuromoral” network for responding to moral dilemmas centered in the ventromedial prefrontal cortex and its connections, particularly on the right. The neurobiological evidence indicates the existence of automatic “prosocial” mechanisms for identification with others that are part of the moral brain. Patients with disorders involving this moral network have attenuated emotional reactions to the possibility of harming others and may perform sociopathic acts. The existence of this neuromoral system has major clinical implications for the management of patients with dysmoral behavior from brain disorders and for forensic neuropsychiatry. PMID:20173686

Neurochemical Characterization of PSA-NCAM+ Cells in the Human Brain and Phenotypic Quantification in Alzheimer's Disease Entorhinal Cortex.

PubMed

Murray, Helen C; Swanson, Molly E V; Dieriks, B Victor; Turner, Clinton; Faull, Richard L M; Curtis, Maurice A

2018-02-21

Polysialylated neural cell adhesion molecule (PSA-NCAM) is widely expressed in the adult human brain and facilitates structural remodeling of cells through steric inhibition of intercellular NCAM adhesion. We previously showed that PSA-NCAM immunoreactivity is decreased in the entorhinal cortex in Alzheimer's disease (AD). Based on available evidence, we hypothesized that a loss of PSA-NCAM + interneurons may underlie this reduction. PSA-NCAM expression by interneurons has previously been described in the human medial prefrontal cortex. Here we used postmortem human brain tissue to provide further evidence of PSA-NCAM + interneurons throughout the human hippocampal formation and additional cortical regions. Furthermore, PSA-NCAM + cell populations were assessed in the entorhinal cortex of normal and AD cases using fluorescent double labeling and manual cell counting. We found a significant decrease in the number of PSA-NCAM + cells per mm 2 in layer II and V of the entorhinal cortex, supporting our previous description of reduced PSA-NCAM immunoreactivity. Additionally, we found a significant decrease in the proportion of PSA-NCAM + cells that co-labeled with NeuN and parvalbumin, but no change in the proportion that co-labeled with calbindin or calretinin. These results demonstrate that PSA-NCAM is expressed by a variety of interneuron populations throughout the brain. Furthermore, that loss of PSA-NCAM expression by NeuN + cells predominantly contributes to the reduced PSA-NCAM immunoreactivity in the AD entorhinal cortex. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

Sterol Metabolism Disorders and Neurodevelopment--An Update

ERIC Educational Resources Information Center

Kanungo, Shibani; Soares, Neelkamal; He, Miao; Steiner, Robert D.

2013-01-01

Cholesterol has numerous quintessential functions in normal cell physiology, as well as in embryonic and postnatal development. It is a major component of cell membranes and myelin, and is a precursor of steroid hormones and bile acids. The development of the blood brain barrier likely around 12-18 weeks of human gestation makes the developing…

A Unique Procedure to Identify Cell Surface Markers Through a Spherical Self-Organizing Map Applied to DNA Microarray Analysis.

PubMed

Sugii, Yuh; Kasai, Tomonari; Ikeda, Masashi; Vaidyanath, Arun; Kumon, Kazuki; Mizutani, Akifumi; Seno, Akimasa; Tokutaka, Heizo; Kudoh, Takayuki; Seno, Masaharu

2016-01-01

To identify cell-specific markers, we designed a DNA microarray platform with oligonucleotide probes for human membrane-anchored proteins. Human glioma cell lines were analyzed using microarray and compared with normal and fetal brain tissues. For the microarray analysis, we employed a spherical self-organizing map, which is a clustering method suitable for the conversion of multidimensional data into two-dimensional data and displays the relationship on a spherical surface. Based on the gene expression profile, the cell surface characteristics were successfully mirrored onto the spherical surface, thereby distinguishing normal brain tissue from the disease model based on the strength of gene expression. The clustered glioma-specific genes were further analyzed by polymerase chain reaction procedure and immunocytochemical staining of glioma cells. Our platform and the following procedure were successfully demonstrated to categorize the genes coding for cell surface proteins that are specific to glioma cells. Our assessment demonstrates that a spherical self-organizing map is a valuable tool for distinguishing cell surface markers and can be employed in marker discovery studies for the treatment of cancer.

High-Throughput Analysis of Age-Dependent Protein Changes in Layer II/III of the Human Orbitofrontal Cortex

NASA Astrophysics Data System (ADS)

Kapadia, Fenika

Studies on the orbitofrontal cortex (OFC) during normal aging have shown a decline in cognitive functions, a loss of spines/synapses in layer III and gene expression changes related to neural communication. Biological changes during the course of normal aging are summarized into 9 hallmarks based on aging in peripheral tissue. Whether these hallmarks apply to non-dividing brain tissue is not known. Therefore, we opted to perform large-scale proteomic profiling of the OFC layer II/III during normal aging from 15 young and 18 old male subjects. MaxQuant was utilized for label-free quantification and statistical analysis by the Random Intercept Model (RIM) identified 118 differentially expressed (DE) age-related proteins. Altered neural communication was the most represented hallmark of aging (54% of DE proteins), highlighting the importance of communication in the brain. Functional analysis showed enrichment in GABA/glutamate signaling and pro-inflammatory responses. The former may contribute to alterations in excitation/inhibition, leading to cognitive decline during aging.

MET Receptor Tyrosine Kinase as an Autism Genetic Risk Factor

PubMed Central

Peng, Yun; Huentelman, Matthew; Smith, Christopher; Qiu, Shenfeng

2014-01-01

In this chapter, we will briefly discuss recent literature on the role of MET receptor tyrosine kinase (RTK) in brain development and how perturbation of MET signaling may alter normal neurodevelopmental outcomes. Recent human genetic studies have established MET as a risk factor for autism, and the molecular and cellular underpinnings of this genetic risk are only beginning to emerge from obscurity. Unlike many autism risk genes that encode synaptic proteins, the spatial and temporal expression pattern of MET RTK indicates this signaling system is ideally situated to regulate neuronal growth, functional maturation, and establishment of functional brain circuits, particularly in those brain structures involved in higher levels of cognition, social skills, and executive functions. PMID:24290385

A hydroelastic model of hydrocephalus

NASA Astrophysics Data System (ADS)

Smillie, Alan; Sobey, Ian; Molnar, Zoltan

2005-09-01

We combine elements of poroelasticity and of fluid mechanics to construct a mathematical model of the human brain and ventricular system. The model is used to study hydrocephalus, a pathological condition in which the normal flow of the cerebrospinal fluid is disturbed, causing the brain to become deformed. Our model extends recent work in this area by including flow through the aqueduct, by incorporating boundary conditions that we believe accurately represent the anatomy of the brain and by including time dependence. This enables us to construct a quantitative model of the onset, development and treatment of this condition. We formulate and solve the governing equations and boundary conditions for this model and give results that are relevant to clinical observations.

First trimester size charts of embryonic brain structures.

PubMed

Gijtenbeek, M; Bogers, H; Groenenberg, I A L; Exalto, N; Willemsen, S P; Steegers, E A P; Eilers, P H C; Steegers-Theunissen, R P M

2014-02-01

Can reliable size charts of human embryonic brain structures be created from three-dimensional ultrasound (3D-US) visualizations? Reliable size charts of human embryonic brain structures can be created from high-quality images. Previous studies on the visualization of both the cavities and the walls of the brain compartments were performed using 2D-US, 3D-US or invasive intrauterine sonography. However, the walls of the diencephalon, mesencephalon and telencephalon have not been measured non-invasively before. Last-decade improvements in transvaginal ultrasound techniques allow a better visualization and offer the tools to measure these human embryonic brain structures with precision. This study is embedded in a prospective periconceptional cohort study. A total of 141 pregnancies were included before the sixth week of gestation and were monitored until delivery to assess complications and adverse outcomes. For the analysis of embryonic growth, 596 3D-US scans encompassing the entire embryo were obtained from 106 singleton non-malformed live birth pregnancies between 7(+0) and 12(+6) weeks' gestational age (GA). Using 4D View (3D software) the measured embryonic brain structures comprised thickness of the diencephalon, mesencephalon and telencephalon, and the total diameter of the diencephalon and mesencephalon. Of 596 3D scans, 161 (27%) high-quality scans of 79 pregnancies were eligible for analysis. The reliability of all embryonic brain structure measurements, based on the intra-class correlation coefficients (ICCs) (all above 0.98), was excellent. Bland-Altman plots showed moderate agreement for measurements of the telencephalon, but for all other measurements the agreement was good. Size charts were constructed according to crown-rump length (CRL). The percentage of high-quality scans suitable for analysis of these brain structures was low (27%).  The size charts of human embryonic brain structures can be used to study normal and abnormal development of brain development in future. Also, the effects of periconceptional maternal exposures, such as folic acid supplement use and smoking, on human embryonic brain development can be a topic of future research. This study was supported by the Department of Obstetrics and Gynaecology of the Erasmus University Medical Center. M.G. was supported by an additional grant from the Sophia Foundation for Medical Research (SSWO grant number 644). No competing interests are declared.

Mice with reduced brain-derived neurotrophic factor expression show decreased choline acetyltransferase activity, but regular brain monoamine levels and unaltered emotional behavior.

PubMed

Chourbaji, Sabine; Hellweg, Rainer; Brandis, Dorothee; Zörner, Björn; Zacher, Christiane; Lang, Undine E; Henn, Fritz A; Hörtnagl, Heide; Gass, Peter

2004-02-05

The "neurotrophin hypothesis" of depression predicts that depressive disorders in humans coincide with a decreased activity and/or expression of brain-derived neurotrophic factor (BDNF) in the brain. Therefore, we investigated whether mice with a reduced BDNF expression due to heterozygous gene disruption demonstrate depression-like neurochemical changes or behavioral symptoms. BNDF protein levels of adult BDNF(+/-) mice were reduced to about 60% in several brain areas investigated, including the hippocampus, frontal cortex, striatum, and hypothalamus. The content of monoamines (serotonin, norepinephrine, and dopamine) as well as of serotonin and dopamine degradation products was unchanged in these brain regions. By contrast, choline acetyltransferase activity was significantly reduced by 19% in the hippocampus of BDNF(+/-) mice, indicating that the cholinergic system of the basal forebrain is critically dependent on sufficient endogenous BDNF levels in adulthood. Moreover, BDNF(+/-) mice exhibited normal corticosterone and adrenocorticotropic hormone (ACTH) serum levels under baseline conditions and following immobilization stress. In a panel of behavioral tests investigating locomotor activity, exploration, anxiety, fear-associated learning, and behavioral despair, BDNF(+/-) mice were indistinguishable from wild-type littermates. Thus, a chronic reduction of BDNF protein content in adult mice is not sufficient to induce neurochemical or behavioral alterations that are reminiscent of depressive symptoms in humans.

Resolving rates of mutation in the brain using single-neuron genomics

PubMed Central

Evrony, Gilad D; Lee, Eunjung; Park, Peter J; Walsh, Christopher A

2016-01-01

Whether somatic mutations contribute functional diversity to brain cells is a long-standing question. Single-neuron genomics enables direct measurement of somatic mutation rates in human brain and promises to answer this question. A recent study (Upton et al., 2015) reported high rates of somatic LINE-1 element (L1) retrotransposition in the hippocampus and cerebral cortex that would have major implications for normal brain function, and suggested that these events preferentially impact genes important for neuronal function. We identify aspects of the single-cell sequencing approach, bioinformatic analysis, and validation methods that led to thousands of artifacts being interpreted as somatic mutation events. Our reanalysis supports a mutation frequency of approximately 0.2 events per cell, which is about fifty-fold lower than reported, confirming that L1 elements mobilize in some human neurons but indicating that L1 mosaicism is not ubiquitous. Through consideration of the challenges identified, we provide a foundation and framework for designing single-cell genomics studies. DOI: http://dx.doi.org/10.7554/eLife.12966.001 PMID:26901440

Long-term influence of normal variation in neonatal characteristics on human brain development

PubMed Central

Walhovd, Kristine B.; Fjell, Anders M.; Brown, Timothy T.; Kuperman, Joshua M.; Chung, Yoonho; Hagler, Donald J.; Roddey, J. Cooper; Erhart, Matthew; McCabe, Connor; Akshoomoff, Natacha; Amaral, David G.; Bloss, Cinnamon S.; Libiger, Ondrej; Schork, Nicholas J.; Darst, Burcu F.; Casey, B. J.; Chang, Linda; Ernst, Thomas M.; Frazier, Jean; Gruen, Jeffrey R.; Kaufmann, Walter E.; Murray, Sarah S.; van Zijl, Peter; Mostofsky, Stewart; Dale, Anders M.; Jernigan, Terry L.; McCabe, Connor; Chang, Linda; Akshoomoff, Natacha; Newman, Erik; Dale, Anders M.; Ernst, Thomas; Dale, Anders M.; Van Zijl, Peter; Kuperman, Joshua; Murray, Sarah; Bloss, Cinnamon; Schork, Nicholas J.; Appelbaum, Mark; Gamst, Anthony; Thompson, Wesley; Bartsch, Hauke; Jernigan, Terry L.; Dale, Anders M.; Akshoomoff, Natacha; Chang, Linda; Ernst, Thomas; Keating, Brian; Amaral, David; Sowell, Elizabeth; Kaufmann, Walter; Van Zijl, Peter; Mostofsky, Stewart; Casey, B.J.; Ruberry, Erika J.; Powers, Alisa; Rosen, Bruce; Kenet, Tal; Frazier, Jean; Kennedy, David; Gruen, Jeffrey

2012-01-01

It is now recognized that a number of cognitive, behavioral, and mental health outcomes across the lifespan can be traced to fetal development. Although the direct mediation is unknown, the substantial variance in fetal growth, most commonly indexed by birth weight, may affect lifespan brain development. We investigated effects of normal variance in birth weight on MRI-derived measures of brain development in 628 healthy children, adolescents, and young adults in the large-scale multicenter Pediatric Imaging, Neurocognition, and Genetics study. This heterogeneous sample was recruited through geographically dispersed sites in the United States. The influence of birth weight on cortical thickness, surface area, and striatal and total brain volumes was investigated, controlling for variance in age, sex, household income, and genetic ancestry factors. Birth weight was found to exert robust positive effects on regional cortical surface area in multiple regions as well as total brain and caudate volumes. These effects were continuous across birth weight ranges and ages and were not confined to subsets of the sample. The findings show that (i) aspects of later child and adolescent brain development are influenced at birth and (ii) relatively small differences in birth weight across groups and conditions typically compared in neuropsychiatric research (e.g., Attention Deficit Hyperactivity Disorder, schizophrenia, and personality disorders) may influence group differences observed in brain parameters of interest at a later stage in life. These findings should serve to increase our attention to early influences. PMID:23169628

Long-term influence of normal variation in neonatal characteristics on human brain development.

PubMed

Walhovd, Kristine B; Fjell, Anders M; Brown, Timothy T; Kuperman, Joshua M; Chung, Yoonho; Hagler, Donald J; Roddey, J Cooper; Erhart, Matthew; McCabe, Connor; Akshoomoff, Natacha; Amaral, David G; Bloss, Cinnamon S; Libiger, Ondrej; Schork, Nicholas J; Darst, Burcu F; Casey, B J; Chang, Linda; Ernst, Thomas M; Frazier, Jean; Gruen, Jeffrey R; Kaufmann, Walter E; Murray, Sarah S; van Zijl, Peter; Mostofsky, Stewart; Dale, Anders M

2012-12-04

It is now recognized that a number of cognitive, behavioral, and mental health outcomes across the lifespan can be traced to fetal development. Although the direct mediation is unknown, the substantial variance in fetal growth, most commonly indexed by birth weight, may affect lifespan brain development. We investigated effects of normal variance in birth weight on MRI-derived measures of brain development in 628 healthy children, adolescents, and young adults in the large-scale multicenter Pediatric Imaging, Neurocognition, and Genetics study. This heterogeneous sample was recruited through geographically dispersed sites in the United States. The influence of birth weight on cortical thickness, surface area, and striatal and total brain volumes was investigated, controlling for variance in age, sex, household income, and genetic ancestry factors. Birth weight was found to exert robust positive effects on regional cortical surface area in multiple regions as well as total brain and caudate volumes. These effects were continuous across birth weight ranges and ages and were not confined to subsets of the sample. The findings show that (i) aspects of later child and adolescent brain development are influenced at birth and (ii) relatively small differences in birth weight across groups and conditions typically compared in neuropsychiatric research (e.g., Attention Deficit Hyperactivity Disorder, schizophrenia, and personality disorders) may influence group differences observed in brain parameters of interest at a later stage in life. These findings should serve to increase our attention to early influences.

Optimized magnetic resonance diffusion protocol for ex-vivo whole human brain imaging with a clinical scanner

NASA Astrophysics Data System (ADS)

Scherrer, Benoit; Afacan, Onur; Stamm, Aymeric; Singh, Jolene; Warfield, Simon K.

2015-03-01

Diffusion-weighted magnetic resonance imaging (DW-MRI) provides a novel insight into the brain to facilitate our understanding of the brain connectivity and microstructure. While in-vivo DW-MRI enables imaging of living patients and longitudinal studies of brain changes, post-mortem ex-vivo DW-MRI has numerous advantages. Ex-vivo imaging benefits from greater resolution and sensitivity due to the lack of imaging time constraints; the use of tighter fitting coils; and the lack of movement artifacts. This allows characterization of normal and abnormal tissues with unprecedented resolution and sensitivity, facilitating our ability to investigate anatomical structures that are inaccessible in-vivo. This also offers the opportunity to develop today novel imaging biomarkers that will, with tomorrow's MR technology, enable improved in-vivo assessment of the risk of disease in an individual. Post-mortem studies, however, generally rely on the fixation of specimen to inhibit tissue decay which starts as soon as tissue is deprived from its blood supply. Unfortunately, fixation of tissues substantially alters tissue diffusivity profiles. In addition, ex-vivo DW-MRI requires particular care when packaging the specimen because the presence of microscopic air bubbles gives rise to geometric and intensity image distortion. In this work, we considered the specific requirements of post-mortem imaging and designed an optimized protocol for ex-vivo whole brain DW-MRI using a human clinical 3T scanner. Human clinical 3T scanners are available to a large number of researchers and, unlike most animal scanners, have a bore diameter large enough to image a whole human brain. Our optimized protocol will facilitate widespread ex-vivo investigations of large specimen.

Comparison of (/sup 14/C)glucose and (/sup 14/C)deoxyglucose as tracers of brain glucose use

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hawkins, R.A.; Mans, A.M.; Davis, D.W.

1988-03-01

Because glucose metabolism and functional activity in brain regions are normally coupled, knowledge of regional brain glucose use can yield insights into regional functional activity. The deoxyglucose (DG) method is widely used for this purpose in experimental animals and humans but questions have arisen regarding its limits and accuracy. Therefore an experiment was designed to compare the DG method on a structure-by-structure basis with another tracer of glucose use, (6-/sup 14/C)glucose, in normal rats. The cerebral metabolic rates obtained using the two tracers were similar in the telencephalon, but the results using DG were substantially lower in the midbrain andmore » hindbrain (diencephalon, 18%; mesencephalon, 20%; metencephalon, 29%; and myelencephalon, 35%). The primary DG metabolite, DG 6-phosphate (DG-6-P) was found to disappear in a non-uniform manner from the major brain structures: telencephalon less than diencephalon less than mesencephalon = metencephalon less than myelencephalon. Thus a correlation was found between the rate of DG-6-P loss and the extent to which the DG method gave lower values of glucose use. Thus this may explain, at least in part, the discrepancies between the two methods.« less

A dynamic in vivo-like organotypic blood-brain barrier model to probe metastatic brain tumors

NASA Astrophysics Data System (ADS)

Xu, Hui; Li, Zhongyu; Yu, Yue; Sizdahkhani, Saman; Ho, Winson S.; Yin, Fangchao; Wang, Li; Zhu, Guoli; Zhang, Min; Jiang, Lei; Zhuang, Zhengping; Qin, Jianhua

2016-11-01

The blood-brain barrier (BBB) restricts the uptake of many neuro-therapeutic molecules, presenting a formidable hurdle to drug development in brain diseases. We proposed a new and dynamic in vivo-like three-dimensional microfluidic system that replicates the key structural, functional and mechanical properties of the blood-brain barrier in vivo. Multiple factors in this system work synergistically to accentuate BBB-specific attributes-permitting the analysis of complex organ-level responses in both normal and pathological microenvironments in brain tumors. The complex BBB microenvironment is reproduced in this system via physical cell-cell interaction, vascular mechanical cues and cell migration. This model possesses the unique capability to examine brain metastasis of human lung, breast and melanoma cells and their therapeutic responses to chemotherapy. The results suggest that the interactions between cancer cells and astrocytes in BBB microenvironment might affect the ability of malignant brain tumors to traverse between brain and vascular compartments. Furthermore, quantification of spatially resolved barrier functions exists within a single assay, providing a versatile and valuable platform for pharmaceutical development, drug testing and neuroscientific research.

Purification of α-Synuclein from Human Brain Reveals an Instability of Endogenous Multimers as the Protein Approaches Purity

PubMed Central

2015-01-01

Despite two decades of research, the structure–function relationships of endogenous, physiological forms of α-synuclein (αSyn) are not well understood. Most in vitro studies of this Parkinson’s disease-related protein have focused on recombinant αSyn that is unfolded and monomeric, assuming that this represents its state in the normal human brain. Recently, we have provided evidence that αSyn exists in considerable part in neurons, erythrocytes, and other cells as a metastable multimer that principally sizes as a tetramer. In contrast to recombinant αSyn, physiological tetramers purified from human erythrocytes have substantial α-helical content and resist pathological aggregation into β-sheet rich fibers. Here, we report the first method to fully purify soluble αSyn from the most relevant source, human brain. We describe protocols that purify αSyn to homogeneity from nondiseased human cortex using ammonium sulfate precipitation, gel filtration, and ion exchange, hydrophobic interaction, and affinity chromatographies. Cross-linking of the starting material and the partially purified chromatographic fractions revealed abundant αSyn multimers, including apparent tetramers, but these were destabilized in large part to monomers during the final purification step. The method also fully purified the homologue β-synuclein, with a similar outcome. Circular dichroism spectroscopy showed that purified, brain-derived αSyn can display more helical content than the recombinant protein, but this result varied. Collectively, our data suggest that purifying αSyn to homogeneity destabilizes native, α-helix-rich multimers that exist in intact and partially purified brain samples. This finding suggests existence of a stabilizing cofactor (e.g., a small lipid) present inside neurons that is lost during final purification. PMID:25490121

Lag threads organize the brain’s intrinsic activity

PubMed Central

Mitra, Anish; Snyder, Abraham Z.; Blazey, Tyler; Raichle, Marcus E.

2015-01-01

It has been widely reported that intrinsic brain activity, in a variety of animals including humans, is spatiotemporally structured. Specifically, propagated slow activity has been repeatedly demonstrated in animals. In human resting-state fMRI, spontaneous activity has been understood predominantly in terms of zero-lag temporal synchrony within widely distributed functional systems (resting-state networks). Here, we use resting-state fMRI from 1,376 normal, young adults to demonstrate that multiple, highly reproducible, temporal sequences of propagated activity, which we term “lag threads,” are present in the brain. Moreover, this propagated activity is largely unidirectional within conventionally understood resting-state networks. Modeling experiments show that resting-state networks naturally emerge as a consequence of shared patterns of propagation. An implication of these results is that common physiologic mechanisms may underlie spontaneous activity as imaged with fMRI in humans and slowly propagated activity as studied in animals. PMID:25825720

Nonhuman Primate Optogenetics: Recent Advances and Future Directions

PubMed Central

Acker, Leah

2017-01-01

Optogenetics is the use of genetically coded, light-gated ion channels or pumps (opsins) for millisecond resolution control of neural activity. By targeting opsin expression to specific cell types and neuronal pathways, optogenetics can expand our understanding of the neural basis of normal and pathological behavior. To maximize the potential of optogenetics to study human cognition and behavior, optogenetics should be applied to the study of nonhuman primates (NHPs). The homology between NHPs and humans makes these animals the best experimental model for understanding human brain function and dysfunction. Moreover, for genetic tools to have translational promise, their use must be demonstrated effectively in large, wild-type animals such as Rhesus macaques. Here, we review recent advances in primate optogenetics. We highlight the technical hurdles that have been cleared, challenges that remain, and summarize how optogenetic experiments are expanding our understanding of primate brain function. PMID:29118219

Chocolate and the brain: neurobiological impact of cocoa flavanols on cognition and behavior.

PubMed

Sokolov, Alexander N; Pavlova, Marina A; Klosterhalfen, Sibylle; Enck, Paul

2013-12-01

Cocoa products and chocolate have recently been recognized as a rich source of flavonoids, mainly flavanols, potent antioxidant and anti-inflammatory agents with established benefits for cardiovascular health but largely unproven effects on neurocognition and behavior. In this review, we focus on neuromodulatory and neuroprotective actions of cocoa flavanols in humans. The absorbed flavonoids penetrate and accumulate in the brain regions involved in learning and memory, especially the hippocampus. The neurobiological actions of flavanols are believed to occur in two major ways: (i) via direct interactions with cellular cascades yielding expression of neuroprotective and neuromodulatory proteins that promote neurogenesis, neuronal function and brain connectivity, and (ii) via blood-flow improvement and angiogenesis in the brain and sensory systems. Protective effects of long-term flavanol consumption on neurocognition and behavior, including age- and disease-related cognitive decline, were shown in animal models of normal aging, dementia, and stroke. A few human observational and intervention studies appear to corroborate these findings. Evidence on more immediate action of cocoa flavanols remains limited and inconclusive, but warrants further research. As an outline for future research on cocoa flavanol impact on human cognition, mood, and behavior, we underscore combination of functional neuroimaging with cognitive and behavioral measures of performance. Copyright © 2013. Published by Elsevier Ltd.

[2,4-13C2]-β-Hydroxybutyrate Metabolism in Human Brain

PubMed Central

Pan, Jullie W.; de Graaf, Robin A.; Petersen, Kitt F.; Shulman, Gerald I.; Hetherington, Hoby P.; Rothman, Douglas L.

2010-01-01

Summary Infusions of [2,4-13C2]-β-hydroxybutyrate and 1H–13C polarization transfer spectroscopy were used in normal human subjects to detect the entry and metabolism of β-hydroxybutyrate in the brain. During the 2-hour infusion study, 13C label was detectable in the β-hydroxybutyrate resonance positions and in the amino acid pools of glutamate, glutamine, and aspartate. With a plasma concentration of 2.25 ± 0.24 mmol/L (four volunteers), the apparent tissue β-hydroxybutyrate concentration reached 0.18 ± 0.06 mmol/L during the last 20 minutes of the study. The relative fractional enrichment of 13C-4-glutamate labeling was 6.78 ± 1.71%, whereas 13C-4-glutamine was 5.68 ± 1.84%. Steady-state modeling of the 13C label distribution in glutamate and glutamine suggests that, under these conditions, the consumption of the β-hydroxybutyrate is predominantly neuronal, used at a rate of 0.032 ± 0.009 mmol · kg−1 · min−1, and accounts for 6.4 ± 1.6% of total acetyl coenzyme A oxidation. These results are consistent with minimal accumulation of cerebral ketones with rapid utilization, implying blood–brain barrier control of ketone oxidation in the nonfasted adult human brain. PMID:12142574

Distribution of Non-Persistent Endocrine Disruptors in Two Different Regions of the Human Brain

PubMed Central

van der Meer, Thomas P.; Artacho-Cordón, Francisco; Swaab, Dick F.; Struik, Dicky; Makris, Konstantinos C.; Wolffenbuttel, Bruce H. R.; Frederiksen, Hanne; van Vliet-Ostaptchouk, Jana V.

2017-01-01

Non-persistent endocrine disrupting chemicals (npEDCs) can affect multiple organs and systems in the body. Whether npEDCs can accumulate in the human brain is largely unknown. The major aim of this pilot study was to examine the presence of environmental phenols and parabens in two distinct brain regions: the hypothalamus and white-matter tissue. In addition, a potential association between these npEDCs concentrations and obesity was investigated. Post-mortem brain material was obtained from 24 individuals, made up of 12 obese and 12 normal-weight subjects (defined as body mass index (BMI) > 30 and BMI < 25 kg/m2, respectively). Nine phenols and seven parabens were measured by isotope dilution TurboFlow-LC-MS/MS. In the hypothalamus, seven suspect npEDCs (bisphenol A, triclosan, triclocarban and methyl-, ethyl-, n-propyl-, and benzyl paraben) were detected, while five npEDCs (bisphenol A, benzophenone-3, triclocarban, methyl-, and n-propyl paraben) were found in the white-matter brain tissue. We observed higher levels of methylparaben (MeP) in the hypothalamic tissue of obese subjects as compared to controls (p = 0.008). Our findings indicate that some suspected npEDCs are able to cross the blood–brain barrier. Whether the presence of npEDCs can adversely affect brain function and to which extent the detected concentrations are physiologically relevant needs to be further investigated. PMID:28902174

Functional expression of cysteinyl leukotriene receptors on human platelets.

PubMed

Hasegawa, Shunji; Ichiyama, Takashi; Hashimoto, Kunio; Suzuki, Yasuo; Hirano, Reiji; Fukano, Reiji; Furukawa, Susumu

2010-01-01

Normal peripheral blood leukocytes, such as basophils, eosinophils, B lymphocytes and monocytes/macrophages, have a cysteinyl leukotriene 1 (CysLT1) receptor, while the cysteinyl leukotriene 2 (CysLT2) receptor is expressed in cardiac Purkinje cells, endothelium, brain and leukocytes. However, it is unknown whether or not platelets express the CysLT1 or CysLT2 receptor. In this study we identify and characterize the biological function of the CysLT receptor of human platelets. We determined the CysLT1 or CysLT2 receptor mRNA expression in normal human platelets by RT-PCR and determined protein expression by Western blotting and flow cytometry. Moreover, we examined the effect of cysteinyl leukotrienes (CysLTs) in platelets on the induction of RANTES (Regulated on Activation, Normal T Expressed, and presumably Secreted). We also investigated whether the CysLT1 receptor antagonist pranlukast inhibits CysLT-induced RANTES release. In conclusion, we showed the functional expression of CysLT receptors on human platelets and demonstrated that CysLTs induced the release of significant amounts of RANTES, which suggests a novel role for human platelets in CysLT-mediated allergic inflammation.

Revisiting the human polypeptide GalNAc-T1 and T13 paralogs

PubMed Central

Festari, María Florencia; Trajtenberg, Felipe; Berois, Nora; Pantano, Sergio; Revoredo, Leslie; Kong, Yun; Solari-Saquieres, Patricia; Narimatsu, Yoshiki; Freire, Teresa; Bay, Sylvie; Robello, Carlos; Bénard, Jean; Gerken, Thomas A; Clausen, Henrik; Osinaga, Eduardo

2017-01-01

Polypeptide GalNAc-transferases (GalNAc-Ts) constitute a family of 20 human glycosyltransferases (comprising 9 subfamilies), which initiate mucin-type O-glycosylation. The O-glycoproteome is thought to be differentially regulated via the different substrate specificities and expression patterns of each GalNAc-T isoforms. Here, we present a comprehensive in vitro analysis of the peptide substrate specificity of GalNAc-T13, showing that it essentially overlaps with the ubiquitous expressed GalNAc-T1 isoform found in the same subfamily as T13. We have also identified and partially characterized nine splice variants of GalNAc-T13, which add further complexity to the GalNAc-T family. Two variants with changes in their lectin domains were characterized by in vitro glycosylation assays, and one (Δ39Ex9) was inactive while the second one (Ex10b) had essentially unaltered activity. We used reverse transcription-polymerase chain reaction analysis of human neuroblastoma cell lines, normal brain and a small panel of neuroblastoma tumors to demonstrate that several splice variants (Ex10b, ΔEx9, ΔEx2-7 and ΔEx6/8-39bpEx9) were highly expressed in tumor cell lines compared with normal brain, although the functional implications remain to be unveiled. In summary, the GalNAc-T13 isoform is predicted to function similarly to GalNAc-T1 against peptide substrates in vivo, in contrast to a prior report, but is unique by being selectively expressed in the brain. PMID:27913570

Brain injury following trial of hypothermia for neonatal hypoxic–ischaemic encephalopathy

PubMed Central

Shankaran, Seetha; Barnes, Patrick D; Hintz, Susan R; Laptook, Abbott R; Zaterka-Baxter, Kristin M; McDonald, Scott A; Ehrenkranz, Richard A; Walsh, Michele C; Tyson, Jon E; Donovan, Edward F; Goldberg, Ronald N; Bara, Rebecca; Das, Abhik; Finer, Neil N; Sanchez, Pablo J; Poindexter, Brenda B; Van Meurs, Krisa P; Carlo, Waldemar A; Stoll, Barbara J; Duara, Shahnaz; Guillet, Ronnie; Higgins, Rosemary D

2013-01-01

Objective The objective of our study was to examine the relationship between brain injury and outcome following neonatal hypoxic–ischaemic encephalopathy treated with hypothermia. Design and patients Neonatal MRI scans were evaluated in the National Institute of Child Health and Human Development (NICHD) randomised controlled trial of whole-body hypothermia and each infant was categorised based upon the pattern of brain injury on the MRI findings. Brain injury patterns were assessed as a marker of death or disability at 18–22 months of age. Results Scans were obtained on 136 of 208 trial participants (65%); 73 in the hypothermia and 63 in the control group. Normal scans were noted in 38 of 73 infants (52%) in the hypothermia group and 22 of 63 infants (35%) in the control group. Infants in the hypothermia group had fewer areas of infarction (12%) compared to infants in the control group (22%). Fifty-one of the 136 infants died or had moderate or severe disability at 18 months. The brain injury pattern correlated with outcome of death or disability and with disability among survivors. Each point increase in the severity of the pattern of brain injury was independently associated with a twofold increase in the odds of death or disability. Conclusions Fewer areas of infarction and a trend towards more normal scans were noted in brain MRI following whole-body hypothermia. Presence of the NICHD pattern of brain injury is a marker of death or moderate or severe disability at 18–22 months following hypothermia for neonatal encephalopathy. PMID:23080477

Eye-Target Synchrony and Attention

NASA Astrophysics Data System (ADS)

Contreras, R.; Kolster, R.; Basu, S.; Voss, H. U.; Ghajar, J.; Suh, M.; Bahar, S.

2007-03-01

Eye-target synchrony is critical during smooth pursuit. We apply stochastic phase synchronization to human pursuit of a moving target, in both normal and mild traumatic brain injured (TBI) subjects. Smooth pursuit utilizes the same neural networks used by attention. To test whether smooth pursuit is modulated by attention, subjects tracked a target while loaded with tasks involving working memory. Preliminary results suggest that additional cognitive load increases normal subjects' performance, while the effect is reversed in TBI patients. We correlate these results with eye-target synchrony. Additionally, we correlate eye-target synchrony with frequency of target motion, and discuss how the range of frequencies for optimal synchrony depends on the shift from attentional to automatic-response time scales. Synchrony deficits in TBI patients can be correlated with specific regions of brain damage imaged with diffusion tensor imaging (DTI).

Arginine-rich proteins in spherical inclusions of human locus coeruleus neurons demonstrated by benzil modification.

PubMed

Panayotacopoulou, M T; Issidorides, M R

1984-11-01

Previous studies have shown that aminergic neurons in the normal human brain contain acidophilic cytoplasmic inclusions--called protein bodies (PBs)--that are reduced or absent in parkinsonism and disrupted in depression. The purpose of the present study was to elucidate the constitution of PBs in five formalin-fixed normal human brains using histochemical methods specific for histones, protamines, and the amino acid arginine. PBs were revealed with alkaline fast green and bromphenol blue, exhibiting a high content in histones and in protamines. They developed blue metachromasia with phosphotungstic acid-hematoxylin and green fluorescence with phenanthrenequinone, which established the presence of arginyl residues. Using benzil, which selectively modifies the guanido group of arginine, staining was blocked for each of the above two methods. The application of Mallory's trichrome procedure after benzil differentiated the PBs into an unstained core and a still fuchsinophilic rim. Since the fuchsinophilia of the rim was shown to persist after acetylation as well, we suggest that this rim probably contains acidic macromolecules that attach to the basic charges of the amphoteric acid fuchsin. We conclude that the PB are complex structures consisting of a core segregating arginine-rich proteins and a rim which probably contains macromolecules of an acidic nature.

Toward a standardized structural-functional group connectome in MNI space.

PubMed

Horn, Andreas; Blankenburg, Felix

2016-01-01

The analysis of the structural architecture of the human brain in terms of connectivity between its subregions has provided profound insights into its underlying functional organization and has coined the concept of the "connectome", a structural description of the elements forming the human brain and the connections among them. Here, as a proof of concept, we introduce a novel group connectome in standard space based on a large sample of 169 subjects from the Enhanced Nathan Kline Institute-Rockland Sample (eNKI-RS). Whole brain structural connectomes of each subject were estimated with a global tracking approach, and the resulting fiber tracts were warped into standard stereotactic (MNI) space using DARTEL. Employing this group connectome, the results of published tracking studies (i.e., the JHU white matter and Oxford thalamic connectivity atlas) could be largely reproduced directly within MNI space. In a second analysis, a study that examined structural connectivity between regions of a functional network, namely the default mode network, was reproduced. Voxel-wise structural centrality was then calculated and compared to others' findings. Furthermore, including additional resting-state fMRI data from the same subjects, structural and functional connectivity matrices between approximately forty thousand nodes of the brain were calculated. This was done to estimate structure-function agreement indices of voxel-wise whole brain connectivity. Taken together, the combination of a novel whole brain fiber tracking approach and an advanced normalization method led to a group connectome that allowed (at least heuristically) performing fiber tracking directly within MNI space. Such an approach may be used for various purposes like the analysis of structural connectivity and modeling experiments that aim at studying the structure-function relationship of the human connectome. Moreover, it may even represent a first step toward a standard DTI template of the human brain in stereotactic space. The standardized group connectome might thus be a promising new resource to better understand and further analyze the anatomical architecture of the human brain on a population level. Copyright © 2015 Elsevier Inc. All rights reserved.

Functional Neuroimaging of Spike-Wave Seizures

PubMed Central

Motelow, Joshua E.; Blumenfeld, Hal

2013-01-01

Generalized spike-wave seizures are typically brief events associated with dynamic changes in brain physiology, metabolism, and behavior. Functional magnetic resonance imaging (fMRI) provides a relatively high spatio-temporal resolution method for imaging cortical-subcortical network activity during spike-wave seizures. Patients with spike-wave seizures often have episodes of staring and unresponsiveness which interfere with normal behavior. Results from human fMRI studies suggest that spike-wave seizures disrupt specific networks in the thalamus and fronto-parietal association cortex which are critical for normal attentive consciousness. However, the neuronal activity underlying imaging changes seen during fMRI is not well understood, particularly in abnormal conditions such as seizures. Animal models have begun to provide important fundamental insights into the neuronal basis for fMRI changes during spike-wave activity. Work from these models including both fMRI and direct neuronal recordings suggest that, like in humans, specific cortical-subcortical networks are involved in spike-wave, while other regions are spared. Regions showing fMRI increases demonstrate correlated increases in neuronal activity in animal models. The mechanisms of fMRI decreases in spike-wave will require further investigation. A better understanding of the specific brain regions involved in generating spike-wave seizures may help guide efforts to develop targeted therapies aimed at preventing or reversing abnormal excitability in these brain regions, ultimately leading to a cure for this disorder. PMID:18839093

The multidrug resistance 1 gene Abcb1 in brain and placenta: comparative analysis in human and guinea pig.

PubMed

Pappas, Jane J; Petropoulos, Sophie; Suderman, Matthew; Iqbal, Majid; Moisiadis, Vasilis; Turecki, Gustavo; Matthews, Stephen G; Szyf, Moshe

2014-01-01

The Multidrug Resistance 1 (MDR1; alternatively ABCB1) gene product P-glycoprotein (P-gp), an ATP binding cassette transporter, extrudes multiple endogenous and exogenous substrates from the cell, playing an important role in normal physiology and xenobiotic distribution and bioavailability. To date, the predominant animal models used to investigate the role of P-gp have been the mouse and rat, which have two distinct genes, Abcb1a and Abcb1b. In contrast, the human has a single gene, ABCB1, for which only a single isoform has been validated. We and others have previously shown important differences between Abcb1a and Abcb1b, limiting the extrapolation from rodent findings to the human. Since the guinea pig has a relatively long gestation, hemomonochorial placentation and neuroanatomically mature offspring, it is more similar to the human, and may provide a more comparable model for investigating the regulation of P-gp in the brain and placenta, however, to date, the Abcb1 gene in the guinea pig remains to be characterized. The placenta and fetal brain are barrier sites that express P-gp and that play a critical role of protection of the fetus and the fetal brain from maternally administered drugs and other xenobiotics. Using RNA sequencing (RNA-seq), reverse transcription-polymerase chain reaction (RT-PCR) and quantitative PCR (QPCR) to sequence the expressed isoforms of guinea pig Abcb1, we demonstrate that like the human, the guinea pig genome contains one gene for Abcb1 but that it is expressed as at least three different isoforms via alternative splicing and alternate exon usage. Further, we demonstrate that these isoforms are more closely related to human than to rat or mouse isoforms. This striking, overall similarity and evolutionary relatedness between guinea pig Abcb1 and human ABCB1 indicate that the guinea pig represents a relevant animal model for investigating the function and regulation of P-gp in the placenta and brain.

Biological and medical applications of a brain-on-a-chip

PubMed Central

2016-01-01

The desire to develop and evaluate drugs as potential countermeasures for biological and chemical threats requires test systems that can also substitute for the clinical trials normally crucial for drug development. Current animal models have limited predictivity for drug efficacy in humans as the large majority of drugs fails in clinical trials. We have limited understanding of the function of the central nervous system and the complexity of the brain, especially during development and neuronal plasticity. Simple in vitro systems do not represent physiology and function of the brain. Moreover, the difficulty of studying interactions between human genetics and environmental factors leads to lack of knowledge about the events that induce neurological diseases. Microphysiological systems (MPS) promise to generate more complex in vitro human models that better simulate the organ’s biology and function. MPS combine different cell types in a specific three-dimensional (3D) configuration to simulate organs with a concrete function. The final aim of these MPS is to combine different “organoids” to generate a human-on-a-chip, an approach that would allow studies of complex physiological organ interactions. The recent discovery of induced pluripotent stem cells (iPSCs) gives a range of possibilities allowing cellular studies of individuals with different genetic backgrounds (e.g., human disease models). Application of iPSCs from different donors in MPS gives the opportunity to better understand mechanisms of the disease and can be a novel tool in drug development, toxicology, and medicine. In order to generate a brain-on-a-chip, we have established a 3D model from human iPSCs based on our experience with a 3D rat primary aggregating brain model. After four weeks of differentiation, human 3D aggregates stain positive for different neuronal markers and show higher gene expression of various neuronal differentiation markers compared to 2D cultures. Here we present the applications and challenges of this emerging technology. PMID:24912505

Efficient block processing of long duration biotelemetric brain data for health care monitoring

DOE Office of Scientific and Technical Information (OSTI.GOV)

Soumya, I.; Zia Ur Rahman, M., E-mail: mdzr-5@ieee.org; Rama Koti Reddy, D. V.

In real time clinical environment, the brain signals which doctor need to analyze are usually very long. Such a scenario can be made simple by partitioning the input signal into several blocks and applying signal conditioning. This paper presents various block based adaptive filter structures for obtaining high resolution electroencephalogram (EEG) signals, which estimate the deterministic components of the EEG signal by removing noise. To process these long duration signals, we propose Time domain Block Least Mean Square (TDBLMS) algorithm for brain signal enhancement. In order to improve filtering capability, we introduce normalization in the weight update recursion of TDBLMS,more » which results TD-B-normalized-least mean square (LMS). To increase accuracy and resolution in the proposed noise cancelers, we implement the time domain cancelers in frequency domain which results frequency domain TDBLMS and FD-B-Normalized-LMS. Finally, we have applied these algorithms on real EEG signals obtained from human using Emotive Epoc EEG recorder and compared their performance with the conventional LMS algorithm. The results show that the performance of the block based algorithms is superior to the LMS counter-parts in terms of signal to noise ratio, convergence rate, excess mean square error, misadjustment, and coherence.« less

A computational model of oxygen transport in the cerebrocapillary levels for normal and pathologic brain function.

PubMed

Safaeian, Navid; David, Tim

2013-10-01

The oxygen exchange and correlation between the cerebral blood flow (CBF) and cerebral metabolic rate of oxygen consumption (CMRO2) in the cortical capillary levels for normal and pathologic brain functions remain the subject of debate. A 3D realistic mesoscale model of the cortical capillary network (non-tree like) is constructed using a random Voronoi tessellation in which each edge represents a capillary segment. The hemodynamics and oxygen transport are numerically simulated in the model, which involves rheological laws in the capillaries, oxygen diffusion, and non-linear binding of oxygen to hemoglobin, respectively. The findings show that the cerebral hypoxia due to a significant decreased perfusion (as can occur in stroke) can be avoided by a moderate reduction in oxygen demand. Oxygen extraction fraction (OEF) can be an important indicator for the brain oxygen metabolism under normal perfusion and misery-perfusion syndrome (leading to ischemia). The results demonstrated that a disproportionately large increase in blood supply is required for a small increase in the oxygen demand, which, in turn, is strongly dependent on the resting OEF. The predicted flow-metabolism coupling in the model supports the experimental studies of spatiotemporal stimulations in humans by positron emission tomography and functional magnetic resonance imaging.

A computational model of oxygen transport in the cerebrocapillary levels for normal and pathologic brain function

PubMed Central

Safaeian, Navid; David, Tim

2013-01-01

The oxygen exchange and correlation between the cerebral blood flow (CBF) and cerebral metabolic rate of oxygen consumption (CMRO2) in the cortical capillary levels for normal and pathologic brain functions remain the subject of debate. A 3D realistic mesoscale model of the cortical capillary network (non-tree like) is constructed using a random Voronoi tessellation in which each edge represents a capillary segment. The hemodynamics and oxygen transport are numerically simulated in the model, which involves rheological laws in the capillaries, oxygen diffusion, and non-linear binding of oxygen to hemoglobin, respectively. The findings show that the cerebral hypoxia due to a significant decreased perfusion (as can occur in stroke) can be avoided by a moderate reduction in oxygen demand. Oxygen extraction fraction (OEF) can be an important indicator for the brain oxygen metabolism under normal perfusion and misery-perfusion syndrome (leading to ischemia). The results demonstrated that a disproportionately large increase in blood supply is required for a small increase in the oxygen demand, which, in turn, is strongly dependent on the resting OEF. The predicted flow-metabolism coupling in the model supports the experimental studies of spatiotemporal stimulations in humans by positron emission tomography and functional magnetic resonance imaging. PMID:23921901

Responses of the Human Brain to Mild Dehydration and Rehydration Explored In Vivo by 1H-MR Imaging and Spectroscopy.

PubMed

Biller, A; Reuter, M; Patenaude, B; Homola, G A; Breuer, F; Bendszus, M; Bartsch, A J

2015-12-01

As yet, there are no in vivo data on tissue water changes and associated morphometric changes involved in the osmo-adaptation of normal brains. Our aim was to evaluate osmoadaptive responses of the healthy human brain to osmotic challenges of de- and rehydration by serial measurements of brain volume, tissue fluid, and metabolites. Serial T1-weighted and (1)H-MR spectroscopy data were acquired in 15 healthy individuals at normohydration, on 12 hours of dehydration, and during 1 hour of oral rehydration. Osmotic challenges were monitored by serum measures, including osmolality and hematocrit. MR imaging data were analyzed by using FreeSurfer and LCModel. On dehydration, serum osmolality increased by 0.67% and brain tissue fluid decreased by 1.63%, on average. MR imaging morphometry demonstrated corresponding decreases of cortical thickness and volumes of the whole brain, cortex, white matter, and hypothalamus/thalamus. These changes reversed during rehydration. Continuous fluid ingestion of 1 L of water for 1 hour within the scanner lowered serum osmolality by 0.96% and increased brain tissue fluid by 0.43%, on average. Concomitantly, cortical thickness and volumes of the whole brain, cortex, white matter, and hypothalamus/thalamus increased. Changes in brain tissue fluid were related to volume changes of the whole brain, the white matter, and hypothalamus/thalamus. Only volume changes of the hypothalamus/thalamus significantly correlated with serum osmolality. This is the first study simultaneously evaluating changes in brain tissue fluid, metabolites, volume, and cortical thickness. Our results reflect cellular volume regulatory mechanisms at a macroscopic level and emphasize that it is essential to control for hydration levels in studies on brain morphometry and metabolism in order to avoid confounding the findings. © 2015 by American Journal of Neuroradiology.

Early brain response to low-dose radiation exposure involves molecular networks and pathways associated with cognitive functions, advanced aging and Alzheimer's disease.

PubMed

Lowe, Xiu R; Bhattacharya, Sanchita; Marchetti, Francesco; Wyrobek, Andrew J

2009-01-01

Understanding the cognitive and behavioral consequences of brain exposures to low-dose ionizing radiation has broad relevance for health risks from medical radiation diagnostic procedures, radiotherapy and environmental nuclear contamination as well as for Earth-orbit and space missions. Analyses of transcriptome profiles of mouse brain tissue after whole-body irradiation showed that low-dose exposures (10 cGy) induced genes not affected by high-dose radiation (2 Gy) and that low-dose genes were associated with unique pathways and functions. The low-dose response had two major components: pathways that are consistently seen across tissues and pathways that were specific for brain tissue. Low-dose genes clustered into a saturated network (P < 10(-53)) containing mostly down-regulated genes involving ion channels, long-term potentiation and depression, vascular damage, etc. We identified nine neural signaling pathways that showed a high degree of concordance in their transcriptional response in mouse brain tissue after low-dose irradiation, in the aging human brain (unirradiated), and in brain tissue from patients with Alzheimer's disease. Mice exposed to high-dose radiation did not show these effects and associations. Our findings indicate that the molecular response of the mouse brain within a few hours after low-dose irradiation involves the down-regulation of neural pathways associated with cognitive dysfunctions that are also down-regulated in normal human aging and Alzheimer's disease.

The consequences of fetal growth restriction on brain structure and neurodevelopmental outcome.

PubMed

Miller, Suzanne L; Huppi, Petra S; Mallard, Carina

2016-02-15

Fetal growth restriction (FGR) is a significant complication of pregnancy describing a fetus that does not grow to full potential due to pathological compromise. FGR affects 3-9% of pregnancies in high-income countries, and is a leading cause of perinatal mortality and morbidity. Placental insufficiency is the principal cause of FGR, resulting in chronic fetal hypoxia. This hypoxia induces a fetal adaptive response of cardiac output redistribution to favour vital organs, including the brain, and is in consequence called brain sparing. Despite this, it is now apparent that brain sparing does not ensure normal brain development in growth-restricted fetuses. In this review we have brought together available evidence from human and experimental animal studies to describe the complex changes in brain structure and function that occur as a consequence of FGR. In both humans and animals, neurodevelopmental outcomes are influenced by the timing of the onset of FGR, the severity of FGR, and gestational age at delivery. FGR is broadly associated with reduced total brain volume and altered cortical volume and structure, decreased total number of cells and myelination deficits. Brain connectivity is also impaired, evidenced by neuronal migration deficits, reduced dendritic processes, and less efficient networks with decreased long-range connections. Subsequent to these structural alterations, short- and long-term functional consequences have been described in school children who had FGR, most commonly including problems in motor skills, cognition, memory and neuropsychological dysfunctions. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

Technical and experimental features of Magnetic Resonance Spectroscopy of brain glycogen metabolism.

PubMed

Soares, Ana Francisca; Gruetter, Rolf; Lei, Hongxia

2017-07-15

In the brain, glycogen is a source of glucose not only in emergency situations but also during normal brain activity. Altered brain glycogen metabolism is associated with energetic dysregulation in pathological conditions, such as diabetes or epilepsy. Both in humans and animals, brain glycogen levels have been assessed non-invasively by Carbon-13 Magnetic Resonance Spectroscopy ( 13 C-MRS) in vivo. With this approach, glycogen synthesis and degradation may be followed in real time, thereby providing valuable insights into brain glycogen dynamics. However, compared to the liver and muscle, where glycogen is abundant, the sensitivity for detection of brain glycogen by 13 C-MRS is inherently low. In this review we focus on strategies used to optimize the sensitivity for 13 C-MRS detection of glycogen. Namely, we explore several technical perspectives, such as magnetic field strength, field homogeneity, coil design, decoupling, and localization methods. Furthermore, we also address basic principles underlying the use of 13 C-labeled precursors to enhance the detectable glycogen signal, emphasizing specific experimental aspects relevant for obtaining kinetic information on brain glycogen. Copyright © 2016 Elsevier Inc. All rights reserved.

IGFBP3 Colocalizes with and Regulates Hypocretin (Orexin)

PubMed Central

Honda, Makoto; Eriksson, Krister S.; Zhang, Shengwen; Tanaka, Susumu; Lin, Ling; Salehi, Ahmad; Hesla, Per Egil; Maehlen, Jan; Gaus, Stephanie E.; Yanagisawa, Masashi; Sakurai, Takeshi; Taheri, Shahrad; Tsuchiya, Kuniaki; Honda, Yutaka; Mignot, Emmanuel

2009-01-01

Background The sleep disorder narcolepsy is caused by a vast reduction in neurons producing the hypocretin (orexin) neuropeptides. Based on the tight association with HLA, narcolepsy is believed to result from an autoimmune attack, but the cause of hypocretin cell loss is still unknown. We performed gene expression profiling in the hypothalamus to identify novel genes dysregulated in narcolepsy, as these may be the target of autoimmune attack or modulate hypocretin gene expression. Methodology/Principal Findings We used microarrays to compare the transcriptome in the posterior hypothalamus of (1) narcoleptic versus control postmortem human brains and (2) transgenic mice lacking hypocretin neurons versus wild type mice. Hypocretin was the most downregulated gene in human narcolepsy brains. Among many additional candidates, only one, insulin-like growth factor binding protein 3 (IGFBP3), was downregulated in both human and mouse models and co-expressed in hypocretin neurons. Functional analysis indicated decreased hypocretin messenger RNA and peptide content, and increased sleep in transgenic mice overexpressing human IGFBP3, an effect possibly mediated through decreased hypocretin promotor activity in the presence of excessive IGFBP3. Although we found no IGFBP3 autoantibodies nor a genetic association with IGFBP3 polymorphisms in human narcolepsy, we found that an IGFBP3 polymorphism known to increase serum IGFBP3 levels was associated with lower CSF hypocretin-1 in normal individuals. Conclusions/Significance Comparison of the transcriptome in narcolepsy and narcolepsy model mouse brains revealed a novel dysregulated gene which colocalized in hypocretin cells. Functional analysis indicated that the identified IGFBP3 is a new regulator of hypocretin cell physiology that may be involved not only in the pathophysiology of narcolepsy, but also in the regulation of sleep in normal individuals, most notably during adolescence. Further studies are required to address the hypothesis that excessive IGFBP3 expression may initiate hypocretin cell death and cause narcolepsy. PMID:19158946

Computational modeling of resting-state activity demonstrates markers of normalcy in children with prenatal or perinatal stroke.

PubMed

Adhikari, Mohit H; Raja Beharelle, Anjali; Griffa, Alessandra; Hagmann, Patric; Solodkin, Ana; McIntosh, Anthony R; Small, Steven L; Deco, Gustavo

2015-06-10

Children who sustain a prenatal or perinatal brain injury in the form of a stroke develop remarkably normal cognitive functions in certain areas, with a particular strength in language skills. A dominant explanation for this is that brain regions from the contralesional hemisphere "take over" their functions, whereas the damaged areas and other ipsilesional regions play much less of a role. However, it is difficult to tease apart whether changes in neural activity after early brain injury are due to damage caused by the lesion or by processes related to postinjury reorganization. We sought to differentiate between these two causes by investigating the functional connectivity (FC) of brain areas during the resting state in human children with early brain injury using a computational model. We simulated a large-scale network consisting of realistic models of local brain areas coupled through anatomical connectivity information of healthy and injured participants. We then compared the resulting simulated FC values of healthy and injured participants with the empirical ones. We found that the empirical connectivity values, especially of the damaged areas, correlated better with simulated values of a healthy brain than those of an injured brain. This result indicates that the structural damage caused by an early brain injury is unlikely to have an adverse and sustained impact on the functional connections, albeit during the resting state, of damaged areas. Therefore, these areas could continue to play a role in the development of near-normal function in certain domains such as language in these children. Copyright © 2015 the authors 0270-6474/15/358914-11$15.00/0.

Brain oxygen utilization is unchanged by hypoglycemia in normal humans: lactate, alanine, and leucine uptake are not sufficient to offset energy deficit.

PubMed

Lubow, Jeffrey M; Piñón, Ivan G; Avogaro, Angelo; Cobelli, Claudio; Treeson, David M; Mandeville, Katherine A; Toffolo, Gianna; Boyle, Patrick J

2006-01-01

During hypoglycemia, substrates other than glucose have been suggested to serve as alternate neural fuels. We evaluated brain uptake of endogenously produced lactate, alanine, and leucine at euglycemia and during insulin-induced hypoglycemia in 17 normal subjects. Cross-brain arteriovenous differences for plasma glucose, lactate, alanine, leucine, and oxygen content were quantitated. Cerebral blood flow (CBF) was measured by Fick methodology using N(2)O as the dilution indicator gas. Substrate uptake was measured as the product of CBF and the arteriovenous concentration difference. As arterial glucose concentration fell, cerebral oxygen utilization and CBF remained unchanged. Brain glucose uptake (BGU) decreased from 36.3+/-2.6 to 26.6+/-2.1 micromol.100 g of brain(-1).min(-1) (P<0.001), equivalent to a drop in ATP of 291 micromol.100 g(-1).min(-1). Arterial lactate rose (P<0.001), whereas arterial alanine and leucine fell (P<0.009 and P<0.001, respectively). Brain lactate uptake (BLU) increased from a net release of -1.8+/- 0.6 to a net uptake of 2.5+/-1.2 micromol.100 g(-1).min(-1) (P<0.001), equivalent to an increase in ATP of 74 micromol.100 g(-1).min(-1). Brain leucine uptake decreased from 7.1+/-1.2 to 2.5 +/- 0.5 micromol.100 g(-1).min(-1) (P<0.001), and brain alanine uptake trended downward (P<0.08). We conclude that the ATP generated from the physiological increase in BLU during hypoglycemia accounts for no more than 25% of the brain glucose energy deficit.

Personal relevance and the human right hemisphere.

PubMed

Van Lancker, D

1991-09-01

Brain damage can selectively disrupt or distort information and ability across the range of human behaviors. One domain that has not been considered as an independent attribute consists of acquisition and maintenance of personal relevant entities such as "familiar" faces, persons, voices, names, linguistic expressions, handwriting, topography, and so on. In experimental studies of normal mentation, personal relevance is revealed in studies of emotion, arousal, affect, preference and familiarity judgments, and memory. Following focal brain damage, deficits and distortions in the experience of personal relevance, as well as in recognizing formerly personally relevant phenomena, are well known to occur. A review and interpretation of these data lead to a proposal that the right hemisphere has a special role in establishing, maintaining, and processing personally relevant aspects of the individual's world.

From Central Pattern Generator to Sensory Template in the Evolution of Birdsong

ERIC Educational Resources Information Center

Konishi, Masakazu

2010-01-01

Central nervous networks, be they a part of the human brain or a group of neurons in a snail, may be designed to produce distinct patterns of movement. Central pattern generators can account for the development and production of normal vocal signals without auditory feedback in non-songbirds. Songbirds need auditory feedback to develop and…

Dissociable effects of local inhibitory and excitatory theta-burst stimulation on large-scale brain dynamics

PubMed Central

Sale, Martin V.; Lord, Anton; Zalesky, Andrew; Breakspear, Michael; Mattingley, Jason B.

2015-01-01

Normal brain function depends on a dynamic balance between local specialization and large-scale integration. It remains unclear, however, how local changes in functionally specialized areas can influence integrated activity across larger brain networks. By combining transcranial magnetic stimulation with resting-state functional magnetic resonance imaging, we tested for changes in large-scale integration following the application of excitatory or inhibitory stimulation on the human motor cortex. After local inhibitory stimulation, regions encompassing the sensorimotor module concurrently increased their internal integration and decreased their communication with other modules of the brain. There were no such changes in modular dynamics following excitatory stimulation of the same area of motor cortex nor were there changes in the configuration and interactions between core brain hubs after excitatory or inhibitory stimulation of the same area. These results suggest the existence of selective mechanisms that integrate local changes in neural activity, while preserving ongoing communication between brain hubs. PMID:25717162

Inability to produce a model of dialysis encephalopathy in the rat by aluminum administration.

PubMed

Perry, T L; Yong, V W; Godolphin, W J; Sutter, M; Hansen, S; Kish, S J; Foulks, J G; Ito, M

1987-04-01

We attempted to produce a rat model of brain aluminum toxicity in order to explore whether or not aluminum accumulation produces the neurochemical changes observed in brains of patients who die with dialysis encephalopathy. Daily subcutaneous injection of Al(OH)3 caused marked elevation of serum aluminum concentrations, but did not increase brain aluminum contents, either in rats with normal renal function, or in rats with unilateral or 5/6 nephrectomies. LiCl pretreatment, which has been reported to cause irreversible renal failure, did not impair renal function nor aid in achieving elevated brain aluminum contents. No reductions in brain contents of gamma-aminobutyric acid (GABA) or in glutamic acid decarboxylase (GAD, E.C.4.1.1.15) and choline acetyltransferase (ChAT, E.C.2.3.1.6) activities were observed in aluminum-treated rats. We conclude that the rat is not a suitable laboratory animal to explore the role of aluminum toxicity in causing the GABA and ChAT deficits present in brains of hemodialyzed human patients.

Glucose metabolism in the developing brain.

PubMed

Vannucci, R C; Vannucci, S J

2000-04-01

As in adults, glucose is the predominant cerebral energy fuel for the fetus and newborn. Studies in experimental animals and humans indicate that cerebral glucose utilization initially is low and increases with maturation with increasing regional heterogeneity. The increases in cerebral glucose utilization with advancing age occurs as a consequence of increasing functional activity and cerebral energy demands. The levels of expression of the 2 primary facilitative glucose transporter proteins in brain, GLUT1 (blood-brain barrier and glia) and GLUT3 (neuronal), display a similar maturational pattern. Alternate cerebral energy fuels, specifically the ketone bodies and lactate, can substitute for glucose, especially during hypoglycemia, thereby protecting the immature brain from potential untoward effects of hypoglycemia. Unlike adults, glucose supplementation during hypoxia-ischemia is protective in the immature brain, whereas hypoglycemia is deleterious. Accordingly, glucose plays a critical role in the developing brain, not only as the primary substrate for energy production but also to allow for normal biosynthetic processes to proceed.

A Proposal of New Reference System for the Standard Axial, Sagittal, Coronal Planes of Brain Based on the Serially-Sectioned Images

PubMed Central

Park, Jin Seo; Park, Hyo Seok; Shin, Dong Sun; Har, Dong-Hwan; Cho, Zang-Hee; Kim, Young-Bo; Han, Jae-Yong; Chi, Je-Geun

2010-01-01

Sectional anatomy of human brain is useful to examine the diseased brain as well as normal brain. However, intracerebral reference points for the axial, sagittal, and coronal planes of brain have not been standardized in anatomical sections or radiological images. We made 2,343 serially-sectioned images of a cadaver head with 0.1 mm intervals, 0.1 mm pixel size, and 48 bit color and obtained axial, sagittal, and coronal images based on the proposed reference system. This reference system consists of one principal reference point and two ancillary reference points. The two ancillary reference points are the anterior commissure and the posterior commissure. And the principal reference point is the midpoint of two ancillary reference points. It resides in the center of whole brain. From the principal reference point, Cartesian coordinate of x, y, z could be made to be the standard axial, sagittal, and coronal planes. PMID:20052359

Neuroprotective properties of epoetin alfa.

PubMed

Cerami, Anthony; Brines, Michael; Ghezzi, Pietro; Cerami, Carla; Itri, Loretta M

2002-01-01

Erythropoietin and its receptor function as primary mediators of the normal physiological response to hypoxia. Erythropoietin is recognized for its central role in erythropoiesis, but studies in which recombinant human erythropoietin (epoetin alfa) is injected directly into ischaemic rodent brain show that erythropoietin also mediates neuroprotection. Abundant expression of the erythropoietin receptor has been observed at brain capillaries, which could provide a route for circulating erythropoietin to enter the brain. In confirmation of this hypothesis, systemic administration of epoetin alfa before or up to 6 h after focal brain ischaemia reduced injury by 50-75%. Epoetin alfa also limited the extent of concussive brain injury, the immune damage in experimental autoimmune encephalomyelitis and excitotoxicity induced by kainate. Thus, systemically administered epoetin alfa in animal models has neuroprotective effects, demonstrating its potential use after brain injury, trauma and multiple sclerosis. It is evident that erythropoietin has biological activities in addition to increasing red cell mass. Given the excellent safety profile of epoetin alfa, clinical trials evaluating systemically administered epoetin alfa as a general neuroprotective treatment are warranted.

Validation of In utero Tractography of Human Fetal Commissural and Internal Capsule Fibers with Histological Structure Tensor Analysis

PubMed Central

Mitter, Christian; Jakab, András; Brugger, Peter C.; Ricken, Gerda; Gruber, Gerlinde M.; Bettelheim, Dieter; Scharrer, Anke; Langs, Georg; Hainfellner, Johannes A.; Prayer, Daniela; Kasprian, Gregor

2015-01-01

Diffusion tensor imaging (DTI) and tractography offer the unique possibility to visualize the developing white matter macroanatomy of the human fetal brain in vivo and in utero and are currently under investigation for their potential use in the diagnosis of developmental pathologies of the human central nervous system. However, in order to establish in utero DTI as a clinical imaging tool, an independent comparison between macroscopic imaging and microscopic histology data in the same subject is needed. The present study aimed to cross-validate normal as well as abnormal in utero tractography results of commissural and internal capsule fibers in human fetal brains using postmortem histological structure tensor (ST) analysis. In utero tractography findings from two structurally unremarkable and five abnormal fetal brains were compared to the results of postmortem ST analysis applied to digitalized whole hemisphere sections of the same subjects. An approach to perform ST-based deterministic tractography in histological sections was implemented to overcome limitations in correlating in utero tractography to postmortem histology data. ST analysis and histology-based tractography of fetal brain sections enabled the direct assessment of the anisotropic organization and main fiber orientation of fetal telencephalic layers on a micro- and macroscopic scale, and validated in utero tractography results of corpus callosum and internal capsule fiber tracts. Cross-validation of abnormal in utero tractography results could be achieved in four subjects with agenesis of the corpus callosum (ACC) and in two cases with malformations of internal capsule fibers. In addition, potential limitations of current DTI-based in utero tractography could be demonstrated in several brain regions. Combining the three-dimensional nature of DTI-based in utero tractography with the microscopic resolution provided by histological ST analysis may ultimately facilitate a more complete morphologic characterization of axon guidance disorders at prenatal stages of human brain development. PMID:26732460

Selective anti-tumor activity of the novel fluoropyrimidine polymer F10 towards G48a orthotopic GBM tumors.

PubMed

Gmeiner, William H; Lema-Tome, Carla; Gibo, Denise; Jennings-Gee, Jamie; Milligan, Carol; Debinski, Waldemar

2014-02-01

F10 is a novel anti-tumor agent with minimal systemic toxicity in vivo and which displays strong cytotoxicity towards glioblastoma (GBM) cells in vitro. Here we investigate the cytotoxicity of F10 towards GBM cells and evaluate the anti-tumor activity of locally-administered F10 towards an orthotopic xenograft model of GBM. The effects of F10 on thymidylate synthase (TS) inhibition and Topoisomerase 1 (Top1) cleavage complex formation were evaluated using TS activity assays and in vivo complex of enzyme bioassays. Cytotoxicity of F10 towards normal brain was evaluated using cortices from embryonic (day 18) mice. F10 displays minimal penetrance of the blood-brain barrier and was delivered by intra-cerebral (i.c.) administration and prospective anti-tumor response towards luciferase-expressing G48a human GBM tumors in nude mice was evaluated using IVIS imaging. Histological examination of tumor and normal brain tissue was used to assess the selectivity of anti-tumor activity. F10 is cytotoxic towards G48a, SNB-19, and U-251 MG GBM cells through dual targeting of TS and Top1. F10 is not toxic to murine primary neuronal cultures. F10 is well-tolerated upon i.c. administration and induces significant regression of G48a tumors that is dose-dependent. Histological analysis from F10-treated mice revealed tumors were essentially completely eradicated in F10-treated mice while vehicle-treated mice displayed substantial infiltration into normal tissue. F10 displays strong efficacy for GBM treatment with minimal toxicity upon i.c. administration establishing F10 as a promising drug-candidate for treating GBM in human patients.

The prebiotics 3′Sialyllactose and 6′Sialyllactose diminish stressor-induced anxiety-like behavior and colonic microbiota alterations: evidence for effects on the gut-brain axis

PubMed Central

Tarr, Andrew J.; Galley, Jeffrey D.; Fisher, Sydney; Chichlowski, Maciej; Berg, Brian M.; Bailey, Michael T.

2015-01-01

There are extensive bidirectional interactions between the gut microbiota and the central nervous system (CNS), and studies demonstrate that stressor exposure significantly alters gut microbiota community structure. We tested whether oligosaccharides naturally found in high levels in human milk, which have been reported to impact brain development and enhance the growth of beneficial commensal microbes, would prevent stressor-induced alterations in gut microbial community composition and attenuate stressor-induced anxiety-like behavior. Mice were fed standard laboratory diet, or laboratory diet containing the human milk oligosaccharides 3′Sialyllactose (3′SL) or 6′Sialyllactose (6′SL) for two weeks prior to being exposed to either a social disruption stressor or a non-stressed control condition. Stressor exposure significantly changed the structure of the colonic mucosa-associated microbiota in control mice, as indicated by changes in beta diversity. The stressor resulted in anxiety-like behavior in both the light/dark preference and open field tests in control mice. This effect was associated with a reduction in immature neurons in the dentate gyrus as indicated by doublecortin (DCX) immunostaining. These effects were not evident in mice fed milk oligosaccharides; stressor exposure did not significantly change microbial community structure in mice fed 3′SL or 6′SL. In addition, 3′SL and 6′SL helped maintain normal behavior on tests of anxiety-like behavior and normal numbers of DCX+ immature neurons. These studies indicate that milk oligosaccharides support normal microbial communities and behavioral responses during stressor exposure, potentially through effects on the gut microbiota-brain axis. PMID:26144888

Spectral spatiotemporal imaging of cortical oscillations and interactions in the human brain

PubMed Central

Lin, Fa-Hsuan; Witzel, Thomas; Hämäläinen, Matti S.; Dale, Anders M.; Belliveau, John W.; Stufflebeam, Steven M.

2010-01-01

This paper presents a computationally efficient source estimation algorithm that localizes cortical oscillations and their phase relationships. The proposed method employs wavelet-transformed magnetoencephalography (MEG) data and uses anatomical MRI to constrain the current locations to the cortical mantle. In addition, the locations of the sources can be further confined with the help of functional MRI (fMRI) data. As a result, we obtain spatiotemporal maps of spectral power and phase relationships. As an example, we show how the phase locking value (PLV), that is, the trial-by-trial phase relationship between the stimulus and response, can be imaged on the cortex. We apply the method to spontaneous, evoked, and driven cortical oscillations measured with MEG. We test the method of combining MEG, structural MRI, and fMRI using simulated cortical oscillations along Heschl’s gyrus (HG). We also analyze sustained auditory gamma-band neuromagnetic fields from MEG and fMRI measurements. Our results show that combining the MEG recording with fMRI improves source localization for the non-noise-normalized wavelet power. In contrast, noise-normalized spectral power or PLV localization may not benefit from the fMRI constraint. We show that if the thresholds are not properly chosen, noise-normalized spectral power or PLV estimates may contain false (phantom) sources, independent of the inclusion of the fMRI prior information. The proposed algorithm can be used for evoked MEG/EEG and block-designed or event-related fMRI paradigms, or for spontaneous MEG data sets. Spectral spatiotemporal imaging of cortical oscillations and interactions in the human brain can provide further understanding of large-scale neural activity and communication between different brain regions. PMID:15488408

New techniques for positron emission tomography in the study of human neurological disorders for the period June 15, 1987 through December 14, 1987

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kuhl, D.E.

1987-09-01

A brief progress report is presented describing the preparation of /sup 11/C-scopolamine, /sup 17/F-fluoromethane and /sup 18/F-tetraalkylammonium fluoride. The application of /sup 11/C-scopolamine to map cholinergic receptors in normal human brain. Additional studies entitled ''The Automated Arterial Blood Sampling Systems for PET'' and ''Investigations of Array Processor Based High-Speed Parameter Estimation for Tracer Kinetic Modeling'' are also described. (DT)

Metabolomics and neuroanatomical evaluation of post-mortem changes in the hippocampus.

PubMed

Gonzalez-Riano, Carolina; Tapia-González, Silvia; García, Antonia; Muñoz, Alberto; DeFelipe, Javier; Barbas, Coral

2017-08-01

Understanding the human brain is the ultimate goal in neuroscience, but this is extremely challenging in part due to the fact that brain tissue obtained from autopsy is practically the only source of normal brain tissue and also since changes at different levels of biological organization (genetic, molecular, biochemical, anatomical) occur after death due to multiple mechanisms. Here we used metabolomic and anatomical techniques to study the possible relationship between post-mortem time (PT)-induced changes that may occur at both the metabolomics and anatomical levels in the same brains. Our experiments have mainly focused on the hippocampus of the mouse. We found significant metabolomic changes at 2 h PT, whereas the integrity of neurons and glia, at the anatomical/ neurochemical level, was not significantly altered during the first 5 h PT for the majority of histological markers.

Proton magnetic resonance spectroscopy imaging in the study of human brain cancer.

PubMed

Martínez-Bisbal, M C; Celda, B

2009-12-01

Magnetic resonance spectroscopic imaging (MRSI) is a non-invasive imaging technique that provides metabolic information on brain tumor. This biochemical information can be processed and presented as density maps of several metabolites, among them N-acetylaspartate (marker of neuronal viability), choline (marker of membrane turnover), creatine (related to the energy state of the cells), myo-Inositol (exclusively found in astrocytes), lipids and lactate (observed in necrosis and other pathological processes) which mean relevant information in the context of brain tumors. Thus, this technique is a multiparametrical molecular imaging method that can complete the magnetic resonance imaging (MRI) study enabling the detection of biochemical patterns of different features and aspects of brain tumors. In this article, the role of MRSI as a molecular imaging technique to provide biochemical information on human brain tumors is reviewed. The most frequent questions and situations in the study of human brain tumors in clinical settings will be considered, as well as the distinction of neoplastic lesions from non neoplastic, the tumor type identification, the study of heterogeneity and infiltration of normal appearing white matter and the therapy following with detection of side effects. The great amount of data in MRSI acquisition compared to the single voxel techniques requires the use of automated methods of quantification, but the possibility to obtain self-reference in the non-affected areas allows different strategies for data handling and interpretation, as presented in the literature. The combination of MRSI with other physiological MRI techniques and positron emission tomography is also included in this review.

The Neuropathology of Obesity: Insights from Human Disease

PubMed Central

Lee, Edward B.; Mattson, Mark P.

2013-01-01

Obesity, a pathologic state defined by excess adipose tissue, is a significant public health problem as it affects a large proportion of individuals and is linked with increased risk for numerous chronic diseases. Obesity is the result of fundamental changes associated with modern society including overnutrition and sedentary lifestyles. Proper energy homeostasis is dependent on normal brain function as the master metabolic regulator which integrates peripheral signals, modulates autonomic outflow and controls feeding behavior. Therefore, many human brain diseases are associated with obesity. This review explores the neuropathology of obesity by examining brain diseases which either cause or are influenced by obesity. First, several genetic and acquired brain diseases are discussed as a means to understand the central regulation of peripheral metabolism. These diseases range from monogenetic causes of obesity (leptin deficiency, MC4R deficiency, Bardet-Biedl syndrome and others) to complex neurodevelopmental disorders (Prader-Willi syndrome and Sim1 deficiency) and neurodegenerative conditions (frontotemporal dementia and Gourmand’s syndrome) and serve to highlight the central regulatory mechanisms which have evolved to maintain energy homeostasis. Next, to examine the effect of obesity on the brain, chronic neuropathologic conditions (epilepsy, multiple sclerosis and Alzheimer’s disease) are discussed as examples of obesity leading to maladaptive processes which exacerbate chronic disease. Thus obesity is associated with multiple pathways including abnormal metabolism, altered hormonal signaling and increased inflammation which act in concert to promote downstream neuropathology. Finally, the effect of anti-obesity interventions is discussed in terms of brain structure and function. Together, understanding human diseases and anti-obesity interventions leads to insights into the bidirectional interaction between peripheral metabolism and central brain function, highlighting the need for continued clinicopathologic and mechanistic studies of the neuropathology of obesity. PMID:24096619

Epigenetic Age Acceleration Assessed with Human White-Matter Images.

PubMed

Hodgson, Karen; Carless, Melanie A; Kulkarni, Hemant; Curran, Joanne E; Sprooten, Emma; Knowles, Emma E; Mathias, Samuel; Göring, Harald H H; Yao, Nailin; Olvera, Rene L; Fox, Peter T; Almasy, Laura; Duggirala, Ravi; Blangero, John; Glahn, David C

2017-05-03

The accurate estimation of age using methylation data has proved a useful and heritable biomarker, with acceleration in epigenetic age predicting a number of age-related phenotypes. Measures of white matter integrity in the brain are also heritable and highly sensitive to both normal and pathological aging processes across adulthood. We consider the phenotypic and genetic interrelationships between epigenetic age acceleration and white matter integrity in humans. Our goal was to investigate processes that underlie interindividual variability in age-related changes in the brain. Using blood taken from a Mexican-American extended pedigree sample ( n = 628; age = 23.28-93.11 years), epigenetic age was estimated using the method developed by Horvath (2013). For n = 376 individuals, diffusion tensor imaging scans were also available. The interrelationship between epigenetic age acceleration and global white matter integrity was investigated with variance decomposition methods. To test for neuroanatomical specificity, 16 specific tracts were additionally considered. We observed negative phenotypic correlations between epigenetic age acceleration and global white matter tract integrity (ρ pheno = -0.119, p = 0.028), with evidence of shared genetic (ρ gene = -0.463, p = 0.013) but not environmental influences. Negative phenotypic and genetic correlations with age acceleration were also seen for a number of specific white matter tracts, along with additional negative phenotypic correlations between granulocyte abundance and white matter integrity. These findings (i.e., increased acceleration in epigenetic age in peripheral blood correlates with reduced white matter integrity in the brain and shares common genetic influences) provide a window into the neurobiology of aging processes within the brain and a potential biomarker of normal and pathological brain aging. SIGNIFICANCE STATEMENT Epigenetic measures can be used to predict age with a high degree of accuracy and so capture acceleration in biological age, relative to chronological age. The white matter tracts within the brain are also highly sensitive to aging processes. We show that increased biological aging (measured using epigenetic data from blood samples) is correlated with reduced integrity of white matter tracts within the human brain (measured using diffusion tensor imaging) with data from a large sample of Mexican-American families. Given the family design of the sample, we are also able to demonstrate that epigenetic aging and white matter tract integrity also share common genetic influences. Therefore, epigenetic age may be a potential, and accessible, biomarker of brain aging. Copyright © 2017 the authors 0270-6474/17/374735-09$15.00/0.

Computational analysis of transcranial magnetic stimulation in the presence of deep brain stimulation probes

NASA Astrophysics Data System (ADS)

Syeda, F.; Holloway, K.; El-Gendy, A. A.; Hadimani, R. L.

2017-05-01

Transcranial Magnetic Stimulation is an emerging non-invasive treatment for depression, Parkinson's disease, and a variety of other neurological disorders. Many Parkinson's patients receive the treatment known as Deep Brain Stimulation, but often require additional therapy for speech and swallowing impairment. Transcranial Magnetic Stimulation has been explored as a possible treatment by stimulating the mouth motor area of the brain. We have calculated induced electric field, magnetic field, and temperature distributions in the brain using finite element analysis and anatomically realistic heterogeneous head models fitted with Deep Brain Stimulation leads. A Figure of 8 coil, current of 5000 A, and frequency of 2.5 kHz are used as simulation parameters. Results suggest that Deep Brain Stimulation leads cause surrounding tissues to experience slightly increased E-field (Δ Emax =30 V/m), but not exceeding the nominal values induced in brain tissue by Transcranial Magnetic Stimulation without leads (215 V/m). The maximum temperature in the brain tissues surrounding leads did not change significantly from the normal human body temperature of 37 °C. Therefore, we ascertain that Transcranial Magnetic Stimulation in the mouth motor area may stimulate brain tissue surrounding Deep Brain Stimulation leads, but will not cause tissue damage.

Joint Estimation of Effective Brain Wave Activation Modes Using EEG/MEG Sensor Arrays and Multimodal MRI Volumes.

PubMed

Galinsky, Vitaly L; Martinez, Antigona; Paulus, Martin P; Frank, Lawrence R

2018-04-13

In this letter, we present a new method for integration of sensor-based multifrequency bands of electroencephalography and magnetoencephalography data sets into a voxel-based structural-temporal magnetic resonance imaging analysis by utilizing the general joint estimation using entropy regularization (JESTER) framework. This allows enhancement of the spatial-temporal localization of brain function and the ability to relate it to morphological features and structural connectivity. This method has broad implications for both basic neuroscience research and clinical neuroscience focused on identifying disease-relevant biomarkers by enhancing the spatial-temporal resolution of the estimates derived from current neuroimaging modalities, thereby providing a better picture of the normal human brain in basic neuroimaging experiments and variations associated with disease states.

Topographic brain mapping of emotion-related hemisphere asymmetries.

PubMed

Roschmann, R; Wittling, W

1992-03-01

The study used topographic brain mapping of visual evoked potentials to investigate emotion-related hemisphere asymmetries. The stimulus material consisted of color photographs of human faces, grouped into two emotion-related categories: normal faces (neutral stimuli) and faces deformed by dermatological diseases (emotional stimuli). The pictures were presented tachistoscopically to 20 adult right-handed subjects. Brain activity was recorded by 30 EEG electrodes with linked ears as reference. The waveforms were averaged separately with respect to each of the two stimulus conditions. Statistical analysis by means of significance probability mapping revealed significant differences between stimulus conditions for two periods of time, indicating right hemisphere superiority in emotion-related processing. The results are discussed in terms of a 2-stage-model of emotional processing in the cerebral hemispheres.

MET receptor tyrosine kinase as an autism genetic risk factor.

PubMed

Peng, Yun; Huentelman, Matthew; Smith, Christopher; Qiu, Shenfeng

2013-01-01

In this chapter, we will briefly discuss recent literature on the role of MET receptor tyrosine kinase (RTK) in brain development and how perturbation of MET signaling may alter normal neurodevelopmental outcomes. Recent human genetic studies have established MET as a risk factor for autism, and the molecular and cellular underpinnings of this genetic risk are only beginning to emerge from obscurity. Unlike many autism risk genes that encode synaptic proteins, the spatial and temporal expression pattern of MET RTK indicates this signaling system is ideally situated to regulate neuronal growth, functional maturation, and establishment of functional brain circuits, particularly in those brain structures involved in higher levels of cognition, social skills, and executive functions. © 2013 Elsevier Inc. All rights reserved.

HIP1, a human homologue of S. cerevisiae Sla2p, interacts with membrane-associated huntingtin in the brain.

PubMed

Kalchman, M A; Koide, H B; McCutcheon, K; Graham, R K; Nichol, K; Nishiyama, K; Kazemi-Esfarjani, P; Lynn, F C; Wellington, C; Metzler, M; Goldberg, Y P; Kanazawa, I; Gietz, R D; Hayden, M R

1997-05-01

Huntington disease (HD) is associated with the expansion of a polyglutamine tract, greater than 35 repeats, in the HD gene product, huntingtin. Here we describe a novel huntingtin interacting protein, HIP1, which co-localizes with huntingtin and shares sequence homology and biochemical characteristics with Sla2p, a protein essential for function of the cytoskeleton in Saccharomyces cerevisiae. The huntingtin-HIP1 interaction is restricted to the brain and is inversely correlated to the polyglutamine length in huntingtin. This provides the first molecular link between huntingtin and the neuronal cytoskeleton and suggests that, in HD, loss of normal huntingtin-HIP1 interaction may contribute to a defect in membrane-cytoskeletal integrity in the brain.

Studies of the endothelial origin of cells in systemic angioendotheliomatosis and other vascular lesions of the brain and meninges using ulex europaeus lectin stains.

PubMed

Schelper, R L; Olson, S P; Carroll, T J; Hart, M N; Witters, E

1986-01-01

Ulex europaeus agglutinin I (UEA-I) is a plant lectin which binds specifically to alpha-L-fucose moieties on the surface glycoproteins of human endothelial cells. The binding is completely inhibited by preincubation of the lectin with fucose. UEA-I can be conjugated directly to fluorescein or peroxidase and can be used to stain endothelium of paraffin embedded tissues. UEA-I staining was evaluated on normal and infarcted brain, systemic angioendotheliomatosis, metastatic epidural angiosarcoma, hemangioendothelioma, hemangioblastoma, angioblastic meningioma of both the hemangioblastic and hemangiopericytic types, and vascular meningioma. The endothelium, but not neuropil of normal and infarcted brain was positive for UEA-I. The tumor cells of hemangioendothelioma and angiosarcoma also stained. However, no staining was seen in malignant intravascular cells of angioendotheliomatosis, the stromal cells of hemangioblastoma, or pericytes of angioblastic meningioma. It is concluded that the malignant cells in angioendotheliomatosis, the stromal cells of hemangioblastoma and the pericytes of angioblastic meningioma do not produce surface glycoproteins characteristic of endothelial cells.

Effects of irregular cerebrospinal fluid production rate in human brain ventricular system

NASA Astrophysics Data System (ADS)

Hadzri, Edi Azali; Shamsudin, Amir Hamzah; Osman, Kahar; Abdul Kadir, Mohammed Rafiq; Aziz, Azian Abd

2012-06-01

Hydrocephalus is an abnormal accumulation of fluid in the ventricles and cavities in the brain. It occurs when the cerebrospinal fluid (CSF) flow or absorption is blocked or when excessive CSF is secreted. The excessive accumulation of CSF results in an abnormal widening of the ventricles. This widening creates potentially harmful pressure on the tissues of the brain. In this study, flow analysis of CSF was conducted on a three-dimensional model of the third ventricle and aqueduct of Sylvius, derived from MRI scans. CSF was modeled as Newtonian Fluid and its flow through the region of interest (ROI) was done using EFD. Lab software. Different steady flow rates through the Foramen of Monro, classified by normal and hydrocephalus cases, were modeled to investigate its effects. The results show that, for normal and hydrocephalus cases, the pressure drop of CSF flow across the third ventricle was observed to be linearly proportionally to the production rate increment. In conclusion, flow rates that cause pressure drop of 5 Pa was found to be the threshold for the initial sign of hydrocephalus.

Strategic Resource Allocation in the Human Brain Supports Cognitive Coordination of Object and Spatial Working Memory

PubMed Central

Jackson, Margaret C; Morgan, Helen M; Shapiro, Kimron L; Mohr, Harald; Linden, David EJ

2011-01-01

The ability to integrate different types of information (e.g., object identity and spatial orientation) and maintain or manipulate them concurrently in working memory (WM) facilitates the flow of ongoing tasks and is essential for normal human cognition. Research shows that object and spatial information is maintained and manipulated in WM via separate pathways in the brain (object/ventral versus spatial/dorsal). How does the human brain coordinate the activity of different specialized systems to conjoin different types of information? Here we used functional magnetic resonance imaging to investigate conjunction- versus single-task manipulation of object (compute average color blend) and spatial (compute intermediate angle) information in WM. Object WM was associated with ventral (inferior frontal gyrus, occipital cortex), and spatial WM with dorsal (parietal cortex, superior frontal, and temporal sulci) regions. Conjoined object/spatial WM resulted in intermediate activity in these specialized areas, but greater activity in different prefrontal and parietal areas. Unique to our study, we found lower temporo-occipital activity and greater deactivation in temporal and medial prefrontal cortices for conjunction- versus single-tasks. Using structural equation modeling, we derived a conjunction-task connectivity model that comprises a frontoparietal network with a bidirectional DLPFC-VLPFC connection, and a direct parietal-extrastriate pathway. We suggest that these activation/deactivation patterns reflect efficient resource allocation throughout the brain and propose a new extended version of the biased competition model of WM. Hum Brain Mapp, 2011. © 2010 Wiley-Liss, Inc. PMID:20715083

Label-Free Delineation of Brain Tumors by Coherent Anti-Stokes Raman Scattering Microscopy in an Orthotopic Mouse Model and Human Glioblastoma

PubMed Central

Tamosaityte, Sandra; Leipnitz, Elke; Geiger, Kathrin D.; Schackert, Gabriele; Koch, Edmund; Steiner, Gerald; Kirsch, Matthias

2014-01-01

Background Coherent anti-Stokes Raman scattering (CARS) microscopy provides fine resolution imaging and displays morphochemical properties of unstained tissue. Here, we evaluated this technique to delineate and identify brain tumors. Methods Different human tumors (glioblastoma, brain metastases of melanoma and breast cancer) were induced in an orthotopic mouse model. Cryosections were investigated by CARS imaging tuned to probe C-H molecular vibrations, thereby addressing the lipid content of the sample. Raman microspectroscopy was used as reference. Histopathology provided information about the tumor's localization, cell proliferation and vascularization. Results The morphochemical contrast of CARS images enabled identifying brain tumors irrespective of the tumor type and properties: All tumors were characterized by a lower CARS signal intensity than the normal parenchyma. On this basis, tumor borders and infiltrations could be identified with cellular resolution. Quantitative analysis revealed that the tumor-related reduction of CARS signal intensity was more pronounced in glioblastoma than in metastases. Raman spectroscopy enabled relating the CARS intensity variation to the decline of total lipid content in the tumors. The analysis of the immunohistochemical stainings revealed no correlation between tumor-induced cytological changes and the extent of CARS signal intensity reductions. The results were confirmed on samples of human glioblastoma. Conclusions CARS imaging enables label-free, rapid and objective identification of primary and secondary brain tumors. Therefore, it is a potential tool for diagnostic neuropathology as well as for intraoperative tumor delineation. PMID:25198698

Detecting brain tumor in pathological slides using hyperspectral imaging

PubMed Central

Ortega, Samuel; Fabelo, Himar; Camacho, Rafael; de la Luz Plaza, María; Callicó, Gustavo M.; Sarmiento, Roberto

2018-01-01

Hyperspectral imaging (HSI) is an emerging technology for medical diagnosis. This research work presents a proof-of-concept on the use of HSI data to automatically detect human brain tumor tissue in pathological slides. The samples, consisting of hyperspectral cubes collected from 400 nm to 1000 nm, were acquired from ten different patients diagnosed with high-grade glioma. Based on the diagnosis provided by pathologists, a spectral library of normal and tumor tissues was created and processed using three different supervised classification algorithms. Results prove that HSI is a suitable technique to automatically detect high-grade tumors from pathological slides. PMID:29552415

Detecting brain tumor in pathological slides using hyperspectral imaging.

PubMed

Ortega, Samuel; Fabelo, Himar; Camacho, Rafael; de la Luz Plaza, María; Callicó, Gustavo M; Sarmiento, Roberto

2018-02-01

Hyperspectral imaging (HSI) is an emerging technology for medical diagnosis. This research work presents a proof-of-concept on the use of HSI data to automatically detect human brain tumor tissue in pathological slides. The samples, consisting of hyperspectral cubes collected from 400 nm to 1000 nm, were acquired from ten different patients diagnosed with high-grade glioma. Based on the diagnosis provided by pathologists, a spectral library of normal and tumor tissues was created and processed using three different supervised classification algorithms. Results prove that HSI is a suitable technique to automatically detect high-grade tumors from pathological slides.

Antibodies against the voltage-dependent anion channel (VDAC) and its protective ligand hexokinase I in children with autism

PubMed Central

Gonzalez-Gronow, Mario; Cuchacovich, Miguel; Francos, Rina; Cuchacovich, Stephanie; Fernandez, Maria del Pilar; Blanco, Angel; Bowers, Edith V.; Kaczowka, Steven; Pizzo, Salvatore V.

2010-01-01

Autistic children show elevated serum levels of autoantibodies to several proteins essential for the function of normal brains. The voltage-dependent anion channel, VDAC, and hexokinase-I, a VDAC protective ligand, were identified as targets of this autoimmunity in autistic children. These autoantibodies were purified using immunoaffinity chromatographic techniques. Both antibodies induce apoptosis of cultured human neuroblastoma cells. Because VDAC and hexokinase-I are essential for brain protection from ischemic damage, the presence of these autoantibodies suggests a possible causal role in the neurologic pathogenesis of autism. PMID:20576296

Intraoperative optical biopsy for brain tumors using spectro-lifetime properties of intrinsic fluorophores

NASA Astrophysics Data System (ADS)

Vasefi, Fartash; Kittle, David S.; Nie, Zhaojun; Falcone, Christina; Patil, Chirag G.; Chu, Ray M.; Mamelak, Adam N.; Black, Keith L.; Butte, Pramod V.

2016-04-01

We have developed and tested a system for real-time intra-operative optical identification and classification of brain tissues using time-resolved fluorescence spectroscopy (TRFS). A supervised learning algorithm using linear discriminant analysis (LDA) employing selected intrinsic fluorescence decay temporal points in 6 spectral bands was employed to maximize statistical significance difference between training groups. The linear discriminant analysis on in vivo human tissues obtained by TRFS measurements (N = 35) were validated by histopathologic analysis and neuronavigation correlation to pre-operative MRI images. These results demonstrate that TRFS can differentiate between normal cortex, white matter and glioma.

Epilepsy, regulation of brain energy metabolism and neurotransmission.

PubMed

Cloix, Jean-François; Hévor, Tobias

2009-01-01

Seizures are the result of a sudden and temporary synchronization of neuronal activity, the reason for which is not clearly understood. Astrocytes participate in the control of neurotransmitter storage and neurotransmission efficacy. They provide fuel to neurons, which need a high level of energy to sustain normal and pathological neuronal activities, such as during epilepsy. Various genetic or induced animal models have been developed and used to study epileptogenic mechanisms. Methionine sulfoximine induces both seizures and the accumulation of brain glycogen, which might be considered as a putative energy store to neurons in various animals. Animals subjected to methionine sulfoximine develop seizures similar to the most striking form of human epilepsy, with a long pre-convulsive period of several hours, a long convulsive period during up to 48 hours and a post convulsive period during which they recover normal behavior. The accumulation of brain glycogen has been demonstrated in both the cortex and cerebellum as early as the pre-convulsive period, indicating that this accumulation is not a consequence of seizures. The accumulation results from an activation of gluconeogenesis specifically localized to astrocytes, both in vivo and in vitro. Both seizures and brain glycogen accumulation vary when using different inbred strains of mice. C57BL/6J is the most "resistant" strain to methionine sulfoximine, while CBA/J is the most "sensitive" one. The present review describes the data obtained on methionine sulfoximine dependent seizures and brain glycogen in the light of neurotransmission, highlighting the relevance of brain glycogen content in epilepsies.

ASSOCIATION BETWEEN GAB2 HAPLOTYPE AND HIGHER GLUCOSE METABOLISM IN ALZHEIMER'S DISEASE-AFFECTED BRAIN REGIONS IN COGNITIVELY NORMAL APOEε4 CARRIERS

PubMed Central

Liang, Winnie S.; Chen, Kewei; Lee, Wendy; Sidhar, Kunal; Corneveaux, Jason J.; Allen, April N.; Myers, Amanda; Villa, Stephen; Meechoovet, Bessie; Pruzin, Jeremy; Bandy, Daniel; Fleisher, Adam S.; Langbaum, Jessica B.S.; Huentelman, Matthew J.; Jensen, Kendall; Dunckley, Travis; Caselli, Richard J.; Kaib, Susan; Reiman, Eric M.

2010-01-01

In a genome-wide association study (GWAS) of late-onset Alzheimer's disease (AD), we found an association between common haplotypes of the GAB2 gene and AD risk in carriers of the apolipoprotein E (APOE) ε4 allele, the major late-onset AD susceptibility gene. We previously proposed the use of fluorodeoxyglucose positron emission tomography (FDG-PET) measurements as a quantitative presymptomatic endophenotype, more closely related to disease risk than the clinical syndrome itself, to help evaluate putative genetic and non-genetic modifiers of AD risk. In this study, we examined the relationship between the presence or absence of the relatively protective GAB2 haplotype and PET measurements of regional-to-whole brain FDG uptake in several AD-affected brain regions in 158 cognitively normal late-middle-aged APOEε4 homozygotes, heterozygotes, and non-carriers. GAB2 haplotypes were characterized using Affymetrix Genome-Wide Human SNP 6.0 Array data from each of these subjects. As predicted, the possibly protective GAB2 haplotype was associated with higher regional-to-whole brain FDG uptake in AD-affected brain regions in APOEε4 carriers. While additional studies are needed, this study supports the association between the possibly protective GAB2 haplotype and the risk of late-onset AD in APOEε4 carriers. It also supports the use of brain-imaging endophenotypes to help assess possible modifiers of AD risk. PMID:20888920

Differential Lipid Profiles of Normal Human Brain Matter and Gliomas by Positive and Negative Mode Desorption Electrospray Ionization – Mass Spectrometry Imaging

PubMed Central

Pirro, Valentina; Hattab, Eyas M.; Cohen-Gadol, Aaron A.; Cooks, R. Graham

2016-01-01

Desorption electrospray ionization—mass spectrometry (DESI-MS) imaging was used to analyze unmodified human brain tissue sections from 39 subjects sequentially in the positive and negative ionization modes. Acquisition of both MS polarities allowed more complete analysis of the human brain tumor lipidome as some phospholipids ionize preferentially in the positive and others in the negative ion mode. Normal brain parenchyma, comprised of grey matter and white matter, was differentiated from glioma using positive and negative ion mode DESI-MS lipid profiles with the aid of principal component analysis along with linear discriminant analysis. Principal component–linear discriminant analyses of the positive mode lipid profiles was able to distinguish grey matter, white matter, and glioma with an average sensitivity of 93.2% and specificity of 96.6%, while the negative mode lipid profiles had an average sensitivity of 94.1% and specificity of 97.4%. The positive and negative mode lipid profiles provided complementary information. Principal component–linear discriminant analysis of the combined positive and negative mode lipid profiles, via data fusion, resulted in approximately the same average sensitivity (94.7%) and specificity (97.6%) of the positive and negative modes when used individually. However, they complemented each other by improving the sensitivity and specificity of all classes (grey matter, white matter, and glioma) beyond 90% when used in combination. Further principal component analysis using the fused data resulted in the subgrouping of glioma into two groups associated with grey and white matter, respectively, a separation not apparent in the principal component analysis scores plots of the separate positive and negative mode data. The interrelationship of tumor cell percentage and the lipid profiles is discussed, and how such a measure could be used to measure residual tumor at surgical margins. PMID:27658243

Speech-induced striatal dopamine release is left lateralized and coupled to functional striatal circuits in healthy humans: A combined PET, fMRI and DTI study

PubMed Central

Simonyan, Kristina; Herscovitch, Peter; Horwitz, Barry

2013-01-01

Considerable progress has been recently made in understanding the brain mechanisms underlying speech and language control. However, the neurochemical underpinnings of normal speech production remain largely unknown. We investigated the extent of striatal endogenous dopamine release and its influences on the organization of functional striatal speech networks during production of meaningful English sentences using a combination of positron emission tomography (PET) with the dopamine D2/D3 receptor radioligand [11C]raclopride and functional MRI (fMRI). In addition, we used diffusion tensor tractography (DTI) to examine the extent of dopaminergic modulatory influences on striatal structural network organization. We found that, during sentence production, endogenous dopamine was released in the ventromedial portion of the dorsal striatum, in its both associative and sensorimotor functional divisions. In the associative striatum, speech-induced dopamine release established a significant relationship with neural activity and influenced the left-hemispheric lateralization of striatal functional networks. In contrast, there were no significant effects of endogenous dopamine release on the lateralization of striatal structural networks. Our data provide the first evidence for endogenous dopamine release in the dorsal striatum during normal speaking and point to the possible mechanisms behind the modulatory influences of dopamine on the organization of functional brain circuits controlling normal human speech. PMID:23277111

Analysis of alternative splicing associated with aging and neurodegeneration in the human brain

PubMed Central

Tollervey, James R.; Wang, Zhen; Hortobágyi, Tibor; Witten, Joshua T.; Zarnack, Kathi; Kayikci, Melis; Clark, Tyson A.; Schweitzer, Anthony C.; Rot, Gregor; Curk, Tomaž; Zupan, Blaž; Rogelj, Boris; Shaw, Christopher E.; Ule, Jernej

2011-01-01

Age is the most important risk factor for neurodegeneration; however, the effects of aging and neurodegeneration on gene expression in the human brain have most often been studied separately. Here, we analyzed changes in transcript levels and alternative splicing in the temporal cortex of individuals of different ages who were cognitively normal, affected by frontotemporal lobar degeneration (FTLD), or affected by Alzheimer's disease (AD). We identified age-related splicing changes in cognitively normal individuals and found that these were present also in 95% of individuals with FTLD or AD, independent of their age. These changes were consistent with increased polypyrimidine tract binding protein (PTB)–dependent splicing activity. We also identified disease-specific splicing changes that were present in individuals with FTLD or AD, but not in cognitively normal individuals. These changes were consistent with the decreased neuro-oncological ventral antigen (NOVA)–dependent splicing regulation, and the decreased nuclear abundance of NOVA proteins. As expected, a dramatic down-regulation of neuronal genes was associated with disease, whereas a modest down-regulation of glial and neuronal genes was associated with aging. Whereas our data indicated that the age-related splicing changes are regulated independently of transcript-level changes, these two regulatory mechanisms affected expression of genes with similar functions, including metabolism and DNA repair. In conclusion, the alternative splicing changes identified in this study provide a new link between aging and neurodegeneration. PMID:21846794

Aptamer-conjugated PEGylated quantum dots targeting epidermal growth factor receptor variant III for fluorescence imaging of glioma.

PubMed

Tang, Jiaze; Huang, Ning; Zhang, Xiang; Zhou, Tao; Tan, Ying; Pi, Jiangli; Pi, Li; Cheng, Si; Zheng, Huzhi; Cheng, Yuan

2017-01-01

The extent of resection is a significant prognostic factor in glioma patients. However, the maximum safe resection level is difficult to determine due to the inherent infiltrative character of tumors. Recently, fluorescence-guided surgery has emerged as a new technique that allows safe resection of glioma. In this study, we constructed a new kind of quantum dot (QD)-labeled aptamer (QD-Apt) nanoprobe by conjugating aptamer 32 (A32) to the QDs surface, which can specially bind to the tumors. A32 is a single-stranded DNA capable of binding to the epidermal growth factor receptor variant III (EGFRvIII) specially distributed on the surface of glioma cells. To detect the expression of EGFRvIII in human brain tissues, 120 specimens, including 110 glioma tissues and 10 normal brain tissues, were examined by immunohistochemistry, and the results showed that the rate of positive expression of EGFRvIII in the glioma tissues was 41.82%, and 0.00% in normal brain tissues. Besides, the physiochemical properties of QD-Apt nanoparticles (NPs) were thoroughly characterized. Biocompatibility of the NPs was evaluated, and the results suggested that the QD-Apt was nontoxic in vivo and vitro. Furthermore, the use of the QD-Apt in labeling glioma cell lines and human brain glioma tissues, and target gliomas in situ was also investigated. We found that not only could QD-Apt specially bind to the U87-EGFRvIII glioma cells but also bind to human glioma tissues in vitro. Fluorescence imaging in vivo with orthotopic glioma model mice bearing U87-EGFRvIII showed that QD-Apt could penetrate the blood-brain barrier and then selectively accumulate in the tumors through binding to EGFRvIII, and consequently, generate a strong fluorescence, which contributed to the margins of gliomas that were visualized clearly, and thus, help the surgeons realize the maximum safe resection of glioma. In addition, QD-Apt can also be applied in preoperative diagnosis and postoperative examination of glioma. Therefore, these achievements facilitate the use of tumor-targeted fluorescence imaging in the diagnosis, surgical resection, and postoperative examination of glioma.

Aptamer-conjugated PEGylated quantum dots targeting epidermal growth factor receptor variant III for fluorescence imaging of glioma

PubMed Central

Tang, Jiaze; Huang, Ning; Zhang, Xiang; Zhou, Tao; Tan, Ying; Pi, Jiangli; Pi, Li; Cheng, Si; Zheng, Huzhi; Cheng, Yuan

2017-01-01

The extent of resection is a significant prognostic factor in glioma patients. However, the maximum safe resection level is difficult to determine due to the inherent infiltrative character of tumors. Recently, fluorescence-guided surgery has emerged as a new technique that allows safe resection of glioma. In this study, we constructed a new kind of quantum dot (QD)-labeled aptamer (QD-Apt) nanoprobe by conjugating aptamer 32 (A32) to the QDs surface, which can specially bind to the tumors. A32 is a single-stranded DNA capable of binding to the epidermal growth factor receptor variant III (EGFRvIII) specially distributed on the surface of glioma cells. To detect the expression of EGFRvIII in human brain tissues, 120 specimens, including 110 glioma tissues and 10 normal brain tissues, were examined by immunohistochemistry, and the results showed that the rate of positive expression of EGFRvIII in the glioma tissues was 41.82%, and 0.00% in normal brain tissues. Besides, the physiochemical properties of QD-Apt nanoparticles (NPs) were thoroughly characterized. Biocompatibility of the NPs was evaluated, and the results suggested that the QD-Apt was nontoxic in vivo and vitro. Furthermore, the use of the QD-Apt in labeling glioma cell lines and human brain glioma tissues, and target gliomas in situ was also investigated. We found that not only could QD-Apt specially bind to the U87-EGFRvIII glioma cells but also bind to human glioma tissues in vitro. Fluorescence imaging in vivo with orthotopic glioma model mice bearing U87-EGFRvIII showed that QD-Apt could penetrate the blood–brain barrier and then selectively accumulate in the tumors through binding to EGFRvIII, and consequently, generate a strong fluorescence, which contributed to the margins of gliomas that were visualized clearly, and thus, help the surgeons realize the maximum safe resection of glioma. In addition, QD-Apt can also be applied in preoperative diagnosis and postoperative examination of glioma. Therefore, these achievements facilitate the use of tumor-targeted fluorescence imaging in the diagnosis, surgical resection, and postoperative examination of glioma. PMID:28579776

Functional connectivity patterns of normal human swallowing: difference among various viscosity swallows in normal and chin-tuck head positions

PubMed Central

Jestrović, Iva; Coyle, James L.; Perera, Subashan

2016-01-01

Consuming thicker fluids and swallowing in the chin-tuck position has been shown to be advantageous for some patients with neurogenic dysphagia who aspirate due to various causes. The anatomical changes caused by these therapeutic techniques are well known, but it is unclear whether these changes alter the cerebral processing of swallow-related sensorimotor activity. We sought to investigate the effect of increased fluid viscosity and chin-down posture during swallowing on brain networks. 55 healthy adults performed water, nectar-thick, and honey thick liquid swallows in the neutral and chin-tuck positions while EEG signals were recorded. After pre-processing of the EEG timeseries, the time-frequency based synchrony measure was used for forming the brain networks to investigate whether there were differences among the brain networks between the swallowing of different fluid viscosities and swallowing in different head positions. We also investigated whether swallowing under various conditions exhibit small-world properties. Results showed that fluid viscosity affects the brain network in the Delta, Theta, Alpha, Beta, and Gamma frequency bands and that swallowing in the chin-tuck head position affects brain networks in the Alpha, Beta, and Gamma frequency bands. In addition, we showed that swallowing in all tested conditions exhibited small-world properties. Therefore, fluid viscosity and head positions should be considered in future swallowing EEG investigations. PMID:27693396

Comparative evaluation of methylene blue and demeclocycline for enhancing optical contrast of brain neoplasms

NASA Astrophysics Data System (ADS)

Wirth, Dennis J.

Brain tumors cause significant morbidity and mortality even when benign. Completeness of resection of brain tumors has been associated with better quality of life. However, that is often difficult to accomplish. The goal of this study was to evaluate the feasibility of using contrast enhanced multimodal confocal imaging for intraoperative detection of brain neoplasms. Different types of benign and malignant, primary and metastatic brain tumors, stained with Methylene Blue (MB) as a contrast agent, were imaged. MB is a traditional histopathologic stain that absorbs light in the red spectral range and fluoresces in the near infrared. It is FDA-approved for in vivo staining of human skin and breast tissue. Optical images showed good correlation with histopathology, demonstrating the potential of contrast enhanced multimodal confocal imaging for intraoperative detection of brain neoplasms ex vivo. However, the safety of MB for staining human brain in vivo is questionable. Demeclocycline (DMN), an antibiotic of the tetracycline family, has shown to be effective in differentiating normal from cancerous tissue in various organs. DMN is a fluorophore, which absorbs light in the violet spectral range and has a broad emission band covering green and yellow wavelengths. It is commonly used to treat infection and inflammatory disorders, and could provide a safer alternative to MB. To test this hypothesis, fresh excess human brain tissues were bisected and stained with aqueous solutions of either MB or DMN and then imaged. Reflectance and fluorescence images acquired from tissues stained with the two dyes were compared, and correlated with processed H&E histopathology. Comparison showed similar staining patterns and contrast of diagnostic features in glioblastomas, stained using either MB or DMN. The results show potential of both MB and DMN for the intraoperative detection of microscopic nests of brain neoplasms. Further studies will establish safety and efficacy of these agents in vivo.

Functional expression of SGLTs in rat brain.

PubMed

Yu, Amy S; Hirayama, Bruce A; Timbol, Gerald; Liu, Jie; Basarah, Ernest; Kepe, Vladimir; Satyamurthy, Nagichettiar; Huang, Sung-Cheng; Wright, Ernest M; Barrio, Jorge R

2010-12-01

This work provides evidence of previously unrecognized uptake of glucose via sodium-coupled glucose transporters (SGLTs) in specific regions of the brain. The current understanding of functional glucose utilization in brain is largely based on studies using positron emission tomography (PET) with the glucose tracer 2-deoxy-2-[F-18]fluoro-D-glucose (2-FDG). However, 2-FDG is only a good substrate for facilitated-glucose transporters (GLUTs), not for SGLTs. Thus, glucose accumulation measured by 2-FDG omits the role of SGLTs. We designed and synthesized two high-affinity tracers: one, α-methyl-4-[F-18]fluoro-4-deoxy-D-glucopyranoside (Me-4FDG), is a highly specific SGLT substrate and not transported by GLUTs; the other one, 4-[F-18]fluoro-4-deoxy-D-glucose (4-FDG), is transported by both SGLTs and GLUTs and will pass through the blood brain barrier (BBB). In vitro Me-4FDG autoradiography was used to map the distribution of uptake by functional SGLTs in brain slices with a comparable result from in vitro 4-FDG autoradiography. Immunohistochemical assays showed that uptake was consistent with the distribution of SGLT protein. Ex vivo 4-FDG autoradiography showed that SGLTs in these areas are functionally active in the normal in vivo brain. The results establish that SGLTs are a normal part of the physiology of specific areas of the brain, including hippocampus, amygdala, hypothalamus, and cerebral cortices. 4-FDG PET imaging also established that this BBB-permeable SGLT tracer now offers a functional imaging approach in humans to assess regulation of SGLT activity in health and disease.

The habenula in neurosurgery for depression: A convergence of functional neuroanatomy, psychiatry and imaging.

PubMed

Skandalakis, Georgios P; Koutsarnakis, Christos; Kalyvas, Aristotelis V; Skandalakis, Panagiotis; Johnson, Elizabeth O; Stranjalis, George

2018-05-05

The habenula is a small, mostly underrated structure in the pineal region. Multidisciplinary findings demonstrate an underlying complex connectivity of the habenula with the rest of the brain, subserving its major role in normal behavior and the pathophysiology of depression. These findings suggest the potential application of "habenular psychosurgery" in the treatment of mental disorders. The remission of two patients with treatment-resistant major depression treated with deep brain stimulation of the habenula supported the hypothesis that the habenula is an effective target for deep brain stimulation and initiated a surge of basic science research. This review aims to assess the viability of the deep brain stimulation of the habenula as a treatment option for treatment resistant depression. PubMed and the Cochrane Library databases were searched with no chronological restrictions for the identification of relevant articles. The results of this review are presented in a narrative form describing the functional neuroanatomy of the human habenula, its implications in major depression, findings of electrode implantation of this region and findings of deep brain stimulation of the habenula for the treatment of depression. Data assessing the hypothesis are scarce. Nonetheless, findings highlight the major role of the habenula in normal, as well as in pathological brain function, particularly in depression disorders. Moreover, findings of studies utilizing electrode implantation in the region of the habenula underscore our growing realization that research in neuroscience and deep brain stimulation complement each other in a reciprocal relationship; they are as self-reliant, as much as they depend on each other. Copyright © 2018. Published by Elsevier B.V.

Analysis of Resting-State fMRI Topological Graph Theory Properties in Methamphetamine Drug Users Applying Box-Counting Fractal Dimension.

PubMed

Siyah Mansoory, Meysam; Oghabian, Mohammad Ali; Jafari, Amir Homayoun; Shahbabaie, Alireza

2017-01-01

Graph theoretical analysis of functional Magnetic Resonance Imaging (fMRI) data has provided new measures of mapping human brain in vivo. Of all methods to measure the functional connectivity between regions, Linear Correlation (LC) calculation of activity time series of the brain regions as a linear measure is considered the most ubiquitous one. The strength of the dependence obligatory for graph construction and analysis is consistently underestimated by LC, because not all the bivariate distributions, but only the marginals are Gaussian. In a number of studies, Mutual Information (MI) has been employed, as a similarity measure between each two time series of the brain regions, a pure nonlinear measure. Owing to the complex fractal organization of the brain indicating self-similarity, more information on the brain can be revealed by fMRI Fractal Dimension (FD) analysis. In the present paper, Box-Counting Fractal Dimension (BCFD) is introduced for graph theoretical analysis of fMRI data in 17 methamphetamine drug users and 18 normal controls. Then, BCFD performance was evaluated compared to those of LC and MI methods. Moreover, the global topological graph properties of the brain networks inclusive of global efficiency, clustering coefficient and characteristic path length in addict subjects were investigated too. Compared to normal subjects by using statistical tests (P<0.05), topological graph properties were postulated to be disrupted significantly during the resting-state fMRI. Based on the results, analyzing the graph topological properties (representing the brain networks) based on BCFD is a more reliable method than LC and MI.

Three-Dimensional Magnetic Resonance Spectroscopic Imaging of Brain and Prostate Cancer1

PubMed Central

Kurhanewicz, John; Vigneron, Daniel B; Nelson, Sarah J

2000-01-01

Abstract Clinical applications of magnetic resonance spectroscopic imaging (MRSI) for the study of brain and prostate cancer have expanded significantly over the past 10 years. Proton MRSI studies of the brain and prostate have demonstrated the feasibility of noninvasively assessing human cancers based on metabolite levels before and after therapy in a clinically reasonable amount of time. MRSI provides a unique biochemical “window” to study cellular metabolism noninvasively. MRSI studies have demonstrated dramatic spectral differences between normal brain tissue (low choline and high N-acetyl aspartate, NAA) and prostate (low choline and high citrate) compared to brain (low NAA, high choline) and prostate (low citrate, high choline) tumors. The presence of edema and necrosis in both the prostate and brain was reflected by a reduction of the intensity of all resonances due to reduced cell density. MRSI was able to discriminate necrosis (absence of all metabolites, except lipids and lactate) from viable normal tissue and cancer following therapy. The results of current MRSI studies also provide evidence that the magnitude of metabolic changes in regions of cancer before therapy as well as the magnitude and time course of metabolic changes after therapy can improve our understanding of cancer aggressiveness and mechanisms of therapeutic response. Clinically, combined MRI/MRSI has already demonstrated the potential for improved diagnosis, staging and treatment planning of brain and prostate cancer. Additionally, studies are under way to determine the accuracy of anatomic and metabolic parameters in providing an objective quantitative basis for assessing disease progression and response to therapy. PMID:10933075

The maturation of cortical sleep rhythms and networks over early development.

PubMed

Chu, C J; Leahy, J; Pathmanathan, J; Kramer, M A; Cash, S S

2014-07-01

Although neuronal activity drives all aspects of cortical development, how human brain rhythms spontaneously mature remains an active area of research. We sought to systematically evaluate the emergence of human brain rhythms and functional cortical networks over early development. We examined cortical rhythms and coupling patterns from birth through adolescence in a large cohort of healthy children (n=384) using scalp electroencephalogram (EEG) in the sleep state. We found that the emergence of brain rhythms follows a stereotyped sequence over early development. In general, higher frequencies increase in prominence with striking regional specificity throughout development. The coordination of these rhythmic activities across brain regions follows a general pattern of maturation in which broadly distributed networks of low-frequency oscillations increase in density while networks of high frequency oscillations become sparser and more highly clustered. Our results indicate that a predictable program directs the development of key rhythmic components and physiological brain networks over early development. This work expands our knowledge of normal cortical development. The stereotyped neurophysiological processes observed at the level of rhythms and networks may provide a scaffolding to support critical periods of cognitive growth. Furthermore, these conserved patterns could provide a sensitive biomarker for cortical health across development. Copyright © 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

The maturation of cortical sleep rhythms and networks over early development

PubMed Central

Chu, CJ; Leahy, J; Pathmanathan, J; Kramer, MA; Cash, SS

2014-01-01

Objective Although neuronal activity drives all aspects of cortical development, how human brain rhythms spontaneously mature remains an active area of research. We sought to systematically evaluate the emergence of human brain rhythms and functional cortical networks over early development. Methods We examined cortical rhythms and coupling patterns from birth through adolescence in a large cohort of healthy children (n=384) using scalp electroencephalogram (EEG) in the sleep state. Results We found that the emergence of brain rhythms follows a stereotyped sequence over early development. In general, higher frequencies increase in prominence with striking regional specificity throughout development. The coordination of these rhythmic activities across brain regions follows a general pattern of maturation in which broadly distributed networks of low-frequency oscillations increase in density while networks of high frequency oscillations become sparser and more highly clustered. Conclusion Our results indicate that a predictable program directs the development of key rhythmic components and physiological brain networks over early development. Significance This work expands our knowledge of normal cortical development. The stereotyped neurophysiological processes observed at the level of rhythms and networks may provide a scaffolding to support critical periods of cognitive growth. Furthermore, these conserved patterns could provide a sensitive biomarker for cortical health across development. PMID:24418219

Early Neurodegeneration in the Brain of a Child Without Functional PKR-like Endoplasmic Reticulum Kinase.

PubMed

Bruch, Julius; Kurz, Carolin; Vasiljevic, Alexandre; Nicolino, Marc; Arzberger, Thomas; Höglinger, Günter U

2015-08-01

We report the first detailed examination of the brain of a patient with Wolcott-Rallison syndrome. Wolcott-Rallison syndrome is an extremely rare clinical manifestation of a lack of protein kinase R-like endoplasmic reticulum kinase (PERK) function caused by mutations in the PERK gene EIF2AK3. Protein kinase R-like endoplasmic reticulum kinase is thought to play a significant pathogenetic role in several neurodegenerative diseases, including Alzheimer disease, other tauopathies, and Parkinson disease. The brain of a male patient aged 4 years 7 months showed pathologic and immunohistochemical evidence that the absence of PERK for several years is sufficient to induce early changes reminiscent of various neurodegenerative conditions. These include neurofibrillary tangles (as in progressive supranuclear palsy), FUS-immunopositive and p62-immunopositive neurons, and reactive glial changes. We also detected an increased amount of p62-positive puncta coimmunostaining for LC3 and ubiquitin, suggesting changes in autophagic flux. Studying a human brain with absent PERK function presents the opportunity to assess the long-term consequences of nonfunctioning of PERK in the presence of all of the compensatory mechanisms that are normally active in a living human, thereby confirming the importance of PERK for autophagy in the brain and for neurodegeneration.

Reward-based hypertension control by a synthetic brain-dopamine interface.

PubMed

Rössger, Katrin; Charpin-El Hamri, Ghislaine; Fussenegger, Martin

2013-11-05

Synthetic biology has significantly advanced the design of synthetic trigger-controlled devices that can reprogram mammalian cells to interface with complex metabolic activities. In the brain, the neurotransmitter dopamine coordinates communication with target neurons via a set of dopamine receptors that control behavior associated with reward-driven learning. This dopamine transmission has recently been suggested to increase central sympathetic outflow, resulting in plasma dopamine levels that correlate with corresponding brain activities. By functionally rewiring the human dopamine receptor D1 (DRD1) via the second messenger cyclic adenosine monophosphate (cAMP) to synthetic promoters containing cAMP response element-binding protein 1(CREB1)-specific cAMP-responsive operator modules, we have designed a synthetic dopamine-sensitive transcription controller that reversibly fine-tunes specific target gene expression at physiologically relevant brain-derived plasma dopamine levels. Following implantation of circuit-transgenic human cell lines insulated by semipermeable immunoprotective microcontainers into mice, the designer device interfaced with dopamine-specific brain activities and produced a systemic expression response when the animal's reward system was stimulated by food, sexual arousal, or addictive drugs. Reward-triggered brain activities were able to remotely program peripheral therapeutic implants to produce sufficient amounts of the atrial natriuretic peptide, which reduced the blood pressure of hypertensive mice to the normal physiologic range. Seamless control of therapeutic transgenes by subconscious behavior may provide opportunities for treatment strategies of the future.

Study on Brain Dynamics by Non Linear Analysis of Music Induced EEG Signals

NASA Astrophysics Data System (ADS)

Banerjee, Archi; Sanyal, Shankha; Patranabis, Anirban; Banerjee, Kaushik; Guhathakurta, Tarit; Sengupta, Ranjan; Ghosh, Dipak; Ghose, Partha

2016-02-01

Music has been proven to be a valuable tool for the understanding of human cognition, human emotion, and their underlying brain mechanisms. The objective of this study is to analyze the effect of Hindustani music on brain activity during normal relaxing conditions using electroencephalography (EEG). Ten male healthy subjects without special musical education participated in the study. EEG signals were acquired at the frontal (F3/F4) lobes of the brain while listening to music at three experimental conditions (rest, with music and without music). Frequency analysis was done for the alpha, theta and gamma brain rhythms. The finding shows that arousal based activities were enhanced while listening to Hindustani music of contrasting emotions (romantic/sorrow) for all the subjects in case of alpha frequency bands while no significant changes were observed in gamma and theta frequency ranges. It has been observed that when the music stimulus is removed, arousal activities as evident from alpha brain rhythms remain for some time, showing residual arousal. This is analogous to the conventional 'Hysteresis' loop where the system retains some 'memory' of the former state. This is corroborated in the non linear analysis (Detrended Fluctuation Analysis) of the alpha rhythms as manifested in values of fractal dimension. After an input of music conveying contrast emotions, withdrawal of music shows more retention as evidenced by the values of fractal dimension.

Abnormal Injury Response in Spontaneous Mild Ventriculomegaly Wistar Rat Brains: A Pathological Correlation Study of Diffusion Tensor and Magnetization Transfer Imaging in Mild Traumatic Brain Injury.

PubMed

Tu, Tsang-Wei; Lescher, Jacob D; Williams, Rashida A; Jikaria, Neekita; Turtzo, L Christine; Frank, Joseph A

2017-01-01

Spontaneous mild ventriculomegaly (MVM) was previously reported in ∼43% of Wistar rats in association with vascular anomalies without phenotypic manifestation. This mild traumatic brain injury (TBI) weight drop model study investigates whether MVM rats (n = 15) have different injury responses that could inadvertently complicate the interpretation of imaging studies compared with normal rats (n = 15). Quantitative MRI, including diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI), and immunohistochemistry (IHC) analysis were used to examine the injury pattern up to 8 days post-injury in MVM and normal rats. Prior to injury, the MVM brain showed significant higher mean diffusivity, axial diffusivity, and radial diffusivity, and lower fractional anisotropy (FA) and magnetization transfer ratio (MTR) in the corpus callosum than normal brain (p < 0.05). Following TBI, normal brains exhibited significant decreases of FA in the corpus callosum, whereas MVM brains demonstrated insignificant changes in FA, suggesting less axonal injury. At day 8 after mild TBI, MTR of the normal brains significantly decreased whereas the MTR of the MVM brains significantly increased. IHC staining substantiated the MRI findings, demonstrating limited axonal injury with significant increase of microgliosis and astrogliosis in MVM brain compared with normal animals. The radiological-pathological correlation data showed that both DTI and MTI were sensitive in detecting mild diffuse brain injury, although DTI metrics were more specific in correlating with histologically identified pathologies. Compared with the higher correlation levels reflecting axonal injury pathology in the normal rat mild TBI, the DTI and MTR metrics were more affected by the increased inflammation in the MVM rat mild TBI. Because MVM Wistar rats appear normal, there was a need to screen rats prior to TBI research to rule out the presence of ventriculomegaly, which may complicate the interpretation of imaging and IHC observations.

Abnormal Injury Response in Spontaneous Mild Ventriculomegaly Wistar Rat Brains: A Pathological Correlation Study of Diffusion Tensor and Magnetization Transfer Imaging in Mild Traumatic Brain Injury

PubMed Central

Lescher, Jacob D.; Williams, Rashida A.; Jikaria, Neekita; Turtzo, L. Christine; Frank, Joseph A.

2017-01-01

Abstract Spontaneous mild ventriculomegaly (MVM) was previously reported in ∼43% of Wistar rats in association with vascular anomalies without phenotypic manifestation. This mild traumatic brain injury (TBI) weight drop model study investigates whether MVM rats (n = 15) have different injury responses that could inadvertently complicate the interpretation of imaging studies compared with normal rats (n = 15). Quantitative MRI, including diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI), and immunohistochemistry (IHC) analysis were used to examine the injury pattern up to 8 days post-injury in MVM and normal rats. Prior to injury, the MVM brain showed significant higher mean diffusivity, axial diffusivity, and radial diffusivity, and lower fractional anisotropy (FA) and magnetization transfer ratio (MTR) in the corpus callosum than normal brain (p < 0.05). Following TBI, normal brains exhibited significant decreases of FA in the corpus callosum, whereas MVM brains demonstrated insignificant changes in FA, suggesting less axonal injury. At day 8 after mild TBI, MTR of the normal brains significantly decreased whereas the MTR of the MVM brains significantly increased. IHC staining substantiated the MRI findings, demonstrating limited axonal injury with significant increase of microgliosis and astrogliosis in MVM brain compared with normal animals. The radiological-pathological correlation data showed that both DTI and MTI were sensitive in detecting mild diffuse brain injury, although DTI metrics were more specific in correlating with histologically identified pathologies. Compared with the higher correlation levels reflecting axonal injury pathology in the normal rat mild TBI, the DTI and MTR metrics were more affected by the increased inflammation in the MVM rat mild TBI. Because MVM Wistar rats appear normal, there was a need to screen rats prior to TBI research to rule out the presence of ventriculomegaly, which may complicate the interpretation of imaging and IHC observations. PMID:26905805

A Review of Sleep and Its Disorders in Patients with Parkinson's Disease in Relation to Various Brain Structures

PubMed Central

French, Isobel T.; Muthusamy, Kalai A.

2016-01-01

Sleep is an indispensable normal physiology of the human body fundamental for healthy functioning. It has been observed that Parkinson's disease (PD) not only exhibits motor symptoms, but also non-motor symptoms such as metabolic irregularities, altered olfaction, cardiovascular dysfunction, gastrointestinal complications and especially sleep disorders which is the focus of this review. A good understanding and knowledge of the different brain structures involved and how they function in the development of sleep disorders should be well comprehended in order to treat and alleviate these symptoms and enhance quality of life for PD patients. Therefore it is vital that the normal functioning of the body in relation to sleep is well understood before proceeding on to the pathophysiology of PD correlating to its symptoms. Suitable treatment can then be administered toward enhancing the quality of life of these patients, perhaps even discovering the cause for this disease. PMID:27242523

Crosstalk between metabolic and neuropsychiatric disorders

PubMed Central

Cha, Danielle S.

2012-01-01

Evidence supporting the concurrence of metabolic disturbances (e.g. insulin resistance, diabetes and obesity) and neuropsychiatric disorders has been demonstrated in both human and animal studies, suggesting the possibility that they have shared pathophysiological mechanisms. During the past decade, our understanding for the role of insulin in both normal and abnormal central nervous system (CNS) processes has become increasingly refined. Evidence indicates that insulin is a pleiotropic peptide, critical to neurotrophism, neuroplasticity, and neuromodulation. Moreover, the role of insulin underscores its importance in the development of several neuropsychiatric disorders, including, but not limited to, mechanisms involved in the pathogenesis and progression towards diabetes, obesity, and neurodegenerative disorders, such as Alzheimer's disease. This review focuses on the insulin-mediated effects on normal and abnormal brain function and discusses why targeting insulin-related pathways in the brain may emerge as a new approach for refining treatment of neurological and psychiatric disorders. PMID:22802875

Crosstalk between metabolic and neuropsychiatric disorders.

PubMed

Kaidanovich-Beilin, Oksana; Cha, Danielle S; McIntyre, Roger S

2012-01-01

Evidence supporting the concurrence of metabolic disturbances (e.g. insulin resistance, diabetes and obesity) and neuropsychiatric disorders has been demonstrated in both human and animal studies, suggesting the possibility that they have shared pathophysiological mechanisms. During the past decade, our understanding for the role of insulin in both normal and abnormal central nervous system (CNS) processes has become increasingly refined. Evidence indicates that insulin is a pleiotropic peptide, critical to neurotrophism, neuroplasticity, and neuromodulation. Moreover, the role of insulin underscores its importance in the development of several neuropsychiatric disorders, including, but not limited to, mechanisms involved in the pathogenesis and progression towards diabetes, obesity, and neurodegenerative disorders, such as Alzheimer's disease. This review focuses on the insulin-mediated effects on normal and abnormal brain function and discusses why targeting insulin-related pathways in the brain may emerge as a new approach for refining treatment of neurological and psychiatric disorders.

Resting state brain networks in the prairie vole.

PubMed

Ortiz, Juan J; Portillo, Wendy; Paredes, Raul G; Young, Larry J; Alcauter, Sarael

2018-01-19

Resting state functional magnetic resonance imaging (rsfMRI) has shown the hierarchical organization of the human brain into large-scale complex networks, referred as resting state networks. This technique has turned into a promising translational research tool after the finding of similar resting state networks in non-human primates, rodents and other animal models of great value for neuroscience. Here, we demonstrate and characterize the presence of resting states networks in Microtus ochrogaster, the prairie vole, an extraordinary animal model to study complex human-like social behavior, with potential implications for the research of normal social development, addiction and neuropsychiatric disorders. Independent component analysis of rsfMRI data from isoflurane-anestethized prairie voles resulted in cortical and subcortical networks, including primary motor and sensory networks, but also included putative salience and default mode networks. We further discuss how future research could help to close the gap between the properties of the large scale functional organization and the underlying neurobiology of several aspects of social cognition. These results contribute to the evidence of preserved resting state brain networks across species and provide the foundations to explore the use of rsfMRI in the prairie vole for basic and translational research.

White matter changes linked to visual recovery after nerve decompression

PubMed Central

Paul, David A.; Gaffin-Cahn, Elon; Hintz, Eric B.; Adeclat, Giscard J.; Zhu, Tong; Williams, Zoë R.; Vates, G. Edward; Mahon, Bradford Z.

2015-01-01

The relationship between the integrity of white matter tracts and cortical function in the human brain remains poorly understood. Here we use a model of reversible white matter injury, compression of the optic chiasm by tumors of the pituitary gland, to study the structural and functional changes that attend spontaneous recovery of cortical function and visual abilities after surgical tumor removal and subsequent decompression of the nerves. We show that compression of the optic chiasm leads to demyelination of the optic tracts, which reverses as quickly as 4 weeks after nerve decompression. Furthermore, variability across patients in the severity of demyelination in the optic tracts predicts visual ability and functional activity in early cortical visual areas, and pre-operative measurements of myelination in the optic tracts predicts the magnitude of visual recovery after surgery. These data indicate that rapid regeneration of myelin in the human brain is a significant component of the normalization of cortical activity, and ultimately the recovery of sensory and cognitive function, after nerve decompression. More generally, our findings demonstrate the utility of diffusion tensor imaging as an in vivo measure of myelination in the human brain. PMID:25504884

A Scalable Framework For Segmenting Magnetic Resonance Images

PubMed Central

Hore, Prodip; Goldgof, Dmitry B.; Gu, Yuhua; Maudsley, Andrew A.; Darkazanli, Ammar

2009-01-01

A fast, accurate and fully automatic method of segmenting magnetic resonance images of the human brain is introduced. The approach scales well allowing fast segmentations of fine resolution images. The approach is based on modifications of the soft clustering algorithm, fuzzy c-means, that enable it to scale to large data sets. Two types of modifications to create incremental versions of fuzzy c-means are discussed. They are much faster when compared to fuzzy c-means for medium to extremely large data sets because they work on successive subsets of the data. They are comparable in quality to application of fuzzy c-means to all of the data. The clustering algorithms coupled with inhomogeneity correction and smoothing are used to create a framework for automatically segmenting magnetic resonance images of the human brain. The framework is applied to a set of normal human brain volumes acquired from different magnetic resonance scanners using different head coils, acquisition parameters and field strengths. Results are compared to those from two widely used magnetic resonance image segmentation programs, Statistical Parametric Mapping and the FMRIB Software Library (FSL). The results are comparable to FSL while providing significant speed-up and better scalability to larger volumes of data. PMID:20046893

Extracts from black carrot tissue culture as potent anticancer agents.

PubMed

Sevimli-Gur, Canan; Cetin, Burcu; Akay, Seref; Gulce-Iz, Sultan; Yesil-Celiktas, Ozlem

2013-09-01

Black carrots contain anthocyanins possessing enhanced physiological activities. Explants of young black carrot shoots were cultured in Murashige and Skoog (MS) medium for callus initiation and were transferred to new MS medium supplemented with four different combinations of 2,4-dichlorophenoxyacetic acid and kinetin. Subsequently, the lyophilized calli and black carrot harvested from fields were subjected to ultrasound extraction with ethanol at a ratio of 1:15 (w:v). Obtained extracts were applied to various human cancer cell lines including MCF-7 SK-BR-3 and MDA-MB-231 (human breast adenocarcinomas), HT-29 (human colon adenocarcinoma), PC-3 (human prostate adenocarcinoma), Neuro 2A (Musmusculus neuroblastoma) cancer cell lines and VERO (African green monkey kidney) normal cell line by MTT assay. The highest cytotoxic activity was achieved against Neuro-2A cell lines exhibiting viability of 38-46% at 6.25 μg/ml concentration for all calli and natural extracts. However, a significantly high IC50 value of 170.13 μg/ml was attained in normal cell line VERO indicating that its natural counterpart is an ideal candidate for treatment of brain cancer without causing negative effects to normal healthy cells.

Cerebral localization, then and now.

PubMed

Marshall, John C; Fink, Gereon R

2003-11-01

We review some of the progress made in understanding the nature of functional specialization in the human brain, beginning with the anatomical claim that all mental faculties have their own distinct material substrate in different regions of the brain and the psychological claim that each mental faculty is characterized by the content domain with which it deals. This conceptual framework led behavioral neurologists to show how discrete brain lesions provoked different types of language, praxic, gnostic, spatial, and memory disorders. The simplest way of interpreting these anatomoclinical associations was to conjecture that the normal function (now impaired by brain damage) was localized within that lesioned region. It was also realized that cognitive impairments could arise from lesions that spared the functional centers themselves but disconnected them from other centers. Nonetheless, many neuroscientists remained skeptical of the entire paradigm. Accordingly, in the late 19th century functional localization began to be studied in the intact human brain by such techniques as measuring the temperature of different brain regions when different cognitive tasks were performed. During the 20th century these crude techniques gave way to positron emission tomography, functional magnetic resonance imaging, and magnetoencephalography. The relatively precise spatial and temporal resolution of modern methods now raises a crucial question: Do the functional localizations obtained by the anatomoclinical method converge with those implied by the functional neuroimaging of cognition in healthy volunteers? We then conclude with some recent suggestions that functional specialization is not such a fixed property of brain regions as previously supposed.

Use of Brain MRI Atlases to Determine Boundaries of Age-Related Pathology: The Importance of Statistical Method

PubMed Central

Dickie, David Alexander; Job, Dominic E.; Gonzalez, David Rodriguez; Shenkin, Susan D.; Wardlaw, Joanna M.

2015-01-01

Introduction Neurodegenerative disease diagnoses may be supported by the comparison of an individual patient’s brain magnetic resonance image (MRI) with a voxel-based atlas of normal brain MRI. Most current brain MRI atlases are of young to middle-aged adults and parametric, e.g., mean ±standard deviation (SD); these atlases require data to be Gaussian. Brain MRI data, e.g., grey matter (GM) proportion images, from normal older subjects are apparently not Gaussian. We created a nonparametric and a parametric atlas of the normal limits of GM proportions in older subjects and compared their classifications of GM proportions in Alzheimer’s disease (AD) patients. Methods Using publicly available brain MRI from 138 normal subjects and 138 subjects diagnosed with AD (all 55–90 years), we created: a mean ±SD atlas to estimate parametrically the percentile ranks and limits of normal ageing GM; and, separately, a nonparametric, rank order-based GM atlas from the same normal ageing subjects. GM images from AD patients were then classified with respect to each atlas to determine the effect statistical distributions had on classifications of proportions of GM in AD patients. Results The parametric atlas often defined the lower normal limit of the proportion of GM to be negative (which does not make sense physiologically as the lowest possible proportion is zero). Because of this, for approximately half of the AD subjects, 25–45% of voxels were classified as normal when compared to the parametric atlas; but were classified as abnormal when compared to the nonparametric atlas. These voxels were mainly concentrated in the frontal and occipital lobes. Discussion To our knowledge, we have presented the first nonparametric brain MRI atlas. In conditions where there is increasing variability in brain structure, such as in old age, nonparametric brain MRI atlases may represent the limits of normal brain structure more accurately than parametric approaches. Therefore, we conclude that the statistical method used for construction of brain MRI atlases should be selected taking into account the population and aim under study. Parametric methods are generally robust for defining central tendencies, e.g., means, of brain structure. Nonparametric methods are advisable when studying the limits of brain structure in ageing and neurodegenerative disease. PMID:26023913

Cumulative Brain Injury from Motor Vehicle-Induced Whole-Body Vibration and Prevention by Human Apolipoprotein A-I Molecule Mimetic (4F) Peptide (an Apo A-I Mimetic)

PubMed Central

Yan, Ji-Geng; Zhang, Lin-ling; Agresti, Michael; Yan, Yuhui; LoGiudice, John; Sanger, James R.; Matloub, Hani S.; Pritchard, Kirkwood A.; Jaradeh, Safwan S.; Havlik, Robert

2017-01-01

Background Insidious cumulative brain injury from motor vehicle-induced whole-body vibration (MV-WBV) has not yet been studied. The objective of the present study is to validate whether whole-body vibration for long periods causes cumulative brain injury and impairment of the cerebral function. We also explored a preventive method for MV-WBV injury. Methods A study simulating whole-body vibration was conducted in 72 male Sprague-Dawley rats divided into 9 groups (N = 8): (1) 2-week normal control; (2) 2-week sham control (in the tube without vibration); (3) 2-week vibration (exposed to whole-body vibration at 30 Hz and .5 G acceleration for 4 hours/day, 5 days/week for 2 weeks; vibration parameters in the present study are similar to the most common driving conditions); (4) 4-week sham control; (5) 4-week vibration; (6) 4-week vibration with human apolipoprotein A-I molecule mimetic (4F)-preconditioning; (7) 8-week sham control; (8) 8-week vibration; and (9) 8-week 4F-preconditioning group. All the rats were evaluated by behavioral, physiological, and histological studies of the brain. Results Brain injury from vibration is a cumulative process starting with cerebral vasoconstriction, squeezing of the endothelial cells, increased free radicals, decreased nitric oxide, insufficient blood supply to the brain, and repeated reperfusion injury to brain neurons. In the 8-week vibration group, which indicated chronic brain edema, shrunken neuron numbers increased and whole neurons atrophied, which strongly correlated with neural functional impairment. There was no prominent brain neuronal injury in the 4F groups. Conclusions The present study demonstrated cumulative brain injury from MV-WBV and validated the preventive effects of 4F preconditioning. PMID:26433438

Unmasking Language Lateralization in Human Brain Intrinsic Activity

PubMed Central

McAvoy, Mark; Mitra, Anish; Coalson, Rebecca S.; d'Avossa, Giovanni; Keidel, James L.; Petersen, Steven E.; Raichle, Marcus E.

2016-01-01

Lateralization of function is a fundamental feature of the human brain as exemplified by the left hemisphere dominance of language. Despite the prominence of lateralization in the lesion, split-brain and task-based fMRI literature, surprisingly little asymmetry has been revealed in the increasingly popular functional imaging studies of spontaneous fluctuations in the fMRI BOLD signal (so-called resting-state fMRI). Here, we show the global signal, an often discarded component of the BOLD signal in resting-state studies, reveals a leftward asymmetry that maps onto regions preferential for semantic processing in left frontal and temporal cortex and the right cerebellum and a rightward asymmetry that maps onto putative attention-related regions in right frontal, temporoparietal, and parietal cortex. Hemispheric asymmetries in the global signal resulted from amplitude modulation of the spontaneous fluctuations. To confirm these findings obtained from normal, healthy, right-handed subjects in the resting-state, we had them perform 2 semantic processing tasks: synonym and numerical magnitude judgment and sentence comprehension. In addition to establishing a new technique for studying lateralization through functional imaging of the resting-state, our findings shed new light on the physiology of the global brain signal. PMID:25636911

Clinical protocol. Gene therapy of Canavan disease: AAV-2 vector for neurosurgical delivery of aspartoacylase gene (ASPA) to the human brain.

PubMed

Janson, Christopher; McPhee, Scott; Bilaniuk, Larissa; Haselgrove, John; Testaiuti, Mark; Freese, Andrew; Wang, Dah-Jyuu; Shera, David; Hurh, Peter; Rupin, Joan; Saslow, Elizabeth; Goldfarb, Olga; Goldberg, Michael; Larijani, Ghassem; Sharrar, William; Liouterman, Larisa; Camp, Angelique; Kolodny, Edwin; Samulski, Jude; Leone, Paola

2002-07-20

This clinical protocol describes virus-based gene transfer for Canavan disease, a childhood leukodystrophy. Canavan disease, also known as Van Bogaert-Bertrand disease, is a monogeneic, autosomal recessive disease in which the gene coding for the enzyme aspartoacylase (ASPA) is defective. The lack of functional enzyme leads to an increase in the central nervous system of the substrate molecule, N-acetyl-aspartate (NAA), which impairs normal myelination and results in spongiform degeneration of the brain. No effective treatment currently exists; however, virus-based gene transfer has the potential to arrest or reverse the course of this otherwise fatal condition. This procedure involves neurosurgical administration of approximately 900 billion genomic particles (approximately 10 billion infectious particles) of recombinant adeno-associated virus (AAV) containing the aspartoacylase gene (ASPA) directly to affected regions of the brain in each of 21 patients with Canavan disease. Pre- and post-delivery assessments include a battery of noninvasive biochemical, radiological, and neurological tests. This gene transfer study represents the first clinical use of AAV in the human brain and the first instance of viral gene transfer for a neurodegenerative disease.

Glutamate and Glutamine: A Review of In Vivo MRS in the Human Brain

PubMed Central

Ramadan, Saadallah; Lin, Alexander; Stanwell, Peter

2013-01-01

Our understanding of the roles that the amino acids glutamate (Glu) and glutamine (Gln) play in the mammalian central nervous system has increased rapidly in recent times. Many conditions are known to exhibit a disturbance in Glu-Gln equilibrium and the exact relationship between these changed conditions and these amino acids are not fully understood. This has led to increased interest in Glu/Gln quantitation in the human brain in an array of conditions (e.g. mental illness, tumor, neuro-degeneration) as well as in normal brain function. Accordingly, this review has been undertaken to describe the increasing number of in vivo techniques available to study Glu and Gln separately, or pooled as ‘Glx’. The present range of magnetic resonance spectroscopy (MRS) methods used to assess Glu and Gln, vary in approach, complexity and outcome, thus the focus of this review is on a description of MRS acquisition approaches, and an indication of relative utility of each technique rather than brain pathologies associated to Glu and/or Gln perturbation. Consequently, this review focuses particularly on (1) one-dimensional (1D) 1H MRS, (2) two-dimensional (2D) 1H MRS, and (3) 1D 13C MRS techniques. PMID:24123328

Accelerated protein damage in brains of PIMT+/- mice; a possible model for the variability of cognitive decline in human aging.

PubMed

Qin, Zhenxia; Dimitrijevic, Aleksandra; Aswad, Dana W

2015-02-01

Isoaspartate formation is a common type of protein damage normally kept in check by the repair enzyme protein-L-isoaspartyl methyltransferase (PIMT). Mice with a knockout of the gene (Pcmt1) for this enzyme (KO, -/-) exhibit a pronounced neuropathology with fatal epileptic seizures at 30-60 days. Heterozygous (HZ, +/-) mice have 50% of the PIMT activity found in wild-type (WT, +/+) mice, but appear normal. To see if HZ mice exhibit accelerated aging at the molecular level, we compared brain extracts from HZ and WT mice at 8 months and 2 years with regard to PIMT activity, isoaspartate levels, and activity of an endogenous PIMT substrate, creatine kinase B. PIMT activity declined modestly with age in both genotypes. Isoaspartate was significantly higher in HZ than WT mice at 8 months and more so at 2 years, rising 5× faster in HZ males and 3× faster in females. Creatine kinase activity decreased with age and was always lower in the HZ mice. These findings suggest the individual variation of human PIMT levels may significantly influence the course of age-related central nervous system dysfunction. Copyright © 2015 Elsevier Inc. All rights reserved.

Anatomical Variations of the Circulus Arteriosus in Cadaveric Human Brains

PubMed Central

Gunnal, S. A.; Farooqui, M. S.; Wabale, R. N.

2014-01-01

Objective. Circulus arteriosus/circle of Willis (CW) is a polygonal anastomotic channel at the base of the brain which unites the internal carotid and vertebrobasilar system. It maintains the steady and constant supply to the brain. The variations of CW are seen often. The Aim of the present work is to find out the percentage of normal pattern of CW, and the frequency of variations of the CW and to study the morphological and morphometric aspects of all components of CW. Methods. Circulus arteriosus of 150 formalin preserved brains were dissected. Dimensions of all the components forming circles were measured. Variations of all the segments were noted and well photographed. The variations such as aplasia, hypoplasia, duplication, fenestrations, and difference in dimensions with opposite segments were noted. The data collected in the study was analyzed. Results. Twenty-one different types of CW were found in the present study. Normal and complete CW was found in 60%. CW with gross morphological variations was seen in 40%. Maximum variations were seen in the PCoA followed by the ACoA in 50% and 40%, respectively. Conclusion. As it confirms high percentage of variations, all surgical interventions should be preceded by angiography. Awareness of these anatomical variations is important in neurovascular procedures. PMID:24891951

Increased brain lysosomal pepstatin-insensitive proteinase activity in patients with neurodegenerative diseases.

PubMed

Junaid, M A; Pullarkat, R K

1999-04-02

A recent study has shown mutations in CLN2 gene, that encodes a novel lysosomal pepstatin-insensitive proteinase (LPIP), in the pathophysiology of late-infantile neuronal ceroid lipofuscinosis (LINCL). We have measured the LPIP activities in brains from various forms of human neuronal ceroid lipofuscinoses (NCL), canine ceroid lipofuscinosis and other neurodegenerative disorders with a highly sensitive assay using a tetrapeptide Gly-Phe-Phe-Leu-amino-trifluoromethyl coumarin (AFC) as substrate. Brain LPIP has a pH optimum of 3.5 and an apparent km of 100 microM for the crude enzyme. The enzyme activity is totally absent in LINCL patients. Pronounced increase in the LPIP activity was seen in patients suffering from infantile (INCL), juvenile (JNCL) and adult (ANCL) forms of neuronal ceroid lipofuscinoses. LPIP activity was also found to be increased about two-fold in Alzheimer's disease when compared with normal or age-matched controls, while in globoidal-cell leukodystrophy (Krabbe's disease) it was similar to the normal controls. Although mannose-6-phosphorylated LPIP is increased 13-fold in brains of patients with JNCL, this form of LPIP did not have any enzyme activity. The mechanism by which LPIP activities are increased in a wide range of neurodegenerative diseases is unknown, although neuronal loss, followed by gliosis are common characteristics of these diseases.

Differentiation of sCJD and vCJD forms by automated analysis of basal ganglia intensity distribution in multisequence MRI of the brain--definition and evaluation of new MRI-based ratios.

PubMed

Linguraru, Marius George; Ayache, Nicholas; Bardinet, Eric; Ballester, Miguel Angel González; Galanaud, Damien; Haïk, Stéphane; Faucheux, Baptiste; Hauw, Jean-Jacques; Cozzone, Patrick; Dormont, Didier; Brandel, Jean-Philippe

2006-08-01

We present a method for the analysis of basal ganglia (including the thalamus) for accurate detection of human spongiform encephalopathy in multisequence magnetic resonance imaging (MRI) of the brain. One common feature of most forms of prion protein diseases is the appearance of hyperintensities in the deep grey matter area of the brain in T2-weighted magnetic resonance (MR) images. We employ T1, T2, and Flair-T2 MR sequences for the detection of intensity deviations in the internal nuclei. First, the MR data are registered to a probabilistic atlas and normalized in intensity. Then smoothing is applied with edge enhancement. The segmentation of hyperintensities is performed using a model of the human visual system. For more accurate results, a priori anatomical data from a segmented atlas are employed to refine the registration and remove false positives. The results are robust over the patient data and in accordance with the clinical ground truth. Our method further allows the quantification of intensity distributions in basal ganglia. The caudate nuclei are highlighted as main areas of diagnosis of sporadic Creutzfeldt-Jakob Disease (sCJD), in agreement with the histological data. The algorithm permitted the classification of the intensities of abnormal signals in sCJD patient FLAIR images with a higher hypersignal in caudate nuclei (10/10) and putamen (6/10) than in thalami. Defining normalized MRI measures of the intensity relations between the internal grey nuclei of patients, we robustly differentiate sCJD and variant CJD (vCJD) patients, in an attempt to create an automatic classification tool of human spongiform encephalopathies.

The developing human connectome project: A minimal processing pipeline for neonatal cortical surface reconstruction.

PubMed

Makropoulos, Antonios; Robinson, Emma C; Schuh, Andreas; Wright, Robert; Fitzgibbon, Sean; Bozek, Jelena; Counsell, Serena J; Steinweg, Johannes; Vecchiato, Katy; Passerat-Palmbach, Jonathan; Lenz, Gregor; Mortari, Filippo; Tenev, Tencho; Duff, Eugene P; Bastiani, Matteo; Cordero-Grande, Lucilio; Hughes, Emer; Tusor, Nora; Tournier, Jacques-Donald; Hutter, Jana; Price, Anthony N; Teixeira, Rui Pedro A G; Murgasova, Maria; Victor, Suresh; Kelly, Christopher; Rutherford, Mary A; Smith, Stephen M; Edwards, A David; Hajnal, Joseph V; Jenkinson, Mark; Rueckert, Daniel

2018-06-01

The Developing Human Connectome Project (dHCP) seeks to create the first 4-dimensional connectome of early life. Understanding this connectome in detail may provide insights into normal as well as abnormal patterns of brain development. Following established best practices adopted by the WU-MINN Human Connectome Project (HCP), and pioneered by FreeSurfer, the project utilises cortical surface-based processing pipelines. In this paper, we propose a fully automated processing pipeline for the structural Magnetic Resonance Imaging (MRI) of the developing neonatal brain. This proposed pipeline consists of a refined framework for cortical and sub-cortical volume segmentation, cortical surface extraction, and cortical surface inflation, which has been specifically designed to address considerable differences between adult and neonatal brains, as imaged using MRI. Using the proposed pipeline our results demonstrate that images collected from 465 subjects ranging from 28 to 45 weeks post-menstrual age (PMA) can be processed fully automatically; generating cortical surface models that are topologically correct, and correspond well with manual evaluations of tissue boundaries in 85% of cases. Results improve on state-of-the-art neonatal tissue segmentation models and significant errors were found in only 2% of cases, where these corresponded to subjects with high motion. Downstream, these surfaces will enhance comparisons of functional and diffusion MRI datasets, supporting the modelling of emerging patterns of brain connectivity. Copyright © 2018 Elsevier Inc. All rights reserved.

Neural correlates of conscious self-regulation of emotion.

PubMed

Beauregard, M; Lévesque, J; Bourgouin, P

2001-09-15

A fundamental question about the relationship between cognition and emotion concerns the neural substrate underlying emotional self-regulation. To address this issue, brain activation was measured in normal male subjects while they either responded in a normal manner to erotic film excerpts or voluntarily attempted to inhibit the sexual arousal induced by viewing erotic stimuli. Results demonstrated that the sexual arousal experienced, in response to the erotic film excerpts, was associated with activation in "limbic" and paralimbic structures, such as the right amygdala, right anterior temporal pole, and hypothalamus. In addition, the attempted inhibition of the sexual arousal generated by viewing the erotic stimuli was associated with activation of the right superior frontal gyrus and right anterior cingulate gyrus. No activation was found in limbic areas. These findings reinforce the view that emotional self-regulation is normally implemented by a neural circuit comprising various prefrontal regions and subcortical limbic structures. They also suggest that humans have the capacity to influence the electrochemical dynamics of their brains, by voluntarily changing the nature of the mind processes unfolding in the psychological space.

SU-E-T-568: Improving Normal Brain Sparing with Increasing Number of Arc Beams for Volume Modulated Arc Beam Radiosurgery of Multiple Brain Metastases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hossain, S; Hildebrand, K; Ahmad, S

Purpose: Intensity modulated arc beams have been newly reported for treating multiple brain metastases. The purpose of this study was to determine the variations in the normal brain doses with increasing number of arc beams for multiple brain metastases treatments via the TrueBeam Rapidarc system (Varian Oncology, Palo Alto, CA). Methods: A patient case with 12 metastatic brain lesions previously treated on the Leksell Gamma Knife Perfexion (GK) was used for the study. All lesions and organs at risk were contoured by a senior radiation oncologist and treatment plans for a subset of 3, 6, 9 and all 12 targetsmore » were developed for the TrueBeam Rapidarc system via 3 to 7 intensity modulated arc-beams with each target covered by at least 99% of the prescribed dose of 20 Gy. The peripheral normal brain isodose volumes as well as the total beam-on time were analyzed with increasing number of arc beams for these targets. Results: All intensisty modulated arc-beam plans produced efficient treatment delivery with the beam-on time averaging 0.6–1.5 min per lesion at an output of 1200 MU/min. With increasing number of arc beams, the peripheral normal brain isodose volumes such as the 12-Gy isodose line enclosed normal brain tissue volumes were on average decreased by 6%, 11%, 18%, and 28% for the 3-, 6-, 9-, 12-target treatment plans respectively. The lowest normal brain isodose volumes were consistently found for the 7-arc treatment plans for all the cases. Conclusion: With nearly identical beam-on times, the peripheral normal brain dose was notably decreased when the total number of intensity modulated arc beams was increased when treating multiple brain metastases. Dr Sahgal and Dr Ma are currently serving on the board of international society of stereotactic radiosurgery.« less

Dependence of normal brain integral dose and normal tissue complication probability on the prescription isodose values for γ-knife radiosurgery

NASA Astrophysics Data System (ADS)

Ma, Lijun

2001-11-01

A recent multi-institutional clinical study suggested possible benefits of lowering the prescription isodose lines for stereotactic radiosurgery procedures. In this study, we investigate the dependence of the normal brain integral dose and the normal tissue complication probability (NTCP) on the prescription isodose values for γ-knife radiosurgery. An analytical dose model was developed for γ-knife treatment planning. The dose model was commissioned by fitting the measured dose profiles for each helmet size. The dose model was validated by comparing its results with the Leksell gamma plan (LGP, version 5.30) calculations. The normal brain integral dose and the NTCP were computed and analysed for an ensemble of treatment cases. The functional dependence of the normal brain integral dose and the NCTP versus the prescribing isodose values was studied for these cases. We found that the normal brain integral dose and the NTCP increase significantly when lowering the prescription isodose lines from 50% to 35% of the maximum tumour dose. Alternatively, the normal brain integral dose and the NTCP decrease significantly when raising the prescribing isodose lines from 50% to 65% of the maximum tumour dose. The results may be used as a guideline for designing future dose escalation studies for γ-knife applications.

Long-term valproic acid exposure increases the number of neocortical neurons in the developing rat brain. A possible new animal model of autism.

PubMed

Sabers, Anne; Bertelsen, Freja C B; Scheel-Krüger, Jørgen; Nyengaard, Jens R; Møller, Arne

2014-09-19

The aim of this study was to test the hypothesis that long-term fetal valproic acid (VPA) exposure at doses relevant to the human clinic interferes with normal brain development. Pregnant rats were given intraperitoneal injections of VPA (20mg/kg or 100mg/kg) continuously during the last 9-12 days of pregnancy and during the lactation period until sacrifice on the 23rd postnatal day. Total number of neocortical neurons was estimated using the optical fractionator and frontal cortical thicknesses were sampled in VPA exposed pups compared with an unexposed control group. We found that pups exposed to 20mg/kg and 100mg/kg doses of VPA had statistically significant higher total number of neurons in neocortex by 15.8% and 12.3%, respectively (p<0.05) compared to controls amounting to 15.5×10(6) neocortical neurons (p<0.01). There was no statistical difference between the two VPA groups. Pups exposed to100mg/kg, but not to 20mg/kg VPA displayed a significant (p<0.05) broader (7.5%) of frontal cortical thickness compared to controls. Our results support the hypothesis that fetal exposure of VPA may interfere with normal brain development by disturbing neocortical organization, resulting in overgrowth of frontal lobes and increased neuronal cell numbers. The results indirectly suggest that prenatal VPA may contribute as a causative factor in the brain developmental disturbances equivalent to those seen in human autism spectrum disorders. We therefore suggest that this version of the VPA model may provide a translational model of autism. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Nucleus Accumbens Invulnerability to Methamphetamine Neurotoxicity

PubMed Central

Kuhn, Donald M.; Angoa-Pérez, Mariana; Thomas, David M.

2016-01-01

Methamphetamine (Meth) is a neurotoxic drug of abuse that damages neurons and nerve endings throughout the central nervous system. Emerging studies of human Meth addicts using both postmortem analyses of brain tissue and noninvasive imaging studies of intact brains have confirmed that Meth causes persistent structural abnormalities. Animal and human studies have also defined a number of significant functional problems and comorbid psychiatric disorders associated with long-term Meth abuse. This review summarizes the salient features of Meth-induced neurotoxicity with a focus on the dopamine (DA) neuronal system. DA nerve endings in the caudate-putamen (CPu) are damaged by Meth in a highly delimited manner. Even within the CPu, damage is remarkably heterogeneous, with ventral and lateral aspects showing the greatest deficits. The nucleus accumbens (NAc) is largely spared the damage that accompanies binge Meth intoxication, but relatively subtle changes in the disposition of DA in its nerve endings can lead to dramatic increases in Meth-induced toxicity in the CPu and overcome the normal resistance of the NAc to damage. In contrast to the CPu, where DA neuronal deficiencies are persistent, alterations in the NAc show a partial recovery. Animal models have been indispensable in studies of the causes and consequences of Meth neurotoxicity and in the development of new therapies. This research has shown that increases in cytoplasmic DA dramatically broaden the neurotoxic profile of Meth to include brain structures not normally targeted for damage. The resistance of the NAc to Meth-induced neurotoxicity and its ability to recover reveal a fundamentally different neuroplasticity by comparison to the CPu. Recruitment of the NAc as a target of Meth neurotoxicity by alterations in DA homeostasis is significant in light of the numerous important roles played by this brain structure. PMID:23382149

Nucleus accumbens invulnerability to methamphetamine neurotoxicity.

PubMed

Kuhn, Donald M; Angoa-Pérez, Mariana; Thomas, David M

2011-01-01

Methamphetamine (Meth) is a neurotoxic drug of abuse that damages neurons and nerve endings throughout the central nervous system. Emerging studies of human Meth addicts using both postmortem analyses of brain tissue and noninvasive imaging studies of intact brains have confirmed that Meth causes persistent structural abnormalities. Animal and human studies have also defined a number of significant functional problems and comorbid psychiatric disorders associated with long-term Meth abuse. This review summarizes the salient features of Meth-induced neurotoxicity with a focus on the dopamine (DA) neuronal system. DA nerve endings in the caudate-putamen (CPu) are damaged by Meth in a highly delimited manner. Even within the CPu, damage is remarkably heterogeneous, with ventral and lateral aspects showing the greatest deficits. The nucleus accumbens (NAc) is largely spared the damage that accompanies binge Meth intoxication, but relatively subtle changes in the disposition of DA in its nerve endings can lead to dramatic increases in Meth-induced toxicity in the CPu and overcome the normal resistance of the NAc to damage. In contrast to the CPu, where DA neuronal deficiencies are persistent, alterations in the NAc show a partial recovery. Animal models have been indispensable in studies of the causes and consequences of Meth neurotoxicity and in the development of new therapies. This research has shown that increases in cytoplasmic DA dramatically broaden the neurotoxic profile of Meth to include brain structures not normally targeted for damage. The resistance of the NAc to Meth-induced neurotoxicity and its ability to recover reveal a fundamentally different neuroplasticity by comparison to the CPu. Recruitment of the NAc as a target of Meth neurotoxicity by alterations in DA homeostasis is significant in light of the numerous important roles played by this brain structure.

Expression of hypoxia-inducible carbonic anhydrases in brain tumors

PubMed Central

Proescholdt, Martin A.; Mayer, Christina; Kubitza, Marion; Schubert, Thomas; Liao, Shu-Yuan; Stanbridge, Eric J.; Ivanov, Sergey; Oldfield, Edward H.; Brawanski, Alexander; Merrill, Marsha J.

2005-01-01

Malignant brain tumors exhibit distinct metabolic characteristics. Despite high levels of lactate, the intracellular pH of brain tumors is more alkaline than normal brain. Additionally, with increasing malignancy, brain tumors display intratumoral hypoxia. Carbonic anhydrase (CA) IX and XII are transmembrane isoenzymes that are induced by tissue hypoxia. They participate in regulation of pH homeostasis by catalyzing the reversible hydration of carbon dioxide. The aim of our study was to investigate whether brain tumors of different histology and grade of malignancy express elevated levels of CA IX and XII as compared to normal brain. We analyzed 120 tissue specimens from brain tumors (primary and metastatic) and normal brain for CA IX and XII expression by immunohistochemistry, Western blot, and in situ hybridization. Whereas normal brain tissue showed minimal levels of CA IX and XII expression, expression in tumors was found to be upregulated with increased level of malignancy. Hemangioblastomas, from patients with von Hippel–Lindau disease, also displayed high levels of CA IX and XII expression. Comparison of CA IX and XII staining with HIF-1α staining revealed a similar microanatomical distribution, indicating hypoxia as a major, but not the only, induction factor. The extent of CA IX and XII staining correlated with cell proliferation, as indicated by Ki67 labeling. The results demonstrate that CA IX and XII are upregulated in intrinsic and metastatic brain tumors as compared to normal brain tissue. This may contribute to the management of tumor-specific acid load and provide a therapeutic target. PMID:16212811

Attentional performance is correlated with the local regional efficiency of intrinsic brain networks.

PubMed

Xu, Junhai; Yin, Xuntao; Ge, Haitao; Han, Yan; Pang, Zengchang; Tang, Yuchun; Liu, Baolin; Liu, Shuwei

2015-01-01

Attention is a crucial brain function for human beings. Using neuropsychological paradigms and task-based functional brain imaging, previous studies have indicated that widely distributed brain regions are engaged in three distinct attention subsystems: alerting, orienting and executive control (EC). Here, we explored the potential contribution of spontaneous brain activity to attention by examining whether resting-state activity could account for individual differences of the attentional performance in normal individuals. The resting-state functional images and behavioral data from attention network test (ANT) task were collected in 59 healthy subjects. Graph analysis was conducted to obtain the characteristics of functional brain networks and linear regression analyses were used to explore their relationships with behavioral performances of the three attentional components. We found that there was no significant relationship between the attentional performance and the global measures, while the attentional performance was associated with specific local regional efficiency. These regions related to the scores of alerting, orienting and EC largely overlapped with the regions activated in previous task-related functional imaging studies, and were consistent with the intrinsic dorsal and ventral attention networks (DAN/VAN). In addition, the strong associations between the attentional performance and specific regional efficiency suggested that there was a possible relationship between the DAN/VAN and task performances in the ANT. We concluded that the intrinsic activity of the human brain could reflect the processing efficiency of the attention system. Our findings revealed a robust evidence for the functional significance of the efficiently organized intrinsic brain network for highly productive cognitions and the hypothesized role of the DAN/VAN at rest.

Apolipoprotein ε4 is associated with lower brain volume in cognitively normal Chinese but not white older adults.

PubMed

Yokoyama, Jennifer S; Lee, Allen K L; Takada, Leonel T; Busovaca, Edgar; Bonham, Luke W; Chao, Steven Z; Tse, Marian; He, Jing; Schwarz, Christopher G; Carmichael, Owen T; Matthews, Brandy R; Karydas, Anna; Weiner, Michael W; Coppola, Giovanni; DeCarli, Charles S; Miller, Bruce L; Rosen, Howard J

2015-01-01

Studying ethnically diverse groups is important for furthering our understanding of biological mechanisms of disease that may vary across human populations. The ε4 allele of apolipoprotein E (APOE ε4) is a well-established risk factor for Alzheimer's disease (AD), and may confer anatomic and functional effects years before clinical signs of cognitive decline are observed. The allele frequency of APOE ε4 varies both across and within populations, and the size of the effect it confers for dementia risk may be affected by other factors. Our objective was to investigate the role APOE ε4 plays in moderating brain volume in cognitively normal Chinese older adults, compared to older white Americans. We hypothesized that carrying APOE ε4 would be associated with reduced brain volume and that the magnitude of this effect would be different between ethnic groups. We performed whole brain analysis of structural MRIs from Chinese living in America (n = 41) and Shanghai (n = 30) and compared them to white Americans (n = 71). We found a significant interaction effect of carrying APOE ε4 and being Chinese. The APOE ε4xChinese interaction was associated with lower volume in bilateral cuneus and left middle frontal gyrus (Puncorrected<0.001), with suggestive findings in right entorhinal cortex and left hippocampus (Puncorrected<0.01), all regions that are associated with neurodegeneration in AD. After correction for multiple testing, the left cuneus remained significantly associated with the interaction effect (PFWE = 0.05). Our study suggests there is a differential effect of APOE ε4 on brain volume in Chinese versus white cognitively normal elderly adults. This represents a novel finding that, if verified in larger studies, has implications for how biological, environmental and/or lifestyle factors may modify APOE ε4 effects on the brain in diverse populations.

Compression Stiffening of Brain and its Effect on Mechanosensing by Glioma Cells

NASA Astrophysics Data System (ADS)

Pogoda, Katarzyna

The stiffness of tissues, often characterized by their time-dependent elastic properties, is tightly controlled under normal condition and central nervous system tissue is among the softest tissues. Changes in tissue and organ stiffness occur in some physiological conditions and are frequently symptoms of diseases such as fibrosis, cardiovascular disease and many forms of cancer. Primary cells isolated from various tissues often respond to changes in the mechanical properties of their substrates, and the range of stiffness over which these responses occur appear to be limited to the tissue elastic modulus from which they are derived. Our goal was to test the hypotheses that the stiffness of tumors derived from CNS tissue differs from that of normal brain, and that transformed cells derived from such tumors exhibit mechanical responses that differ from those of normal glial cells. Unlike breast and some other cancers where the stroma and the tumor itself is substantially stiffer than the surrounding normal tissue, our data suggest that gliomas can arise without a gross change in the macroscopic tissue stiffness when measured at low strains without compression. However, both normal brain and glioma samples stiffen with compression, but not in elongation and increased shear strains. On the other hand, different classes of immortalized cells derived from human glioblastoma show substantially different responses to the stiffness of substrates in vitrowhen grown on soft polyacrylamide and hyaluronic acid gels. This outcome supports the hypothesis that compression stiffening, which might occur with increased vascularization and interstitial pressure gradients that are characteristic of tumors, effectively stiffens the environment of glioma cells, and that in situ, the elastic resistance these cells sense might be sufficient to trigger the same responses that are activated in vitro by increased substrate stiffness.

A Unique Four-Hub Protein Cluster Associates to Glioblastoma Progression

PubMed Central

Simeone, Pasquale; Trerotola, Marco; Urbanella, Andrea; Lattanzio, Rossano; Ciavardelli, Domenico; Di Giuseppe, Fabrizio; Eleuterio, Enrica; Sulpizio, Marilisa; Eusebi, Vincenzo; Pession, Annalisa; Piantelli, Mauro; Alberti, Saverio

2014-01-01

Gliomas are the most frequent brain tumors. Among them, glioblastomas are malignant and largely resistant to available treatments. Histopathology is the gold standard for classification and grading of brain tumors. However, brain tumor heterogeneity is remarkable and histopathology procedures for glioma classification remain unsatisfactory for predicting disease course as well as response to treatment. Proteins that tightly associate with cancer differentiation and progression, can bear important prognostic information. Here, we describe the identification of protein clusters differentially expressed in high-grade versus low-grade gliomas. Tissue samples from 25 high-grade tumors, 10 low-grade tumors and 5 normal brain cortices were analyzed by 2D-PAGE and proteomic profiling by mass spectrometry. This led to identify 48 differentially expressed protein markers between tumors and normal samples. Protein clustering by multivariate analyses (PCA and PLS-DA) provided discrimination between pathological samples to an unprecedented extent, and revealed a unique network of deranged proteins. We discovered a novel glioblastoma control module centered on four major network hubs: Huntingtin, HNF4α, c-Myc and 14-3-3ζ. Immunohistochemistry, western blotting and unbiased proteome-wide meta-analysis revealed altered expression of this glioblastoma control module in human glioma samples as compared with normal controls. Moreover, the four-hub network was found to cross-talk with both p53 and EGFR pathways. In summary, the findings of this study indicate the existence of a unifying signaling module controlling glioblastoma pathogenesis and malignant progression, and suggest novel targets for development of diagnostic and therapeutic procedures. PMID:25050814

Impaired pulsation absorber mechanism in idiopathic normal pressure hydrocephalus: laboratory investigation.

PubMed

Park, Eun-Hyoung; Eide, Per Kristian; Zurakowski, David; Madsen, Joseph R

2012-12-01

The pathophysiology of normal pressure hydrocephalus (NPH), and the related problem of patient selection for treatment of this condition, have been of great interest since the description of this seemingly paradoxical condition nearly 50 years ago. Recently, Eide has reported that measurements of the amplitude of the intracranial pressure (ICP) can both positively and negatively predict response to CSF shunting. Specifically, the fraction of time spent in a "high amplitude" (> 4 mm Hg) state predicted response to shunting, which may represent a marker for hydrocephalic pathophysiology. Increased ICP amplitude might suggest decreased brain compliance, meaning a static measure of a pressure-volume ratio. Recent studies of canine data have shown that the brain compliance can be described as a frequency-dependent function. The normal canine brain seems to show enhanced ability to absorb the pulsations around the heart rate, quantified as a cardiac pulsation absorbance (CPA), with properties like a notch filter in engineering. This frequency dependence of the function is diminished with development of hydrocephalus in dogs. In this pilot study, the authors sought to determine whether frequency dependence could be observed in humans, and whether the frequency dependence would be any different in epochs with high ICP amplitude compared with epochs of low ICP amplitude. Systems analysis was applied to arterial blood pressure (ABP) and ICP waveforms recorded from 10 patients undergoing evaluations of idiopathic NPH to calculate a time-varying transfer function that reveals frequency dependence and CPA, the measure of frequency-dependent compliance previously used in animal experiments. The ICP amplitude was also calculated in the same samples, so that epochs with high (> 4 mm Hg) versus low (≤ 4 mm Hg) amplitude could be compared in CPA and transfer functions. Transfer function analysis for the more "normal" epochs with low amplitude exhibits a dip or notch in the physiological frequency range of the heart rate, confirming in humans the pulsation absorber phenomenon previously observed in canine studies. Under high amplitude, however, the dip in the transfer function is absent. An inverse relationship between CPA index and ICP amplitude is evident and statistically significant. Thus, elevated ICP amplitude indicates decreased performance of the human pulsation absorber. The results suggest that the human intracranial system shows frequency dependence as seen in animal experiments. There is an inverse relationship between CPA index and ICP amplitude, indicating that higher amplitudes may occur with a reduced performance of the pulsation absorber. Our findings show that frequency dependence can be observed in humans and imply that reduced frequency-dependent compliance may be responsible for elevated ICP amplitude observed in patients who respond to CSF shunting.

Developmental thyroid hormone insufficiency and brain development: A role for brain-derived neurotrophic factor (BDNF)?*

EPA Science Inventory

Thyroid hormones (TH) are essential for normal brain development. Even subclinical hypothyroidism experienced in utero can result in neuropsychological deficits in children despite normal thyroid status at birth. Neurotrophins have been implicated in a host of brain cellular func...

Neuroimaging Studies of Normal Brain Development and Their Relevance for Understanding Childhood Neuropsychiatric Disorders

ERIC Educational Resources Information Center

Marsh, Rachel; Gerber, Andrew J.; Peterson, Bradley S.

2008-01-01

Neuroimaging findings which identify normal brain development trajectories are presented. Results show that early brain development begins with the neural tube formation and ends with myelintation. How disturbances in brain development patterns are related to childhood psychiatric disorders is examined.

Biodistribution and Pharmacodynamics of Recombinant Human Alpha-L-Iduronidase (rhIDU) in Mucopolysaccharidosis Type I-Affected Cats Following Multiple Intrathecal Administrations

PubMed Central

Vite, Charles H.; Wang, Ping; Patel, Reema T.; Walton, Raquel M.; Walkley, Steven U.; Sellers, Rani S.; Ellinwood, N. Matthew; Cheng, Alphonsus S.; White, Joleen T.; O’Neill, Charles A.; Haskins, Mark

2011-01-01

The storage disorder mucopolysaccharidosis type I (MPS I) is caused by a deficiency in lysosomal α-L-iduronidase activity. The inability to degrade glycosaminoglycans (GAG) results in lysosomal accumulation and widespread tissue lesions. Many symptoms of MPS I are amenable to treatment with recombinant human α-L-iduronidase (rhIDU), however, peripherally administered rhIDU does not cross the blood-brain barrier and has no beneficial effects in the central nervous system (CNS). A feline model of MPS I was used to evaluate the CNS effects of rhIDU following repeated intrathecal (IT) administration. Twelve animals were randomized into four groups based on the time of euthanasia and tissue evaluation following three repeat IT administrations of 0.1 mg/kg rhIDU or placebo on Study Days 1, 4 or 5, and 9. Two days after the final IT injection, the mean tissue α-L-iduronidase (IDU) activity in the brains of the two treated animals were approximately 3-times higher (50.1 and 54.9 U/mg protein) than the activity found in normal cat brains (mean of 18.3 U/mg), and remained higher than untreated MPS1 brain at 1 month (2.4 and 4.1 U/mg protein) before returning to near-baseline levels after 2 months. This activity corresponded with decreased brain GAG concentrations after 2 days (1.4 and 2.0 mcg/mg) and 1 month (0.9 and 1.1 mcg/mg) which approached levels observed in normal animals (0.7 mcg/mg). Attenuation of GAG, gangliosides GM2 and GM3, and cholesterol reaccumulation was identified at both two days and one month following final IT injection. No adverse effects or rhIDU antibody response attributable to IT rhIDU administration were observed. IT rhIDU may be an effective means for providing enzyme replacement therapy for the central manifestations of MPS I. PMID:21482164

Tissue and organ donation for research in forensic pathology: the MRC Sudden Death Brain and Tissue Bank.

PubMed

Millar, T; Walker, R; Arango, J-C; Ironside, J W; Harrison, D J; MacIntyre, D J; Blackwood, D; Smith, C; Bell, J E

2007-12-01

Novel methodological approaches to the investigation of brain and non-central nervous system disorders have led to increased demand for well-characterized, high quality human tissue samples, particularly from control cases. In the setting of the new Human Tissue legislation, we sought to determine whether relatives who have been suddenly bereaved are willing to grant authorization for research use of post mortem tissue samples and organs in sufficient numbers to support the establishment of a brain and tissue bank based in the forensic service. Research authorization was sought from families on the day prior to forensic post mortem examination followed up by written confirmation. We have to date selected individuals who have died suddenly (age range 1-89 years) and who were likely to have normal brains or who had displayed symptoms of a CNS disorder of interest to researchers, including psychiatric disorders. One hundred and eleven families have been approached during the first 2 years of this project. Research use of tissue samples was authorized by 96% of families and 17% agreed to whole brain donation. Audit of families' experience does not suggest that they are further distressed by being approached. Respondents expressed a clear view that the opportunity for research donation should be open to all bereaved families. Despite the sometimes long post mortem intervals, the quality of tissue samples is good, as assessed by a range of markers including Agilent BioAnalyzer quantification of RNA integrity (mean value 6.4). We conclude that the vast majority of families are willing to support research use of post mortem tissues even in the context of sudden bereavement and despite previous adverse publicity. The potential for acquisition of normal CNS and non-CNS tissues and of various hard-to-get CNS disorders suggests that efforts to access the forensic post mortem service for research material are eminently worthwhile. (c) 2007 Pathological Society of Great Britain and Ireland

Comparison of analytical methods of brain [18F]FDG-PET after severe traumatic brain injury.

PubMed

Madsen, Karine; Hesby, Sara; Poulsen, Ingrid; Fuglsang, Stefan; Graff, Jesper; Larsen, Karen B; Kammersgaard, Lars P; Law, Ian; Siebner, Hartwig R

2017-11-01

Loss of consciousness has been shown to reduce cerebral metabolic rates of glucose (CMRglc) measured by brain [ 18 F]FDG-PET. Measurements of regional metabolic patterns by normalization to global cerebral metabolism or cerebellum may underestimate widespread reductions. The aim of this study was to compare quantification methods of whole brain glucose metabolism, including whole brain [18F]FDG uptake normalized to uptake in cerebellum, normalized to injected activity, normalized to plasma tracer concentration, and two methods for estimating CMRglc. Six patients suffering from severe traumatic brain injury (TBI) and ten healthy controls (HC) underwent a 10min static [ 18 F]FDG-PET scan and venous blood sampling. Except from normalizing to cerebellum, all quantification methods found significant lower level of whole brain glucose metabolism of 25-33% in TBI patients compared to HC. In accordance these measurements correlated to level of consciousness. Our study demonstrates that the analysis method of the [ 18 F]FDG PET data has a substantial impact on the estimated whole brain cerebral glucose metabolism in patients with severe TBI. Importantly, the SUVR method which is often used in a clinical setting was not able to distinguish patients with severe TBI from HC at the whole-brain level. We recommend supplementing a static [ 18 F]FDG scan with a single venous blood sample in future studies of patients with severe TBI or reduced level of consciousness. This can be used for simple semi-quantitative uptake values by normalizing brain activity uptake to plasma tracer concentration, or quantitative estimates of CMRglc. Copyright © 2017 Elsevier B.V. All rights reserved.

Resonant Raman spectra of grades of human brain glioma tumors reveal the content of tryptophan by the 1588 cm-1 mode

NASA Astrophysics Data System (ADS)

Zhou, Yan; Liu, Cheng-hui; Zhou, Lixin; Zhu, Ke; Liu, Yulong; Zhang, Lin; Boydston-White, Susie; Cheng, Gangge; Pu, Yang; Bidyut, Das; Alfano, Robert R.

2015-03-01

RR spectra of brain normal tissue, gliomas in low grade I and II, and malignant glioma tumors in grade III and IV were measured using a confocal micro Raman spectrometer. This report focus on the relative contents of tryptophan (W) in various grades of brain glioma tumors by the intrinsic molecular resonance Raman (RR) spectroscopy method using the 1588cm-1 of tryptophan mode by 532 nm excitation. The RR spectra of key fingerprints of tryptophan, with a main vibrational mode at 1588cm-1 (W8b), were observed. It was found that tryptophan contribution was accumulated in grade I to IV gliomas and the mode of 1588cm-1 in grade III and IV malignant gliomas were enhanced by resonance.

The Myth of Optimality in Clinical Neuroscience.

PubMed

Holmes, Avram J; Patrick, Lauren M

2018-03-01

Clear evidence supports a dimensional view of psychiatric illness. Within this framework the expression of disorder-relevant phenotypes is often interpreted as a breakdown or departure from normal brain function. Conversely, health is reified, conceptualized as possessing a single ideal state. We challenge this concept here, arguing that there is no universally optimal profile of brain functioning. The evolutionary forces that shape our species select for a staggering diversity of human behaviors. To support our position we highlight pervasive population-level variability within large-scale functional networks and discrete circuits. We propose that, instead of examining behaviors in isolation, psychiatric illnesses can be best understood through the study of domains of functioning and associated multivariate patterns of variation across distributed brain systems. Copyright © 2018 Elsevier Ltd. All rights reserved.

Sex differences in normal age trajectories of functional brain networks.

PubMed

Scheinost, Dustin; Finn, Emily S; Tokoglu, Fuyuze; Shen, Xilin; Papademetris, Xenophon; Hampson, Michelle; Constable, R Todd

2015-04-01

Resting-state functional magnetic resonance image (rs-fMRI) is increasingly used to study functional brain networks. Nevertheless, variability in these networks due to factors such as sex and aging is not fully understood. This study explored sex differences in normal age trajectories of resting-state networks (RSNs) using a novel voxel-wise measure of functional connectivity, the intrinsic connectivity distribution (ICD). Males and females showed differential patterns of changing connectivity in large-scale RSNs during normal aging from early adulthood to late middle-age. In some networks, such as the default-mode network, males and females both showed decreases in connectivity with age, albeit at different rates. In other networks, such as the fronto-parietal network, males and females showed divergent connectivity trajectories with age. Main effects of sex and age were found in many of the same regions showing sex-related differences in aging. Finally, these sex differences in aging trajectories were robust to choice of preprocessing strategy, such as global signal regression. Our findings resolve some discrepancies in the literature, especially with respect to the trajectory of connectivity in the default mode, which can be explained by our observed interactions between sex and aging. Overall, results indicate that RSNs show different aging trajectories for males and females. Characterizing effects of sex and age on RSNs are critical first steps in understanding the functional organization of the human brain. © 2014 Wiley Periodicals, Inc.

Comparative study of nonlinear properties of EEG signals of normal persons and epileptic patients

PubMed Central

2009-01-01

Background Investigation of the functioning of the brain in living systems has been a major effort amongst scientists and medical practitioners. Amongst the various disorder of the brain, epilepsy has drawn the most attention because this disorder can affect the quality of life of a person. In this paper we have reinvestigated the EEGs for normal and epileptic patients using surrogate analysis, probability distribution function and Hurst exponent. Results Using random shuffled surrogate analysis, we have obtained some of the nonlinear features that was obtained by Andrzejak et al. [Phys Rev E 2001, 64:061907], for the epileptic patients during seizure. Probability distribution function shows that the activity of an epileptic brain is nongaussian in nature. Hurst exponent has been shown to be useful to characterize a normal and an epileptic brain and it shows that the epileptic brain is long term anticorrelated whereas, the normal brain is more or less stochastic. Among all the techniques, used here, Hurst exponent is found very useful for characterization different cases. Conclusion In this article, differences in characteristics for normal subjects with eyes open and closed, epileptic subjects during seizure and seizure free intervals have been shown mainly using Hurst exponent. The H shows that the brain activity of a normal man is uncorrelated in nature whereas, epileptic brain activity shows long range anticorrelation. PMID:19619290

Neocortical glial cell numbers in human brains.

PubMed

Pelvig, D P; Pakkenberg, H; Stark, A K; Pakkenberg, B

2008-11-01

Stereological cell counting was applied to post-mortem neocortices of human brains from 31 normal individuals, age 18-93 years, 18 females (average age 65 years, range 18-93) and 13 males (average age 57 years, range 19-87). The cells were differentiated in astrocytes, oligodendrocytes, microglia and neurons and counting were done in each of the four lobes. The study showed that the different subpopulations of glial cells behave differently as a function of age; the number of oligodendrocytes showed a significant 27% decrease over adult life and a strong correlation to the total number of neurons while the total astrocyte number is constant through life; finally males have a 28% higher number of neocortical glial cells and a 19% higher neocortical neuron number than females. The overall total number of neocortical neurons and glial cells was 49.3 billion in females and 65.2 billion in males, a difference of 24% with a high biological variance. These numbers can serve as reference values in quantitative studies of the human neocortex.

Cortical NMDA receptor expression in human chronic alcoholism: influence of the TaqIA allele of ANKK1.

PubMed

Ridge, Justin P; Dodd, Peter R

2009-10-01

Real-time RT-PCR normalized to GAPDH was used to assay N-methyl-D-aspartate (NMDA) receptor NR1, NR2A and NR2B subunit mRNA in human autopsy cortex tissue from chronic alcoholics with and without comorbid cirrhosis of the liver and matched controls. Subunit expression was influenced by the subject's genotype. The TaqIA polymorphism selectively modulated NMDA receptor mean transcript expression in cirrhotic-alcoholic superior frontal cortex, in diametrically opposite ways in male and female subjects. Genetic make-up may differentially influence vulnerability to brain damage by altering the excitation: inhibition balance, particularly in alcoholics with comorbid cirrhosis of the liver. The TaqIA polymorphism occurs within the poorly characterised ankyrin-repeat containing kinase 1 (ANKK1) gene. Using PCR, ANKK1 mRNA transcript was detected in inferior temporal, occipital, superior frontal and primary motor cortex of control human brain. ANKK1 expression may mediate the influence of the TaqIA polymorphism on phenotype.

Transmission Characteristics of Variably Protease-Sensitive Prionopathy

PubMed Central

Notari, Silvio; Xiao, Xiangzhu; Espinosa, Juan Carlos; Cohen, Yvonne; Qing, Liuting; Aguilar-Calvo, Patricia; Kofskey, Diane; Cali, Ignazio; Cracco, Laura; Kong, Qingzhong; Torres, Juan Maria

2014-01-01

Variably protease-sensitive prionopathy (VPSPr), a recently identified and seemingly sporadic human prion disease, is distinct from Creutzfeldt-Jakob disease (CJD) but shares features of Gerstmann-Sträussler-Scheinker disease (GSS). However, contrary to exclusively inherited GSS, no prion protein (PrP) gene variations have been detected in VPSPr, suggesting that VPSPr might be the long-sought sporadic form of GSS. The VPSPr atypical features raised the issue of transmissibility, a prototypical property of prion diseases. We inoculated VPSPr brain homogenate into transgenic mice expressing various levels of human PrP (PrPC). On first passage, 54% of challenged mice showed histopathologic lesions, and 34% harbored abnormal PrP similar to that of VPSPr. Surprisingly, no prion disease was detected on second passage. We concluded that VPSPr is transmissible; thus, it is an authentic prion disease. However, we speculate that normal human PrPC is not an efficient conversion substrate (or mouse brain not a favorable environment) and therefore cannot sustain replication beyond the first passage. PMID:25418590

Graph Theoretical Analysis Reveals: Women's Brains Are Better Connected than Men's.

PubMed

Szalkai, Balázs; Varga, Bálint; Grolmusz, Vince

2015-01-01

Deep graph-theoretic ideas in the context with the graph of the World Wide Web led to the definition of Google's PageRank and the subsequent rise of the most popular search engine to date. Brain graphs, or connectomes, are being widely explored today. We believe that non-trivial graph theoretic concepts, similarly as it happened in the case of the World Wide Web, will lead to discoveries enlightening the structural and also the functional details of the animal and human brains. When scientists examine large networks of tens or hundreds of millions of vertices, only fast algorithms can be applied because of the size constraints. In the case of diffusion MRI-based structural human brain imaging, the effective vertex number of the connectomes, or brain graphs derived from the data is on the scale of several hundred today. That size facilitates applying strict mathematical graph algorithms even for some hard-to-compute (or NP-hard) quantities like vertex cover or balanced minimum cut. In the present work we have examined brain graphs, computed from the data of the Human Connectome Project, recorded from male and female subjects between ages 22 and 35. Significant differences were found between the male and female structural brain graphs: we show that the average female connectome has more edges, is a better expander graph, has larger minimal bisection width, and has more spanning trees than the average male connectome. Since the average female brain weighs less than the brain of males, these properties show that the female brain has better graph theoretical properties, in a sense, than the brain of males. It is known that the female brain has a smaller gray matter/white matter ratio than males, that is, a larger white matter/gray matter ratio than the brain of males; this observation is in line with our findings concerning the number of edges, since the white matter consists of myelinated axons, which, in turn, roughly correspond to the connections in the brain graph. We have also found that the minimum bisection width, normalized with the edge number, is also significantly larger in the right and the left hemispheres in females: therefore, the differing bisection widths are independent from the difference in the number of edges.

Graph Theoretical Analysis Reveals: Women’s Brains Are Better Connected than Men’s

PubMed Central

Szalkai, Balázs; Varga, Bálint; Grolmusz, Vince

2015-01-01

Deep graph-theoretic ideas in the context with the graph of the World Wide Web led to the definition of Google’s PageRank and the subsequent rise of the most popular search engine to date. Brain graphs, or connectomes, are being widely explored today. We believe that non-trivial graph theoretic concepts, similarly as it happened in the case of the World Wide Web, will lead to discoveries enlightening the structural and also the functional details of the animal and human brains. When scientists examine large networks of tens or hundreds of millions of vertices, only fast algorithms can be applied because of the size constraints. In the case of diffusion MRI-based structural human brain imaging, the effective vertex number of the connectomes, or brain graphs derived from the data is on the scale of several hundred today. That size facilitates applying strict mathematical graph algorithms even for some hard-to-compute (or NP-hard) quantities like vertex cover or balanced minimum cut. In the present work we have examined brain graphs, computed from the data of the Human Connectome Project, recorded from male and female subjects between ages 22 and 35. Significant differences were found between the male and female structural brain graphs: we show that the average female connectome has more edges, is a better expander graph, has larger minimal bisection width, and has more spanning trees than the average male connectome. Since the average female brain weighs less than the brain of males, these properties show that the female brain has better graph theoretical properties, in a sense, than the brain of males. It is known that the female brain has a smaller gray matter/white matter ratio than males, that is, a larger white matter/gray matter ratio than the brain of males; this observation is in line with our findings concerning the number of edges, since the white matter consists of myelinated axons, which, in turn, roughly correspond to the connections in the brain graph. We have also found that the minimum bisection width, normalized with the edge number, is also significantly larger in the right and the left hemispheres in females: therefore, the differing bisection widths are independent from the difference in the number of edges. PMID:26132764

Effect of intravenous gadolinium-DTPA on diffusion-weighted imaging of brain tumors: a short temporal interval assessment.

PubMed

Li, Xiang; Qu, Jin-Rong; Luo, Jun-Peng; Li, Jing; Zhang, Hong-Kai; Shao, Nan-Nan; Kwok, Keith; Zhang, Shou-Ning; Li, Yan-le; Liu, Cui-Cui; Zee, Chi-Shing; Li, Hai-Liang

2014-09-01

To determine the effect of intravenous administration of gadolinium (Gd) contrast medium (Gd-DTPA) on diffusion-weighted imaging (DWI) for the evaluation of normal brain parenchyma vs. brain tumor following a short temporal interval. Forty-four DWI studies using b values of 0 and 1000 s/mm(2) were performed before, immediately after, 1 min after, 3 min after, and 5 min after the administration of Gd-DTPA on 62 separate lesions including 15 meningioma, 17 glioma and 30 metastatic lesions. The signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR) and apparent diffusion coefficient (ADC) values of the brain tumor lesions and normal brain tissues were measured on pre- and postcontrast images. Statistical analysis using paired t-test between precontrast and postcontrast data were obtained on three brain tumors and normal brain tissue. The SNR and CNR of brain tumors and the SNR of normal brain tissue showed no statistical differences between pre- and postcontrast (P > 0.05). The ADC values on the three cases of brain tumors demonstrated significant initial increase on the immediate time point (P < 0.01) and decrease on following the 1 min time point (P < 0.01) after contrast. Significant decrease of ADC value was still found at 3min and 5min time point in the meningioma group (P < 0.01) with gradual normalization over time. The ADC values of normal brain tissues demonstrated significant initial elevation on the immediately postcontrast DWI sequence (P < 0.01). Contrast medium can cause a slight but statistically significant change on the ADC value within a short temporal interval after the contrast administration. The effect is both time and lesion-type dependent. © 2013 Wiley Periodicals, Inc.

Effects of cell phone radiofrequency signal exposure on brain glucose metabolism.

PubMed

Volkow, Nora D; Tomasi, Dardo; Wang, Gene-Jack; Vaska, Paul; Fowler, Joanna S; Telang, Frank; Alexoff, Dave; Logan, Jean; Wong, Christopher

2011-02-23

The dramatic increase in use of cellular telephones has generated concern about possible negative effects of radiofrequency signals delivered to the brain. However, whether acute cell phone exposure affects the human brain is unclear. To evaluate if acute cell phone exposure affects brain glucose metabolism, a marker of brain activity. Randomized crossover study conducted between January 1 and December 31, 2009, at a single US laboratory among 47 healthy participants recruited from the community. Cell phones were placed on the left and right ears and positron emission tomography with ((18)F)fluorodeoxyglucose injection was used to measure brain glucose metabolism twice, once with the right cell phone activated (sound muted) for 50 minutes ("on" condition) and once with both cell phones deactivated ("off" condition). Statistical parametric mapping was used to compare metabolism between on and off conditions using paired t tests, and Pearson linear correlations were used to verify the association of metabolism and estimated amplitude of radiofrequency-modulated electromagnetic waves emitted by the cell phone. Clusters with at least 1000 voxels (volume >8 cm(3)) and P < .05 (corrected for multiple comparisons) were considered significant. Brain glucose metabolism computed as absolute metabolism (μmol/100 g per minute) and as normalized metabolism (region/whole brain). Whole-brain metabolism did not differ between on and off conditions. In contrast, metabolism in the region closest to the antenna (orbitofrontal cortex and temporal pole) was significantly higher for on than off conditions (35.7 vs 33.3 μmol/100 g per minute; mean difference, 2.4 [95% confidence interval, 0.67-4.2]; P = .004). The increases were significantly correlated with the estimated electromagnetic field amplitudes both for absolute metabolism (R = 0.95, P < .001) and normalized metabolism (R = 0.89; P < .001). In healthy participants and compared with no exposure, 50-minute cell phone exposure was associated with increased brain glucose metabolism in the region closest to the antenna. This finding is of unknown clinical significance.

Tinnitus alters resting state functional connectivity (RSFC) in human auditory and non-auditory brain regions as measured by functional near-infrared spectroscopy (fNIRS)

PubMed Central

Hu, Xiao-Su; Issa, Mohamad; Bisconti, Silvia; Kovelman, Ioulia; Kileny, Paul; Basura, Gregory

2017-01-01

Tinnitus, or phantom sound perception, leads to increased spontaneous neural firing rates and enhanced synchrony in central auditory circuits in animal models. These putative physiologic correlates of tinnitus to date have not been well translated in the brain of the human tinnitus sufferer. Using functional near-infrared spectroscopy (fNIRS) we recently showed that tinnitus in humans leads to maintained hemodynamic activity in auditory and adjacent, non-auditory cortices. Here we used fNIRS technology to investigate changes in resting state functional connectivity between human auditory and non-auditory brain regions in normal-hearing, bilateral subjective tinnitus and controls before and after auditory stimulation. Hemodynamic activity was monitored over the region of interest (primary auditory cortex) and non-region of interest (adjacent non-auditory cortices) and functional brain connectivity was measured during a 60-second baseline/period of silence before and after a passive auditory challenge consisting of alternating pure tones (750 and 8000Hz), broadband noise and silence. Functional connectivity was measured between all channel-pairs. Prior to stimulation, connectivity of the region of interest to the temporal and fronto-temporal region was decreased in tinnitus participants compared to controls. Overall, connectivity in tinnitus was differentially altered as compared to controls following sound stimulation. Enhanced connectivity was seen in both auditory and non-auditory regions in the tinnitus brain, while controls showed a decrease in connectivity following sound stimulation. In tinnitus, the strength of connectivity was increased between auditory cortex and fronto-temporal, fronto-parietal, temporal, occipito-temporal and occipital cortices. Together these data suggest that central auditory and non-auditory brain regions are modified in tinnitus and that resting functional connectivity measured by fNIRS technology may contribute to conscious phantom sound perception and potentially serve as an objective measure of central neural pathology. PMID:28604786

A Recombinant Humanized Anti-Cocaine Monoclonal Antibody Inhibits the Distribution of Cocaine to the Brain in Rats

PubMed Central

Gooden, Felicia C. T.; Tabet, Michael R.; Ball, William J.

2014-01-01

The monoclonal antibody (mAb), h2E2, is a humanized version of the chimeric human/murine anti-cocaine mAb 2E2. The recombinant h2E2 protein was produced in vitro from a transfected mammalian cell line and retained high affinity (4 nM Kd) and specificity for cocaine over its inactive metabolites benzoylecgonine (BE) and ecgonine methyl ester. In rats, pharmacokinetic studies of h2E2 (120 mg/kg i.v.) showed a long terminal elimination half-life of 9.0 days and a low volume of distribution at steady state (Vdss) of 0.3 l/kg. Pretreatment with h2E2 produced a dramatic 8.8-fold increase in the area under the plasma cocaine concentration-time curve (AUC) and in brain a concomitant decrease of 68% of cocaine’s AUC following an i.v. injection of an equimolar cocaine dose. Sequestration of cocaine in plasma by h2E2, shown via reduction of cocaine’s Vdss, indicates potential clinical efficacy. Although the binding of cocaine to h2E2 in plasma should inhibit distribution and metabolism, the elimination of cocaine remained multicompartmental and was still rapidly eliminated from plasma despite the presence of h2E2. BE was the major cocaine metabolite, and brain BE concentrations were sixfold higher than in plasma, indicating that cocaine is normally metabolized in the brain. In the presence of h2E2, brain BE concentrations were decreased and plasma BE was increased, consistent with the observed h2E2-induced changes in cocaine disposition. The inhibition of cocaine distribution to the brain confirms the humanized mAb, h2E2, as a lead candidate for development as an immunotherapy for cocaine abuse. PMID:24733787

Brain morphology in children with nevoid basal cell carcinoma syndrome.

PubMed

Shiohama, Tadashi; Fujii, Katsunori; Miyashita, Toshiyuki; Mizuochi, Hiromi; Uchikawa, Hideki; Shimojo, Naoki

2017-04-01

Brain morphology is tightly regulated by diverse signaling pathways. Hedgehog signaling is a candidate pathway considered responsible for regulating brain morphology. Nevoid basal cell carcinoma syndrome (NBCCS), caused by a PTCH1 mutation in the hedgehog signaling pathway, occasionally exhibits macrocephaly and medulloblastoma. Although cerebellar enlargement occurs in ptch1 heterozygous-deficient mice, its impact on human brain development remains unknown. We investigated the brain morphological characteristics of children with NBCCS. We evaluated brain T1-weighted images from nine children with NBCCS and 15 age-matched normal control (NC) children (mean [standard deviation], 12.2 [2.8] vs. 11.6 [2.3] years old). The diameters of the cerebrum, corpus callosum, and brain stem and the cerebellar volume were compared using two-tailed t-tests with Welch's correction. The transverse diameters (150.4 [9.9] vs. 136.0 [5.5] mm, P = 0.002) and longitudinal diameters (165.4 [8.0] vs. 151.3 [8.7] mm, P = 0.0007) of the cerebrum, cross-sectional area of the cerebellar vermis (18.7 [2.6] vs. 11.8 [1.7] cm 2 , P = 0.0001), and total volume of the cerebellar hemispheres (185.1 [13.0] vs. 131.9 [10.4] cm 3 , P = 0.0001) were significantly larger in the children with NBCCS than in NC children. Thinning of the corpus callosum and ventricular enlargement were also confirmed in children with NBCCS. We demonstrate that, on examination of the brain morphology, an increase in the size of the cerebrum, cerebellum, and cerebral ventricles is revealed in children with NBCCS compared to NC children. This suggests that constitutively active hedgehog signaling affects human brain morphology and the PI3K/AKT and RAS/MAPK pathways. © 2017 Wiley Periodicals, Inc.

Random Secretion of Growth Hormone in Humans

NASA Astrophysics Data System (ADS)

Prank, Klaus; Kloppstech, Mirko; Nowlan, Steven J.; Sejnowski, Terrence J.; Brabant, Georg

1996-08-01

In normal humans, growth hormone (GH) is secreted from a gland located adjacent to the brain (pituitary) into the blood in distinct pulses, but in patients bearing a tumor within the pituitary (acromegaly) GH is excessively secreted in an irregular manner. It has been hypothesized that GH secretion in the diseased state becomes random. This hypothesis is supported by demonstrating that GH secretion in patients with acromegaly cannot be distinguished from a variety of linear stochastic processes based on the predictability of the fluctuations of GH concentration in the bloodstream.

Measurement and modification of the EEG and related behavior

NASA Technical Reports Server (NTRS)

Sterman, M. B.

1991-01-01

Electrophysiological changes in the sensorimotor pathways were found to accompany the effect of rhythmic EEG patterns in the sensorimotor cortex. Additionally, several striking behavioral changes were seen, including in particular an enhancement of sleep and an elevation of seizure threshold to epileptogenic agents. This raised the possibility that human seizure disorders might be influenced therapeutically by similar training. Our objective in human EEG feedback training became not only the facilitation of normal rhythmic patterns, but also the suppression of abnormal activity, thus requiring complex contingencies directed to the normalization of the sensorimotor EEG. To achieve this, a multicomponent frequency analysis was developed to extract and separate normal and abnormal elements of the EEG signal. Each of these elements was transduced to a specific component of a visual display system, and these were combined through logic circuits to present the subject with a symbolic display. Variable criteria provided for the gradual shaping of EEG elements towards the desired normal pattern. Some 50-70% of patients with poorly controlled seizure disorders experienced therapeutic benefits from this approach in our laboratory, and subsequently in many others. A more recent application of this approach to the modification of human brain function in our lab has been directed to the dichotomous problems of task overload and underload in the contemporary aviation environment. At least 70% of all aviation accidents have been attributed to the impact of these kinds of problems on crew performance. The use of EEG in this context has required many technical innovations and the application of the latest advances in EEG signal analysis. Our first goal has been the identification of relevant EEG characteristics. Additionally, we have developed a portable recording and analysis system for application in this context. Findings from laboratory and in-flight studies suggest that we will be able to detect appropriate changes in brain function, and feed this information to on-board computers for modification of mission requirements and/or crew status.

A Cocaine Hydrolase Engineered from Human Butyrylcholinesterase Selectively Blocks Cocaine Toxicity and Reinstatement of Drug Seeking in Rats

PubMed Central

Brimijoin, Stephen; Gao, Yang; Anker, Justin J; Gliddon, Luke A; LaFleur, David; Shah, R; Zhao, Qinghai; Singh, M; Carroll, Marilyn E

2008-01-01

Successive rational mutations of human butyrylcholinesterase (BChE) followed by fusion to human serum albumin have yielded an efficient hydrolase that offers realistic options for therapy of cocaine overdose and abuse. This albumin-BChE prevented seizures in rats given a normally lethal cocaine injection (100 mg/kg, i.p.), lowered brain cocaine levels even when administered after the drug, and provided rescue after convulsions commenced. Moreover, it selectively blocked cocaine-induced reinstatement of drug seeking in rats that had previously self-administered cocaine. The enzyme treatment was well tolerated and may be worth exploring for clinical application in humans. PMID:18199998

Genetic enhancement of cognition in a kindred with cone–rod dystrophy due to RIMS1 mutation

PubMed Central

Sisodiya, Sanjay M; Thompson, Pamela J; Need, Anna; Harris, Sarah E; Weale, Michael E; Wilkie, Susan E; Michaelides, Michel; Free, Samantha L; Walley, Nicole; Gumbs, Curtis; Gerrelli, Dianne; Ruddle, Piers; Whalley, Lawrence J; Starr, John M; Hunt, David M; Goldstein, David B; Deary, Ian J; Moore, Anthony T

2007-01-01

Background The genetic basis of variation in human cognitive abilities is poorly understood. RIMS1 encodes a synapse active‐zone protein with important roles in the maintenance of normal synaptic function: mice lacking this protein have greatly reduced learning ability and memory function. Objective An established paradigm examining the structural and functional effects of mutations in genes expressed in the eye and the brain was used to study a kindred with an inherited retinal dystrophy due to RIMS1 mutation. Materials and methods Neuropsychological tests and high‐resolution MRI brain scanning were undertaken in the kindred. In a population cohort, neuropsychological scores were associated with common variation in RIMS1. Additionally, RIMS1 was sequenced in top‐scoring individuals. Evolution of RIMS1 was assessed, and its expression in developing human brain was studied. Results Affected individuals showed significantly enhanced cognitive abilities across a range of domains. Analysis suggests that factors other than RIMS1 mutation were unlikely to explain enhanced cognition. No association with common variation and verbal IQ was found in the population cohort, and no other mutations in RIMS1 were detected in the highest scoring individuals from this cohort. RIMS1 protein is expressed in developing human brain, but RIMS1 does not seem to have been subjected to accelerated evolution in man. Conclusions A possible role for RIMS1 in the enhancement of cognitive function at least in this kindred is suggested. Although further work is clearly required to explore these findings before a role for RIMS1 in human cognition can be formally accepted, the findings suggest that genetic mutation may enhance human cognition in some cases. PMID:17237123

Accuracy of Raman spectroscopy in differentiating brain tumor from normal brain tissue.

PubMed

Zhang, Jing; Fan, Yimeng; He, Min; Ma, Xuelei; Song, Yanlin; Liu, Ming; Xu, Jianguo

2017-05-30

Raman spectroscopy could be applied to distinguish tumor from normal tissues. This meta-analysis was conducted to assess the accuracy of Raman spectroscopy in differentiating brain tumor from normal brain tissue. PubMed and Embase were searched to identify suitable studies prior to Jan 1st, 2016. We estimated the pooled sensitivity, specificity, positive and negative likelihood ratios (LR), diagnostic odds ratio (DOR), and constructed summary receiver operating characteristics (SROC) curves to identity the accuracy of Raman spectroscopy in differentiating brain tumor from normal brain tissue. A total of six studies with 1951 spectra were included. For glioma, the pooled sensitivity and specificity of Raman spectroscopy were 0.96 (95% CI 0.94-0.97) and 0.99 (95% CI 0.98-0.99), respectively. The area under the curve (AUC) was 0.9831. For meningioma, the pooled sensitivity and specificity were 0.98 (95% CI 0.94-1.00) and 1.00 (95% CI 0.98-1.00), respectively. The AUC was 0.9955. This meta-analysis suggested that Raman spectroscopy could be an effective and accurate tool for differentiating glioma and meningioma from normal brain tissue, which would help us both avoid removal of normal tissue and minimize the volume of residual tumor.

Mössbauer Spectra of Mouse Hearts Reveal Age-dependent Changes in Mitochondrial and Ferritin Iron Levels.

PubMed

Wofford, Joshua D; Chakrabarti, Mrinmoy; Lindahl, Paul A

2017-03-31

Cardiac function requires continuous high levels of energy, and so iron, a critical player in mitochondrial respiration, is an important component of the heart. Hearts from 57 Fe-enriched mice were evaluated by Mössbauer spectroscopy. Spectra consisted of a sextet and two quadrupole doublets. One doublet was due to residual blood, whereas the other was due to [Fe 4 S 4 ] 2+ clusters and low-spin Fe II hemes, most of which were associated with mitochondrial respiration. The sextet was due to ferritin; there was no evidence of hemosiderin, a ferritin decomposition product. Iron from ferritin was nearly absent in young hearts, but increased steadily with age. EPR spectra exhibited signals similar to those of brain, liver, and human cells. No age-dependent EPR trends were apparent. Hearts from HFE -/- mice with hemochromatosis contained slightly more iron overall than controls, including more ferritin and less mitochondrial iron; these differences typify slightly older hearts, perhaps reflecting the burden due to this disease. HFE -/- livers were overloaded with ferritin but had low mitochondrial iron levels. IRP2 -/- hearts contained less ferritin than controls but normal levels of mitochondrial iron. Hearts of young mice born to an iron-deficient mother contained normal levels of mitochondrial iron and no ferritin; the heart from the mother contained low ferritin and normal levels of mitochondrial iron. High-spin Fe II ions were nearly undetectable in heart samples; these were evident in brains, livers, and human cells. Previous Mössbauer spectra of unenriched diseased human hearts lacked mitochondrial and blood doublets and included hemosiderin features. This suggests degradation of iron-containing species during sample preparation. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

The Effects of Low-Dose Bisphenol A and Bisphenol F on Neural Differentiation of a Fetal Brain-Derived Neural Progenitor Cell Line.

PubMed

Fujiwara, Yuki; Miyazaki, Wataru; Koibuchi, Noriyuki; Katoh, Takahiko

2018-01-01

Environmental chemicals are known to disrupt the endocrine system in humans and to have adverse effects on several organs including the developing brain. Recent studies indicate that exposure to environmental chemicals during gestation can interfere with neuronal differentiation, subsequently affecting normal brain development in newborns. Xenoestrogen, bisphenol A (BPA), which is widely used in plastic products, is one such chemical. Adverse effects of exposure to BPA during pre- and postnatal periods include the disruption of brain function. However, the effect of BPA on neural differentiation remains unclear. In this study, we explored the effects of BPA or bisphenol F (BPF), an alternative compound for BPA, on neural differentiation using ReNcell, a human fetus-derived neural progenitor cell line. Maintenance in growth factor-free medium initiated the differentiation of ReNcell to neuronal cells including neurons, astrocytes, and oligodendrocytes. We exposed the cells to BPA or BPF for 3 days from the period of initiation and performed real-time PCR for neural markers such as β III-tubulin and glial fibrillary acidic protein (GFAP), and Olig2. The β III-tubulin mRNA level decreased in response to BPA, but not BPF, exposure. We also observed that the number of β III-tubulin-positive cells in the BPA-exposed group was less than that of the control group. On the other hand, there were no changes in the MAP2 mRNA level. These results indicate that BPA disrupts neural differentiation in human-derived neural progenitor cells, potentially disrupting brain development.

SU-E-T-331: Dosimetric Impact of Multileaf Collimator Leaf Width On Stereotactic Radiosurgery (SRS) RapidArc Treatment Plans for Single and Multiple Brain Metastases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hossain, S; Keeling, V; Ahmad, S

Purpose: To determine the effects of multileaf collimator (MLC) leaf width on normal-brain-tissue doses and dose conformity of SRS RapidArc treatment plans for brain tumors. Methods: Ten patients with 24 intracranial tumors (seven with 1–2 and three with 4–6 lesions) were planned using RapidArc for both Varian Millennium 120 MLC (5 mm leaf width) and high definition (HD) MLC (2.5 mm leaf width). Between 2 and 8 arcs were used with two full coplanar arcs and the rest non-coplanar half arcs. 6 MV beams were used and plans were optimized with a high priority to the Normal Tissue Objective (tomore » achieve dose conformity and sharp dose fall-off) and normal brain tissue. Calculation was done using AAA on a 1 mm grid size. The prescription dose ranged from 14–22 Gy. Plans were normalized such that 99% of the target received the prescription dose. Identical beam geometries, optimizations, calculations, and normalizations were used for both plans. Paddick Conformity Index (PCI), V4, V8 and V12 Gy for normal brain tissue and Integral Dose were used for analysis. Results: In all cases, HD MLC plans performed better in sparing normal brain tissue, achieving a higher PCI with a lower Integral Dose. The average PCI for all 24 targets was 0.75±0.23 and 0.70±0.23 (p ≤0.0015) for HD MLC and Millennium MLC plans, respectively. The average ratio of normal brain doses for Millennium MLC to HD MLC plans was 1.30±0.16, 1.27±0.15, and 1.31±0.18 for the V4, V8, and V12, respectively. The differences in normal brain dose for all criteria were statistically significant with p-value < 0.02. On average Millennium MLC plans had a 16% higher integral dose than HD MLC plans. Conclusion: Significantly better dose conformity with reduced volume of normal brain tissue and integral dose was achieved with HD MLC plans compared to Millennium MLC plans.« less

Changes of the directional brain networks related with brain plasticity in patients with long-term unilateral sensorineural hearing loss.

PubMed

Zhang, G-Y; Yang, M; Liu, B; Huang, Z-C; Li, J; Chen, J-Y; Chen, H; Zhang, P-P; Liu, L-J; Wang, J; Teng, G-J

2016-01-28

Previous studies often report that early auditory deprivation or congenital deafness contributes to cross-modal reorganization in the auditory-deprived cortex, and this cross-modal reorganization limits clinical benefit from cochlear prosthetics. However, there are inconsistencies among study results on cortical reorganization in those subjects with long-term unilateral sensorineural hearing loss (USNHL). It is also unclear whether there exists a similar cross-modal plasticity of the auditory cortex for acquired monaural deafness and early or congenital deafness. To address this issue, we constructed the directional brain functional networks based on entropy connectivity of resting-state functional MRI and researched changes of the networks. Thirty-four long-term USNHL individuals and seventeen normally hearing individuals participated in the test, and all USNHL patients had acquired deafness. We found that certain brain regions of the sensorimotor and visual networks presented enhanced synchronous output entropy connectivity with the left primary auditory cortex in the left long-term USNHL individuals as compared with normally hearing individuals. Especially, the left USNHL showed more significant changes of entropy connectivity than the right USNHL. No significant plastic changes were observed in the right USNHL. Our results indicate that the left primary auditory cortex (non-auditory-deprived cortex) in patients with left USNHL has been reorganized by visual and sensorimotor modalities through cross-modal plasticity. Furthermore, the cross-modal reorganization also alters the directional brain functional networks. The auditory deprivation from the left or right side generates different influences on the human brain. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

ALTERATIONS IN BRAIN CREATINE CONCENTRATIONS UNDER LONG-TERM SOCIAL ISOLATION (EXPERIMENTAL STUDY).

PubMed

Koshoridze, N; Kuchukashvili, Z; Menabde, K; Lekiashvili, Sh; Koshoridze, M

2016-02-01

Stress represents one of the main problems of modern humanity. This study was done for understanding more clearly alterations in creatine content of the brain under psycho-emotional stress induced by long-term social isolation. It was shown that under 30 days social isolation creatine amount in the brain was arisen, while decreasing concentrations of synthesizing enzymes (AGAT, GAMT) and creatine transporter protein (CrT). Another important point was that such changes were accompanied by down-regulation of creatine kinase (CK), therefore the enzyme's concentration was lowered. In addition, it was observed that content of phosphocreatine (PCr) and ATP were also reduced, thus indicating down-regulation of energy metabolism of brain that is really a crucial point for its normal functioning. To sum up the results it can be underlined that long-term social isolation has negative influence on energy metabolism of brain; and as a result reduce ATP content, while increase of free creatine concentration, supposedly maintaining maximal balance for ATP amount, but here must be also noted that up-regulated oxidative pathways might have impact on blood brain barrier, resulting on its permeability.

Role of mechanical factors in cortical folding development

NASA Astrophysics Data System (ADS)

Razavi, Mir Jalil; Zhang, Tuo; Li, Xiao; Liu, Tianming; Wang, Xianqiao

2015-09-01

Deciphering mysteries of the structure-function relationship in cortical folding has emerged as the cynosure of recent research on brain. Understanding the mechanism of convolution patterns can provide useful insight into the normal and pathological brain function. However, despite decades of speculation and endeavors the underlying mechanism of the brain folding process remains poorly understood. This paper focuses on the three-dimensional morphological patterns of a developing brain under different tissue specification assumptions via theoretical analyses, computational modeling, and experiment verifications. The living human brain is modeled with a soft structure having outer cortex and inner core to investigate the brain development. Analytical interpretations of differential growth of the brain model provide preliminary insight into the critical growth ratio for instability and crease formation of the developing brain followed by computational modeling as a way to offer clues for brain's postbuckling morphology. Especially, tissue geometry, growth ratio, and material properties of the cortex are explored as the most determinant parameters to control the morphogenesis of a growing brain model. As indicated in results, compressive residual stresses caused by the sufficient growth trigger instability and the brain forms highly convoluted patterns wherein its gyrification degree is specified with the cortex thickness. Morphological patterns of the developing brain predicted from the computational modeling are consistent with our neuroimaging observations, thereby clarifying, in part, the reason of some classical malformation in a developing brain.

Blood-Brain Glucose Transfer: Repression in Chronic Hyperglycemia

NASA Astrophysics Data System (ADS)

Gjedde, Albert; Crone, Christian

1981-10-01

Diabetic patients with increased plasma glucose concentrations may develop cerebral symptoms of hypoglycemia when their plasma glucose is rapidly lowered to normal concentrations. The symptoms may indicate insufficient transport of glucose from blood to brain. In rats with chronic hyperglycemia the maximum glucose transport capacity of the blood-brain barrier decreased from 400 to 290 micromoles per 100 grams per minute. When plasma glucose was lowered to normal values, the glucose transport rate into brain was 20 percent below normal. This suggests that repressive changes of the glucose transport mechanism occur in brain endothelial cells in response to increased plasma glucose.

CD4 Count in HIV- Brain-Dead Donors: Insight into Donor Risk Assessment for HIV+ Donors.

PubMed

Serrano, Oscar Kenneth; Kerwin, Scott; Payne, William D; Pruett, Timothy L

2017-04-01

The Human Immunodeficiency Virus (HIV) Organ Policy Equity Act allows for transplantation of organs from HIV-infected individuals (HIV+), provided it is performed under a research protocol. The safety assessment of an organ for transplantation is an essential element of the donation process. The risk for HIV-associated opportunistic infections increases as circulating CD4+ lymphocytes decrease to less than 200 cells/μL; however, the numbers of circulating CD4+ cells in the HIV-negative (HIV-) brain-dead donor (BDD) is not known. Circulating T-lymphocyte subset profiles in conventional HIV- BDD were measured in 20 BDD in a clinical laboratory. The mean age of the BDD cohort was 48.7 years, 95% were white and 45% were women. The average body mass index was 29.2 kg/m. Cerebrovascular accident (40%) was the most prevalent cause of death. Sixteen (80%) subjects had a CD4 count ≤441 cells/μL (lower limit of normal) and 11 (55%) had a CD4 count less than 200 cells/μL; 11 (55%) subjects had a CD8 count ≤125 cells/μL (lower limit of normal). CD4/CD8 ratio was below normal in 3 patients (normal, 1.4-2.6). No recipient had a recognized donor-associated adverse event. Absolute numbers of CD4 and CD8 T-lymphocytes are commonly reduced after brain death in HIV- individuals. Thus, CD4 absolute numbers are an inconsistent metric for assessing organ donor risk, irrespective of HIV status.

The Multidrug Resistance 1 Gene Abcb1 in Brain and Placenta: Comparative Analysis in Human and Guinea Pig

PubMed Central

Pappas, Jane J.; Petropoulos, Sophie; Suderman, Matthew; Iqbal, Majid; Moisiadis, Vasilis; Turecki, Gustavo; Matthews, Stephen G.; Szyf, Moshe

2014-01-01

The Multidrug Resistance 1 (MDR1; alternatively ABCB1) gene product P-glycoprotein (P-gp), an ATP binding cassette transporter, extrudes multiple endogenous and exogenous substrates from the cell, playing an important role in normal physiology and xenobiotic distribution and bioavailability. To date, the predominant animal models used to investigate the role of P-gp have been the mouse and rat, which have two distinct genes, Abcb1a and Abcb1b. In contrast, the human has a single gene, ABCB1, for which only a single isoform has been validated. We and others have previously shown important differences between Abcb1a and Abcb1b, limiting the extrapolation from rodent findings to the human. Since the guinea pig has a relatively long gestation, hemomonochorial placentation and neuroanatomically mature offspring, it is more similar to the human, and may provide a more comparable model for investigating the regulation of P-gp in the brain and placenta, however, to date, the Abcb1 gene in the guinea pig remains to be characterized. The placenta and fetal brain are barrier sites that express P-gp and that play a critical role of protection of the fetus and the fetal brain from maternally administered drugs and other xenobiotics. Using RNA sequencing (RNA-seq), reverse transcription-polymerase chain reaction (RT-PCR) and quantitative PCR (QPCR) to sequence the expressed isoforms of guinea pig Abcb1, we demonstrate that like the human, the guinea pig genome contains one gene for Abcb1 but that it is expressed as at least three different isoforms via alternative splicing and alternate exon usage. Further, we demonstrate that these isoforms are more closely related to human than to rat or mouse isoforms. This striking, overall similarity and evolutionary relatedness between guinea pig Abcb1 and human ABCB1 indicate that the guinea pig represents a relevant animal model for investigating the function and regulation of P-gp in the placenta and brain. PMID:25353162

Young APOE[subscript 4] Targeted Replacement Mice Exhibit Poor Spatial Learning and Memory, with Reduced Dendritic Spine Density in the Medial Entorhinal Cortex

ERIC Educational Resources Information Center

Rodriguez, Gustavo A.; Burns, Mark P.; Weeber, Edwin J.; Rebeck, G. William

2013-01-01

The apolipoprotein E4 ("APOE-[epsilon]4") allele is the strongest genetic risk factor for developing late-onset Alzheimer's disease, and may predispose individuals to Alzheimer's-related cognitive decline by affecting normal brain function early in life. To investigate the impact of human APOE alleles on cognitive performance in mice, we trained…

Differential gene expression analysis in glioblastoma cells and normal human brain cells based on GEO database.

PubMed

Wang, Anping; Zhang, Guibin

2017-11-01

The differentially expressed genes between glioblastoma (GBM) cells and normal human brain cells were investigated to performed pathway analysis and protein interaction network analysis for the differentially expressed genes. GSE12657 and GSE42656 gene chips, which contain gene expression profile of GBM were obtained from Gene Expression Omniub (GEO) database of National Center for Biotechnology Information (NCBI). The 'limma' data packet in 'R' software was used to analyze the differentially expressed genes in the two gene chips, and gene integration was performed using 'RobustRankAggreg' package. Finally, pheatmap software was used for heatmap analysis and Cytoscape, DAVID, STRING and KOBAS were used for protein-protein interaction, Gene Ontology (GO) and KEGG analyses. As results: i) 702 differentially expressed genes were identified in GSE12657, among those genes, 548 were significantly upregulated and 154 were significantly downregulated (p<0.01, fold-change >1), and 1,854 differentially expressed genes were identified in GSE42656, among the genes, 1,068 were significantly upregulated and 786 were significantly downregulated (p<0.01, fold-change >1). A total of 167 differentially expressed genes including 100 upregulated genes and 67 downregulated genes were identified after gene integration, and the genes showed significantly different expression levels in GBM compared with normal human brain cells (p<0.05). ii) Interactions between the protein products of 101 differentially expressed genes were identified using STRING and expression network was established. A key gene, called CALM3, was identified by Cytoscape software. iii) GO enrichment analysis showed that differentially expressed genes were mainly enriched in 'neurotransmitter:sodium symporter activity' and 'neurotransmitter transporter activity', which can affect the activity of neurotransmitter transportation. KEGG pathway analysis showed that the differentially expressed genes were mainly enriched in 'protein processing in endoplasmic reticulum', which can affect protein processing in endoplasmic reticulum. The results showed that: i) 167 differentially expressed genes were identified from two gene chips after integration; and ii) protein interaction network was established, and GO and KEGG pathway analyses were successfully performed to identify and annotate the key gene, which provide new insights for the studies on GBN at gene level.

Biodistribution and Subcellular Localization of an Unnatural Boron-Containing Amino Acid (Cis-ABCPC) by Imaging Secondary Ion Mass Spectrometry for Neutron Capture Therapy of Melanomas and Gliomas

PubMed Central

Chandra, Subhash; Barth, Rolf F.; Haider, Syed A.; Yang, Weilian; Huo, Tianyao; Shaikh, Aarif L.; Kabalka, George W.

2013-01-01

The development of new boron-delivery agents is a high priority for improving the effectiveness of boron neutron capture therapy. In the present study, 1-amino-3-borono-cyclopentanecarboxylic acid (cis-ABCPC) as a mixture of its L- and D- enantiomers was evaluated in vivo using the B16 melanoma model for the human tumor and the F98 rat glioma as a model for human gliomas. A secondary ion mass spectrometry (SIMS) based imaging instrument, CAMECA IMS 3F SIMS Ion Microscope, was used for quantitative imaging of boron at 500 nm spatial resolution. Both in vivo and in vitro studies in melanoma models demonstrated that boron was localized in the cytoplasm and nuclei with some cell-to-cell variability. Uptake of cis-ABCPC in B16 cells was time dependent with a 7.5:1 partitioning ratio of boron between cell nuclei and the nutrient medium after 4 hrs. incubation. Furthermore, cis-ABCPC delivered boron to cells in all phases of the cell cycle, including S-phase. In vivo SIMS studies using the F98 rat glioma model revealed an 8:1 boron partitioning ratio between the main tumor mass and normal brain tissue with a 5:1 ratio between infiltrating tumor cells and contiguous normal brain. Since cis-ABCPC is water soluble and can cross the blood-brain-barrier via the L-type amino acid transporters (LAT), it may accumulate preferentially in infiltrating tumor cells in normal brain due to up-regulation of LAT in high grade gliomas. Once trapped inside the tumor cell, cis-ABCPC cannot be metabolized and remains either in a free pool or bound to cell matrix components. The significant improvement in boron uptake by both the main tumor mass and infiltrating tumor cells compared to those reported in animal and clinical studies of p-boronophenylalanine strongly suggest that cis-ABCPC has the potential to become a novel new boron delivery agent for neutron capture therapy of gliomas and melanomas. PMID:24058680

Normalization is a general neural mechanism for context-dependent decision making

PubMed Central

Louie, Kenway; Khaw, Mel W.; Glimcher, Paul W.

2013-01-01

Understanding the neural code is critical to linking brain and behavior. In sensory systems, divisive normalization seems to be a canonical neural computation, observed in areas ranging from retina to cortex and mediating processes including contrast adaptation, surround suppression, visual attention, and multisensory integration. Recent electrophysiological studies have extended these insights beyond the sensory domain, demonstrating an analogous algorithm for the value signals that guide decision making, but the effects of normalization on choice behavior are unknown. Here, we show that choice models using normalization generate significant (and classically irrational) choice phenomena driven by either the value or number of alternative options. In value-guided choice experiments, both monkey and human choosers show novel context-dependent behavior consistent with normalization. These findings suggest that the neural mechanism of value coding critically influences stochastic choice behavior and provide a generalizable quantitative framework for examining context effects in decision making. PMID:23530203

Functional connectivity patterns of normal human swallowing: difference among various viscosity swallows in normal and chin-tuck head positions.

PubMed

Jestrović, Iva; Coyle, James L; Perera, Subashan; Sejdić, Ervin

2016-12-01

Consuming thicker fluids and swallowing in the chin-tuck position has been shown to be advantageous for some patients with neurogenic dysphagia who aspirate due to various causes. The anatomical changes caused by these therapeutic techniques are well known, but it is unclear whether these changes alter the cerebral processing of swallow-related sensorimotor activity. We sought to investigate the effect of increased fluid viscosity and chin-down posture during swallowing on brain networks. 55 healthy adults performed water, nectar-thick, and honey thick liquid swallows in the neutral and chin-tuck positions while EEG signals were recorded. After pre-processing of the EEG timeseries, the time-frequency based synchrony measure was used for forming the brain networks to investigate whether there were differences among the brain networks between the swallowing of different fluid viscosities and swallowing in different head positions. We also investigated whether swallowing under various conditions exhibit small-world properties. Results showed that fluid viscosity affects the brain network in the Delta, Theta, Alpha, Beta, and Gamma frequency bands and that swallowing in the chin-tuck head position affects brain networks in the Alpha, Beta, and Gamma frequency bands. In addition, we showed that swallowing in all tested conditions exhibited small-world properties. Therefore, fluid viscosity and head positions should be considered in future swallowing EEG investigations. Copyright © 2016 Elsevier B.V. All rights reserved.

Human face processing is tuned to sexual age preferences

PubMed Central

Ponseti, J.; Granert, O.; van Eimeren, T.; Jansen, O.; Wolff, S.; Beier, K.; Deuschl, G.; Bosinski, H.; Siebner, H.

2014-01-01

Human faces can motivate nurturing behaviour or sexual behaviour when adults see a child or an adult face, respectively. This suggests that face processing is tuned to detecting age cues of sexual maturity to stimulate the appropriate reproductive behaviour: either caretaking or mating. In paedophilia, sexual attraction is directed to sexually immature children. Therefore, we hypothesized that brain networks that normally are tuned to mature faces of the preferred gender show an abnormal tuning to sexual immature faces in paedophilia. Here, we use functional magnetic resonance imaging (fMRI) to test directly for the existence of a network which is tuned to face cues of sexual maturity. During fMRI, participants sexually attracted to either adults or children were exposed to various face images. In individuals attracted to adults, adult faces activated several brain regions significantly more than child faces. These brain regions comprised areas known to be implicated in face processing, and sexual processing, including occipital areas, the ventrolateral prefrontal cortex and, subcortically, the putamen and nucleus caudatus. The same regions were activated in paedophiles, but with a reversed preferential response pattern. PMID:24850896

Distinct representations of configural and part information across multiple face-selective regions of the human brain

PubMed Central

Golarai, Golijeh; Ghahremani, Dara G.; Eberhardt, Jennifer L.; Gabrieli, John D. E.

2015-01-01

Several regions of the human brain respond more strongly to faces than to other visual stimuli, such as regions in the amygdala (AMG), superior temporal sulcus (STS), and the fusiform face area (FFA). It is unclear if these brain regions are similar in representing the configuration or natural appearance of face parts. We used functional magnetic resonance imaging of healthy adults who viewed natural or schematic faces with internal parts that were either normally configured or randomly rearranged. Response amplitudes were reduced in the AMG and STS when subjects viewed stimuli whose configuration of parts were digitally rearranged, suggesting that these regions represent the 1st order configuration of face parts. In contrast, response amplitudes in the FFA showed little modulation whether face parts were rearranged or if the natural face parts were replaced with lines. Instead, FFA responses were reduced only when both configural and part information were reduced, revealing an interaction between these factors, suggesting distinct representation of 1st order face configuration and parts in the AMG and STS vs. the FFA. PMID:26594191

Placental growth factor deficiency is associated with impaired cerebral vascular development in mice.

PubMed

Luna, Rayana Leal; Kay, Vanessa R; Rätsep, Matthew T; Khalaj, Kasra; Bidarimath, Mallikarjun; Peterson, Nichole; Carmeliet, Peter; Jin, Albert; Croy, B Anne

2016-02-01

Placental growth factor (PGF) is expressed in the developing mouse brain and contributes to vascularization and vessel patterning. PGF is dynamically expressed in fetal mouse brain, particularly forebrain, and is essential for normal cerebrovascular development. PGF rises in maternal plasma over normal human and mouse pregnancy but is low in many women with the acute onset hypertensive syndrome, pre-eclampsia (PE). Little is known about the expression of PGF in the fetus during PE. Pgf  (-/-) mice appear normal but recently cerebral vascular defects were documented in adult Pgf  (-/-) mice. Here, temporal-spatial expression of PGF is mapped in normal fetal mouse brains and cerebral vasculature development is compared between normal and congenic Pgf  (-/-) fetuses to assess the actions of PGF during cerebrovascular development. Pgf/PGF, Vegfa/VEGF, Vegf receptor (Vegfr)1 and Vegfr2 expression were examined in the brains of embryonic day (E)12.5, 14.5, 16.5 and 18.5 C57BL/6 (B6) mice using quantitative PCR and immunohistochemistry. The cerebral vasculature was compared between Pgf  (-/-) and B6 embryonic and adult brains using whole mount techniques. Vulnerability to cerebral ischemia was investigated using a left common carotid ligation assay. Pgf/PGF and Vegfr1 are highly expressed in E12.5-14.5 forebrain relative to VEGF and Vegfr2. Vegfa/VEGF is relatively more abundant in hindbrain (HB). PGF and VEGF expression were similar in midbrain. Delayed HB vascularization was seen at E10.5 and 11.5 in Pgf  (-/-) brains. At E14.5, Pgf  (-/-) circle of Willis showed unilateral hypoplasia and fewer collateral vessels, defects that persisted post-natally. Functionally, adult Pgf  (-/-) mice experienced cerebral ischemia after left common carotid arterial occlusion while B6 mice did not. Since Pgf  (-/-) mice were used, consequences of complete absence of maternal and fetal PGF were defined. Therefore, the effects of maternal versus fetal PGF deficiency on cerebrovascular development cannot be separated. However, as PGF was strongly expressed in the developing brain at all timepoints, we suggest that local PGF has a more important role than distant maternal or placental sources. Full PGF loss is not expected in PE pregnancies, predicting that the effects of PGF deficiency identified in this model will be more severe than any effects in PE-offspring. These studies provoke the question of whether PGF expression is decreased and cerebral vascular maldevelopment occurs in fetuses who experience a preeclamptic gestation. These individuals have already been reported to have elevated risk for stroke and cognitive impairments. N/A. This work was supported by awards from the Natural Sciences and Engineering Research Council, the Canada Research Chairs Program and the Canadian Foundation for Innovation to B.A.C. and by training awards from the Universidade Federal de Pernambuco and Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq), Brazil to R.L.L.; Queen's University to V.R.K. and the Canadian Institutes of Health Research to M.T.R. The work of P.C. is supported by the Belgian Science Policy BELSPO-IUAP7/03, Structural funding by the Flemish Government-Methusalem funding, and the Flemish Science Fund-FWO grants. There were no competing interests. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

No effect of ablation of surfactant protein-D on acute cerebral infarction in mice.

PubMed

Lambertsen, Kate L; Østergaard, Kamilla; Clausen, Bettina H; Hansen, Søren; Stenvang, Jan; Thorsen, Stine B; Meldgaard, Michael; Kristensen, Bjarne W; Hansen, Pernille B; Sorensen, Grith L; Finsen, Bente

2014-07-19

Crosstalk between the immune system in the brain and the periphery may contribute to the long-term outcome both in experimental and clinical stroke. Although, the immune defense collectin surfactant protein-D (SP-D) is best known for its role in pulmonary innate immunity, SP-D is also known to be involved in extrapulmonary modulation of inflammation in mice. We investigated whether SP-D affected cerebral ischemic infarction and ischemia-induced inflammatory responses in mice. The effect of SP-D was studied by comparing the size of ischemic infarction and the inflammatory and astroglial responses in SP-D knock out (KO) and wild type (WT) mice subjected to permanent middle cerebral artery occlusion. SP-D mRNA production was assessed in isolated cerebral arteries and in the whole brain by PCR, and SP-D protein in normal appearing and ischemic human brain by immunohistochemistry. Changes in plasma SP-D and TNF were assessed by ELISA and proximity ligation assay, respectively. Infarct volumetric analysis showed that ablation of SP-D had no effect on ischemic infarction one and five days after induction of ischemia. Further, ablation of SP-D had no effect on the ischemia-induced increase in TNF mRNA production one day after induction of ischemia; however the TNF response to the ischemic insult was affected at five days. SP-D mRNA was not detected in parenchymal brain cells in either naïve mice or in mice subjected to focal cerebral ischemia. However, SP-D mRNA was detected in middle cerebral artery cells in WT mice and SP-D protein in vascular cells both in normal appearing and ischemic human brain tissue. Measurements of the levels of SP-D and TNF in plasma in mice suggested that levels were unaffected by the ischemic insult. Microglial-leukocyte and astroglial responses were comparable in SP-D KO and WT mice. SP-D synthesis in middle cerebral artery cells is consistent with SP-D conceivably leaking into the infarcted area and affecting local cytokine production. However, there was no SP-D synthesis in parenchymal brain cells and ablation of SP-D had no effect on ischemic cerebral infarction.

Digital atlas of fetal brain MRI.

PubMed

Chapman, Teresa; Matesan, Manuela; Weinberger, Ed; Bulas, Dorothy I

2010-02-01

Fetal MRI can be performed in the second and third trimesters. During this time, the fetal brain undergoes profound structural changes. Interpretation of appropriate development might require comparison with normal age-based models. Consultation of a hard-copy atlas is limited by the inability to compare multiple ages simultaneously. To provide images of normal fetal brains from weeks 18 through 37 in a digital format that can be reviewed interactively. This will facilitate recognition of abnormal brain development. T2-W images for the atlas were obtained from fetal MR studies of normal brains scanned for other indications from 2005 to 2007. Images were oriented in standard axial, coronal and sagittal projections, with laterality established by situs. Gestational age was determined by last menstrual period, earliest US measurements and sonogram performed on the same day as the MR. The software program used for viewing the atlas, written in C#, permits linked scrolling and resizing the images. Simultaneous comparison of varying gestational ages is permissible. Fetal brain images across gestational ages 18 to 37 weeks are provided as an interactive digital atlas and are available for free download from http://radiology.seattlechildrens.org/teaching/fetal_brain . Improved interpretation of fetal brain abnormalities can be facilitated by the use of digital atlas cataloging of the normal changes throughout fetal development. Here we provide a description of the atlas and a discussion of normal fetal brain development.

A cognitive neurobiological account of deception: evidence from functional neuroimaging.

PubMed Central

Spence, Sean A; Hunter, Mike D; Farrow, Tom F D; Green, Russell D; Leung, David H; Hughes, Catherine J; Ganesan, Venkatasubramanian

2004-01-01

An organism may use misinformation, knowingly (through deception) or unknowingly (as in the case of camouflage), to gain advantage in a competitive environment. From an evolutionary perspective, greater tactical deception occurs among primates closer to humans, with larger neocortices. In humans, the onset of deceptive behaviours in childhood exhibits a developmental trajectory, which may be regarded as 'normal' in the majority and deficient among a minority with certain neurodevelopmental disorders (e.g. autism). In the human adult, deception and lying exhibit features consistent with their use of 'higher' or 'executive' brain systems. Accurate detection of deception in humans may be of particular importance in forensic practice, while an understanding of its cognitive neurobiology may have implications for models of 'theory of mind' and social cognition, and societal notions of responsibility, guilt and mitigation. In recent years, functional neuroimaging techniques (especially functional magnetic resonance imaging) have been used to study deception. Though few in number, and using very different experimental protocols, studies published in the peer-reviewed literature exhibit certain consistencies. Attempted deception is associated with activation of executive brain regions (particularly prefrontal and anterior cingulate cortices), while truthful responding has not been shown to be associated with any areas of increased activation (relative to deception). Hence, truthful responding may comprise a relative 'baseline' in human cognition and communication. The subject who lies may necessarily engage 'higher' brain centres, consistent with a purpose or intention (to deceive). While the principle of executive control during deception remains plausible, its precise anatomy awaits elucidation. PMID:15590616

The brain's emotional foundations of human personality and the Affective Neuroscience Personality Scales.

PubMed

Davis, Kenneth L; Panksepp, Jaak

2011-10-01

Six of the primary-process subcortical brain emotion systems - SEEKING, RAGE, FEAR, CARE, GRIEF and PLAY - are presented as foundational for human personality development, and hence as a potentially novel template for personality assessment as in the Affective Neurosciences Personality Scales (ANPS), described here. The ANPS was conceptualized as a potential clinical research tool, which would help experimentalists and clinicians situate subjects and clients in primary-process affective space. These emotion systems are reviewed in the context of a multi-tiered framing of consciousness spanning from primary affect, which encodes biological valences, to higher level tertiary (thought mediated) processing. Supporting neuroscience research is presented along with comparisons to Cloninger's Temperament and Character Inventory and the Five Factor Model (FFM). Suggestions are made for grounding the internal structure of the FFM on the primal emotional systems recognized in affective neuroscience, which may promote substantive dialog between human and animal research traditions. Personality is viewed in the context of Darwinian "continuity" with the inherited subcortical brain emotion systems being foundational, providing major forces for personality development in both humans and animals, and providing an affective infrastructure for an expanded five factor descriptive model applying to normal and clinical human populations as well as mammals generally. Links with ontogenetic and epigenetic models of personality development are also presented. Potential novel clinical applications of the CARE maternal-nurturance system and the PLAY system are also discussed. Copyright © 2011 Elsevier Ltd. All rights reserved.

Translation of near infrared brain imaging to assess children with cerebral palsy

NASA Astrophysics Data System (ADS)

Alexandrakis, George; Khan, Bilal; Tian, Fenghua; Asanani, Nayan; Behbehani, Khosrow; Delgado, Mauricio R.; Liu, Hanli

2009-02-01

Cerebral palsy (CP) is the most common motor disorder of central origin in childhood and affects at least 2 children per 1000 live births every year. Neuroimaging techniques are needed to study neuroplastic rearrangements in the human brain in vivo as a result of CP. Unfortunately, accurate imaging from currently available techniques often requires the patients' complete body confinement, steadiness and minimal noise for a long period of time, which limits the success rate to less than 50% for normal children and worse for CP-affected ones. In this work we show that functional near infrared (fNIR) imaging is robust to motion artifacts and has excellent potential as a sensitive diagnostic tool for this motor disorder. We have analyzed data from pediatric normal and CP patients performing finger-tapping and handwaving motor cortex activation tasks. From these analyses we have identified both spatial and temporal metrics of NIR-based motor cortex activation patterns that can clearly distinguish between normal and CP patients. We also present data from additional patients where signal processing methods are applied to filter out concurrently recorded hemodynamic signals due to breathing and cardiac pulsation. It is shown that filtering can substantially improve the quality of activation data, thus enabling more accurate comparison of activation patterns between normal and CP-affected children.

Dystrophic Serotonergic Axons in Neurodegenerative Diseases

PubMed Central

Azmitia, Efrain C.; Nixon, Ralph

2012-01-01

Neurodegenerative diseases such as Parkinson's disease (PD), frontal lobe dementia (FLD) and Diffuse Lewy-Body dementia (DLBD) have diverse neuropathologic features. Here we report that serotonin fibers are dystrophic in the brains of individuals with these three diseases. In neuropathologically normal (control) brains (n=3), serotonin axons immunoreactive (IR) with antibodies against the serotonin transporter (5-HTT) protein were widely distributed in cortex (entorhinal and dorsolateral prefrontal), hippocampus and rostral brainstem. 5-HTT-IR fibers of passage appeared thick, smooth, and un-branched in medial forebrain bundle, medial lemniscus and cortex white matter. The terminal branches were fine, highly branched and varicose in substantia nigra, hippocampus and cortical gray matter. In the diseased brains, however, 5-HTT-IR fibers in the forebrain were reduced in number and were frequently bulbous, splayed, tightly clustered and enlarged. Morphometric analysis revealed significant differences in the size distribution of the 5-HTT-IR profiles in dorsolateral prefrontal area between neurodegenerative diseases and controls. Our observations provide direct morphologic evidence for degeneration of human serotonergic axons in the brains of patients with neurodegenerative diseases despite the limited size (n=3 slices for each region (3) from each brain (4), total slices was n=36) and lack of extensive clinical characterization of the analyzed cohort. This is the first report of dystrophic 5-HTT-IR axons in postmortem human tissue PMID:18502405

The construction of the multifunctional targeting ursolic acids liposomes and its apoptosis effects to C6 glioma stem cells

PubMed Central

Ying, Xue; Wang, Yahua; Xu, Haolun; Li, Xia; Yan, Helu; Tang, Hui; Wen, Chen; Li, Yingchun

2017-01-01

Brain gliomas, one of the most fatal tumors to human, severely threat the health and life of human. They are capable of extremely strong invasion ability. And invasive glioma cells could rapidly penetrate into normal brain tissues and break them. We prepared a kind of functional liposomes, which could be transported acrossing the blood-brain barrier (BBB) and afterwards induce the apoptosis of glioma stem cells. In this research, we chose ursolic acids (UA) as an anti-cancer drug to inhibit the growth of C6 glioma cells, while epigallocatechin 3-gallate(EGCG) as the agent that could induce the apoptosis of C6 glioma stem cells. With the targeting ability of MAN, the liposomes could be delivered through the BBB and finally were concentrated on the brain gliomas. Cell experiments in vitro demonstrated that the functional liposomes were able to significantly enhance the anti-cancer effects of the drugs due to promoting the apoptosis and endocytosis effects of C6 glioma cells and C6 glioma stem cells at the same time. Furthermore, the evaluations through animal models showed that the drugs could obviously prolong the survival period of brain glioma-bearing mice and inhibit the tumor growth. Consequently, multifunctional targeting ursolic acids liposomes could potentially improve the therapeutic effects on C6 glioma cells and C6 glioma stem cells. PMID:28969057

Brain extraction from normal and pathological images: A joint PCA/Image-Reconstruction approach.

PubMed

Han, Xu; Kwitt, Roland; Aylward, Stephen; Bakas, Spyridon; Menze, Bjoern; Asturias, Alexander; Vespa, Paul; Van Horn, John; Niethammer, Marc

2018-08-01

Brain extraction from 3D medical images is a common pre-processing step. A variety of approaches exist, but they are frequently only designed to perform brain extraction from images without strong pathologies. Extracting the brain from images exhibiting strong pathologies, for example, the presence of a brain tumor or of a traumatic brain injury (TBI), is challenging. In such cases, tissue appearance may substantially deviate from normal tissue appearance and hence violates algorithmic assumptions for standard approaches to brain extraction; consequently, the brain may not be correctly extracted. This paper proposes a brain extraction approach which can explicitly account for pathologies by jointly modeling normal tissue appearance and pathologies. Specifically, our model uses a three-part image decomposition: (1) normal tissue appearance is captured by principal component analysis (PCA), (2) pathologies are captured via a total variation term, and (3) the skull and surrounding tissue is captured by a sparsity term. Due to its convexity, the resulting decomposition model allows for efficient optimization. Decomposition and image registration steps are alternated to allow statistical modeling of normal tissue appearance in a fixed atlas coordinate system. As a beneficial side effect, the decomposition model allows for the identification of potentially pathological areas and the reconstruction of a quasi-normal image in atlas space. We demonstrate the effectiveness of our approach on four datasets: the publicly available IBSR and LPBA40 datasets which show normal image appearance, the BRATS dataset containing images with brain tumors, and a dataset containing clinical TBI images. We compare the performance with other popular brain extraction models: ROBEX, BEaST, MASS, BET, BSE and a recently proposed deep learning approach. Our model performs better than these competing approaches on all four datasets. Specifically, our model achieves the best median (97.11) and mean (96.88) Dice scores over all datasets. The two best performing competitors, ROBEX and MASS, achieve scores of 96.23/95.62 and 96.67/94.25 respectively. Hence, our approach is an effective method for high quality brain extraction for a wide variety of images. Copyright © 2018 Elsevier Inc. All rights reserved.

Aging is associated with altered inflammatory, arachidonic acid cascade and synaptic markers, influenced by epigenetic modifications, in the human frontal cortex

PubMed Central

Keleshian, Vasken L.; Modi, Hiren R.; Rapoport, Stanley I.; Rao, Jagadeesh S.

2013-01-01

Aging is a risk factor for Alzheimer’s disease (AD) and is associated with cognitive decline. However, underlying molecular mechanisms of brain aging are not clear. Recent studies suggest epigenetic influences on gene expression in AD, since DNA methylation levels influence protein and mRNA expression in postmortem AD brain. We hypothesized that some of these changes occur with normal aging. To test this hypothesis, we measured markers of the arachidonic acid (AA) cascade, neuroinflammation, pro- and anti-apoptosis factors, and gene specific epigenetic modifications in postmortem frontal cortex from nine middle-aged (41 ± 1 (SEM) years) and ten aged subjects (70 ± 3 years). The aged compared with middle-aged brain showed elevated levels of neuroinflammatory and AA cascade markers, altered pro and anti-apoptosis factors and loss of synaptophysin. Some of these changes correlated with promoter hypermethylation of BDNF, CREB, and synaptophysin and hypomethylation of BAX. These molecular alterations in aging are different from or more subtle than changes associated with AD pathology. The degree to which they are related to changes in cognition or behavior during normal aging remains to be evaluated. PMID:23336521

Subject-Specific Sparse Dictionary Learning for Atlas-Based Brain MRI Segmentation.

PubMed

Roy, Snehashis; He, Qing; Sweeney, Elizabeth; Carass, Aaron; Reich, Daniel S; Prince, Jerry L; Pham, Dzung L

2015-09-01

Quantitative measurements from segmentations of human brain magnetic resonance (MR) images provide important biomarkers for normal aging and disease progression. In this paper, we propose a patch-based tissue classification method from MR images that uses a sparse dictionary learning approach and atlas priors. Training data for the method consists of an atlas MR image, prior information maps depicting where different tissues are expected to be located, and a hard segmentation. Unlike most atlas-based classification methods that require deformable registration of the atlas priors to the subject, only affine registration is required between the subject and training atlas. A subject-specific patch dictionary is created by learning relevant patches from the atlas. Then the subject patches are modeled as sparse combinations of learned atlas patches leading to tissue memberships at each voxel. The combination of prior information in an example-based framework enables us to distinguish tissues having similar intensities but different spatial locations. We demonstrate the efficacy of the approach on the application of whole-brain tissue segmentation in subjects with healthy anatomy and normal pressure hydrocephalus, as well as lesion segmentation in multiple sclerosis patients. For each application, quantitative comparisons are made against publicly available state-of-the art approaches.

[Human umbilical cord blood mononuclear cell transplantation promotes long-term neurobehavioral functional development of newborn SD rats with hypoxic ischemic brain injury].

PubMed

Huang, Hui-zhi; Wen, Xiao-hong; Liu, Hui; Huang, Jin-hua; Liu, Shang-quan; Ren, Wei-hua; Fang, Wen-xiang; Qian, Yin-feng; Hou, Wei-zhu; Yan, Ming-jie; Yao, You-heng; Li, Wei-Zu; Li, Qian-Jin

2013-06-01

To explore the effect of human umbilical cord blood mononuclear cells (UCBMC) promoting nerve behavior function and brain tissue recovery of neonatal SD rat with hypoxic ischemic brain injury (HIBI). A modified newborn rat model that had a combined hypoxic and ischemic brain injury as described by Rice-Vannucci was used, early nervous reflex, the Morris water maze and walking track analysis were used to evaluate nervous behavioral function, and brain MRI, HE staining to evaluate brain damage recovery. Newborn rat Rice-Vannucci model showed significant brain atrophy, obvious hemiplegia of contralateral limbs,e.g right step length [(7.67 ± 0.46) cm vs. (8.22 ± 0.50) cm, F = 1.494] and toe distance [(0.93 ± 0.06) cm vs. (1.12 ± 0.55) cm, F = 0.186] were significantly reduced compared with left side, learning and memory ability was significantly impaired compared with normal control group (P < 0.01); Cliff aversion [(8.44 ± 2.38) s vs.(14.22 ± 5.07) s, t = 4.618] and negative geotaxis reflex time [(7.26 ± 2.00) s vs. (11.76 ± 3.73) s, t = 4.755] on postnatal 14 days of HIBI+ transplantation group were significantly reduced compared with HIBI+NaCl group (P < 0.01) ; the Morris water maze experiment showed escape latency [ (23.11 ± 6.64) s vs. (34.04 ± 12.95) s, t = 3.356] and swimming distance [ (9.12 ± 1.21) cm vs.(12.70 ± 1.53) cm, t = 17.095] of HIBI+transplantation group were significantly reduced compared with those of HIBI+NaCl group (P < 0.01) ; the residual brain volume on postnatal 10 d [ (75.37 ± 4.53)% vs. (67.17 ± 4.08)%, t = -6.017] and 67 d [ (69.05 ± 3.58)% vs.(60.83 ± 3.69)%, t = -7.148]of HIBI+ transplantation group were significantly larger than those of HIBI+NaCl group (P < 0.01); After human UCBMC transplantation, left cortical edema significantly reduced and nerve cell necrosis of HIBI+ transplantation group is not obvious compared with HIBI+NaCl group. Human UCBMC intraperitoneal transplantation significantly promoted recovery of injured brain cells and neurobehavioral function development.

Metabolic brain networks in aging and preclinical Alzheimer's disease.

PubMed

Arnemann, Katelyn L; Stöber, Franziska; Narayan, Sharada; Rabinovici, Gil D; Jagust, William J

2018-01-01

Metabolic brain networks can provide insight into the network processes underlying progression from healthy aging to Alzheimer's disease. We explore the effect of two Alzheimer's disease risk factors, amyloid-β and ApoE ε4 genotype, on metabolic brain networks in cognitively normal older adults (N = 64, ages 69-89) compared to young adults (N = 17, ages 20-30) and patients with Alzheimer's disease (N = 22, ages 69-89). Subjects underwent MRI and PET imaging of metabolism (FDG) and amyloid-β (PIB). Normal older adults were divided into four subgroups based on amyloid-β and ApoE genotype. Metabolic brain networks were constructed cross-sectionally by computing pairwise correlations of metabolism across subjects within each group for 80 regions of interest. We found widespread elevated metabolic correlations and desegregation of metabolic brain networks in normal aging compared to youth and Alzheimer's disease, suggesting that normal aging leads to widespread loss of independent metabolic function across the brain. Amyloid-β and the combination of ApoE ε4 led to less extensive elevated metabolic correlations compared to other normal older adults, as well as a metabolic brain network more similar to youth and Alzheimer's disease. This could reflect early progression towards Alzheimer's disease in these individuals. Altered metabolic brain networks of older adults and those at the highest risk for progression to Alzheimer's disease open up novel lines of inquiry into the metabolic and network processes that underlie normal aging and Alzheimer's disease.

Age-related changes in brain structural covariance networks.

PubMed

Li, Xinwei; Pu, Fang; Fan, Yubo; Niu, Haijun; Li, Shuyu; Li, Deyu

2013-01-01

Previous neuroimaging studies have suggested that cerebral changes over normal aging are not simply characterized by regional alterations, but rather by the reorganization of cortical connectivity patterns. The investigation of structural covariance networks (SCNs) using voxel-based morphometry is an advanced approach to examining the pattern of covariance in gray matter (GM) volumes among different regions of the human cortex. To date, how the organization of critical SCNs change during normal aging remains largely unknown. In this study, we used an SCN mapping approach to investigate eight large-scale networks in 240 healthy participants aged 18-89 years. These participants were subdivided into young (18-23 years), middle aged (30-58 years), and older (61-89 years) subjects. Eight seed regions were chosen from widely reported functional intrinsic connectivity networks. The voxels showing significant positive associations with these seed regions were used to describe the topological organization of an SCN. All of these networks exhibited non-linear patterns in their spatial extent that were associated with normal aging. These networks, except the primary motor network, had a distributed topology in young participants, a sharply localized topology in middle aged participants, and were relatively stable in older participants. The structural covariance derived using the primary motor cortex was limited to the ipsilateral motor regions in the young and older participants, but included contralateral homologous regions in the middle aged participants. In addition, there were significant between-group differences in the structural networks associated with language-related speech and semantics processing, executive control, and the default-mode network (DMN). Taken together, the results of this study demonstrate age-related changes in the topological organization of SCNs, and provide insights into normal aging of the human brain.