Search

Your search keyword '"National Institute of Health, Bethesda"' showing total 49 results
Start Over Author "National Institute of Health, Bethesda" Topic brain
49 results on '"National Institute of Health, Bethesda"'

1. Layer-fMRI VASO with short stimuli and event-related designs at 7 T.

Author

Dresbach S, Huber LR, Gulban OF, and Goebel R

Subjects
Humans, Brain Mapping methods, Blood Volume physiology, Cerebrovascular Circulation physiology, Magnetic Resonance Imaging methods, Brain physiology
Abstract

Layers and columns are the dominant processing units in the human (neo)cortex at the mesoscopic scale. While the blood oxygenation dependent (BOLD) signal has a high detection sensitivity, it is biased towards unwanted signals from large draining veins at the cortical surface. The additional fMRI contrast of vascular space occupancy (VASO) has the potential to augment the neuroscientific interpretability of layer-fMRI results by means of capturing complementary information of locally specific changes in cerebral blood volume (CBV). Specifically, VASO is not subject to unwanted sensitivity amplifications of large draining veins. Because of constrained sampling efficiency, it has been mainly applied in combination with efficient block task designs and long trial durations. However, to study cognitive processes in neuroscientific contexts, or probe vascular reactivity, short stimulation periods are often necessary. Here, we developed a VASO acquisition procedure with a short acquisition period and sub-millimeter resolution. During visual event-related stimulation, we show reliable responses in visual cortices within a reasonable number of trials (∼20). Furthermore, the short TR and high spatial specificity of our VASO implementation enabled us to show differences in laminar reactivity and onset times. Finally, we explore the generalizability to a different stimulus modality (somatosensation). With this, we showed that CBV-sensitive VASO provides the means to capture layer-specific haemodynamic responses with high spatio-temporal resolution and is able to be used with event-related paradigms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Published
2023
Full Text
View/download PDF

2. An integrated cluster-wise significance measure for fMRI analysis.

Author

Ge Y, Chen G, Waltz JA, Hong LE, Kochunov P, and Chen S

Subjects
Brain Mapping methods, Cluster Analysis, Humans, Brain diagnostic imaging, Brain physiology, Magnetic Resonance Imaging methods
Abstract

Cluster-wise inference is widely used in fMRI analysis. The cluster-level statistic is often obtained by counting the number of intra-cluster voxels which surpass a voxel-level statistical significance threshold. This measure can be sub-optimal regarding the power and false-positive error rate because the suprathreshold voxel count neglects the voxel-wise significance levels and ignores the dependence between voxels. This article aims to provide a new Integrated Cluster-wise significance Measure (ICM) for cluster-level significance determination in cluster-wise fMRI analysis by integrating cluster extent, voxel-level significance (e.g., p values), and activation dependence between within-cluster voxels. We develop a computationally efficient strategy for ICM based on probabilistic approximation theories. Consequently, the computational load for ICM-based cluster-wise inference (e.g., permutation tests) is affordable. We validate the proposed method via extensive simulations and then apply it to two fMRI data sets. The results demonstrate that ICM can improve the power with well-controlled family-wise error (FWE)., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Published
2022
Full Text
View/download PDF

3. On the generalizability of diffusion MRI signal representations across acquisition parameters, sequences and tissue types: Chronicles of the MEMENTO challenge.

Author

De Luca A, Ianus A, Leemans A, Palombo M, Shemesh N, Zhang H, Alexander DC, Nilsson M, Froeling M, Biessels GJ, Zucchelli M, Frigo M, Albay E, Sedlar S, Alimi A, Deslauriers-Gauthier S, Deriche R, Fick R, Afzali M, Pieciak T, Bogusz F, Aja-Fernández S, Özarslan E, Jones DK, Chen H, Jin M, Zhang Z, Wang F, Nath V, Parvathaneni P, Morez J, Sijbers J, Jeurissen B, Fadnavis S, Endres S, Rokem A, Garyfallidis E, Sanchez I, Prchkovska V, Rodrigues P, Landman BA, and Schilling KG

Subjects
Animals, Brain physiology, Humans, Mice, Brain diagnostic imaging, Databases, Factual, Diffusion Magnetic Resonance Imaging methods, Image Processing, Computer-Assisted methods, Neural Networks, Computer
Abstract

Diffusion MRI (dMRI) has become an invaluable tool to assess the microstructural organization of brain tissue. Depending on the specific acquisition settings, the dMRI signal encodes specific properties of the underlying diffusion process. In the last two decades, several signal representations have been proposed to fit the dMRI signal and decode such properties. Most methods, however, are tested and developed on a limited amount of data, and their applicability to other acquisition schemes remains unknown. With this work, we aimed to shed light on the generalizability of existing dMRI signal representations to different diffusion encoding parameters and brain tissue types. To this end, we organized a community challenge - named MEMENTO, making available the same datasets for fair comparisons across algorithms and techniques. We considered two state-of-the-art diffusion datasets, including single-diffusion-encoding (SDE) spin-echo data from a human brain with over 3820 unique diffusion weightings (the MASSIVE dataset), and double (oscillating) diffusion encoding data (DDE/DODE) of a mouse brain including over 2520 unique data points. A subset of the data sampled in 5 different voxels was openly distributed, and the challenge participants were asked to predict the remaining part of the data. After one year, eight participant teams submitted a total of 80 signal fits. For each submission, we evaluated the mean squared error, the variance of the prediction error and the Bayesian information criteria. The received submissions predicted either multi-shell SDE data (37%) or DODE data (22%), followed by cartesian SDE data (19%) and DDE (18%). Most submissions predicted the signals measured with SDE remarkably well, with the exception of low and very strong diffusion weightings. The prediction of DDE and DODE data seemed more challenging, likely because none of the submissions explicitly accounted for diffusion time and frequency. Next to the choice of the model, decisions on fit procedure and hyperparameters play a major role in the prediction performance, highlighting the importance of optimizing and reporting such choices. This work is a community effort to highlight strength and limitations of the field at representing dMRI acquired with trending encoding schemes, gaining insights into how different models generalize to different tissue types and fiber configurations over a large range of diffusion encodings., (Copyright © 2021. Published by Elsevier Inc.)

Published
2021
Full Text
View/download PDF

4. Training in the practice of noninvasive brain stimulation: Recommendations from an IFCN committee.

Author

Fried PJ, Santarnecchi E, Antal A, Bartres-Faz D, Bestmann S, Carpenter LL, Celnik P, Edwards D, Farzan F, Fecteau S, George MS, He B, Kim YH, Leocani L, Lisanby SH, Loo C, Luber B, Nitsche MA, Paulus W, Rossi S, Rossini PM, Rothwell J, Sack AT, Thut G, Ugawa Y, Ziemann U, Hallett M, and Pascual-Leone A

Subjects
Humans, Stereotaxic Techniques education, Stereotaxic Techniques standards, Transcranial Direct Current Stimulation standards, Transcranial Magnetic Stimulation standards, Brain physiology, Clinical Competence standards, Practice Guidelines as Topic standards, Transcranial Direct Current Stimulation methods, Transcranial Magnetic Stimulation methods
Abstract

As the field of noninvasive brain stimulation (NIBS) expands, there is a growing need for comprehensive guidelines on training practitioners in the safe and effective administration of NIBS techniques in their various research and clinical applications. This article provides recommendations on the structure and content of this training. Three different types of practitioners are considered (Technicians, Clinicians, and Scientists), to attempt to cover the range of education and responsibilities of practitioners in NIBS from the laboratory to the clinic. Basic or core competencies and more advanced knowledge and skills are discussed, and recommendations offered regarding didactic and practical curricular components. We encourage individual licensing and governing bodies to implement these guidelines., Competing Interests: Declaration of Competing Interest The content of this manuscript is solely theresponsibility of the authors and does not necessarily represent the official views of any of the institutions involved or any of the funding agencies and bodies. Peter J. Fried has nothing to disclose with regard to this manuscript. Emiliano Santarnecchi serves on the scientific advisory boards for Neuroelectrics, EBNeuro and Neurocare. He is listed as an inventor on several issued and pending patents on the application of noninvasive brain stimulation in patients with dementia and brain tumors. Andrea Antal serves as a paid consultant for NeuroConn, Ilmenau, Germany and Savir GmbH, Magdeburg, Germany. She is supported by the State of Lower Saxony, Germany (76251-12-7/19 (ZN 3456)). David Bartres-Faz has nothing to disclose with regard to this manuscript. Sven Bestmann has nothing to disclose with regard to this manuscript. Linda L. Carpenter is supportedby the National Institute of General Medical Sciencesof the National Institutes of Health under Award Number P20GM130452 (Core Resources of the Butler Hospital COBRE Center for Neuromodulation). She has received consulting income from Neuronetics, Nexstim, Janssen, AffectNeuro, and Sage Therapeutics. She has research support from Neuronetics, Neosync, AffectNeuro, and Nexstim. Pablo Celnik has nothing to disclose with regard to this manuscript. Dylan Edwards has nothing to disclose with regard to this manuscript. Faranak Farzan has nothing to disclose with regard to this manuscript. Shirley Fecteau is a deputy editor of Brain Stimulation and an editor of Scientific Reports.She is regular faculty of yearly intensive mini-fellowships on TMS and tCS offered through Harvard Continuing Medical Education. Mark S. George is an unpaid consultant to Brainsway, Neuronetics, and Magstim. He has received loaned equipment or research grants from Mecta, Brainsway, Magstim, Magventure. He is a paid consultant to Neuralief. He does not own equity in any device company. He is the editor in chief of Brain Stimulation, with a stipend from Elsevier. Bin He has nothing to disclose with regard to this manuscript. Yun-Hee Kim has nothing to disclose with regard to this manuscript. Letizia Leocani is currently shortlisted for the European Commission expert panel on Medical Devices and in vitro diagnostic medical devices for Neurology. Sarah H. Lisanby is inventor on a patent for TMS technology, unrelated to the topic presented here, with no royalties.The opinions expressed in this article are the authors’ own and do not reflect the views of the National Institutes of Health, the Department of Health and Human Services, or the United States government. Colleen Loo has received competitive grant funding from the Australian National Health and Medical Research Council for brain stimulation research. Bruce Luber has nothing to disclose with regard to this manuscript. Michael A. Nitsche serves on the scientific advisory boards for Neuroelectrics and NeuroDevice. Walter Paulus serves as a member of the scientific advisory board of Precisis AG. Simone Rossi serves as a consultant for EB-Neuro and Neurocare Italy group. Paolo M. Rossini has nothing to disclose with regard to this manuscript. John Rothwell has nothing to disclose with regard to this manuscript. Alexander T. Sack serves as head of the scientific advisory board for AlphaSys Brain Technologies BV. He is founder of Neurowear Medical BV, and Director of the European Clinical TMS Certification Course (www.tmscourse.eu). Gregor Thut serves as a Section Editor for European Journal of Neuroscience and Brain Topography and as an Associate Editor for several Frontiers journals (Brain Imaging and Stimulation, Consciousness Research, Perception Science). Yoshikazu Ugawa has nothing to disclose with regard to this manuscript. Ulf Ziemann has received grants from European Research Council (ERC), German Research Foundation (DFG), German Federal Ministry of Education and Research (BMBF), Ministry of Research and Arts of the Federal State of Baden-Würrtemberg (MWK), Bristol Myers Squibb, Janssen Pharmaceutica NV, Servier, Biogen Idec GmbH, and personal fees from Bayer Vital GmbH, Pfizer GmbH, CorTec GmbH, all not related to this work. Mark Hallett was supported by the NINDS Intramural Program. He is an inventor of patents held by NIH for an immunotoxin for the treatment of focal movement disorders and the H-coil for magnetic stimulation; in relation to the latter, he has received license fee payments from the NIH (from Brainsway). He is on the Medical Advisory Boards of CALA Health and Brainsway. He has research grants from Allergan for studies of methods to inject botulinum toxins, Medtronic, Inc. for a study of DBS for dystonia, and CALA Health for studies of a device to suppress tremor. Alvaro Pascual-Leone serves on the scientific advisory boards for Starlab Neuroscience, Neuroelectrics, Magstim, Magventure, MedRhythms, and Cognito. He listed as an inventor on several issued and pending patents on the real-time integration of transcranial magnetic stimulation with electroencephalography and magnetic resonance imaging, and novel methods for transcranial electric stimulation. He is co-founder of Linus Health and TI Solutions A.G. He serves as associate editor for Annals of Neurology. He is co-director of yearly intensive mini-fellowships on TMS and tCS offered through Harvard Continuing Medical Education., (Copyright © 2020. Published by Elsevier B.V.)

Published
2021
Full Text
View/download PDF

5. Neural endophenotypes and predictors of laryngeal dystonia penetrance and manifestation.

Author

Khosravani S, Chen G, Ozelius LJ, and Simonyan K

Subjects
Adult, Aged, Brain physiopathology, Case-Control Studies, Caudate Nucleus diagnostic imaging, Caudate Nucleus physiopathology, Cerebellum diagnostic imaging, Cerebellum physiopathology, Dystonic Disorders genetics, Dystonic Disorders physiopathology, Family, Female, Functional Neuroimaging, Humans, Laryngeal Diseases genetics, Magnetic Resonance Imaging, Male, Middle Aged, Motor Cortex diagnostic imaging, Motor Cortex physiopathology, Parietal Lobe diagnostic imaging, Parietal Lobe physiopathology, Prefrontal Cortex diagnostic imaging, Prefrontal Cortex physiopathology, Risk Assessment, Supervised Machine Learning, Temporal Lobe diagnostic imaging, Temporal Lobe physiopathology, Thalamus diagnostic imaging, Thalamus physiopathology, Brain diagnostic imaging, Dystonic Disorders diagnostic imaging, Endophenotypes, Laryngeal Diseases diagnostic imaging, Penetrance
Abstract

Focal dystonias are the most common forms of isolated dystonia; however, the etiopathophysiological signatures of disorder penetrance and clinical manifestation remain unclear. Using an imaging genetics approach, we investigated functional and structural representations of neural endophenotypes underlying the penetrance and manifestation of laryngeal dystonia in families, including 21 probands and 21 unaffected relatives, compared to 32 unrelated healthy controls. We further used a supervised machine-learning algorithm to predict the risk for dystonia development in susceptible individuals based on neural features of identified endophenotypes. We found that abnormalities in prefrontal-parietal cortex, thalamus, and caudate nucleus were commonly shared between patients and their unaffected relatives, representing an intermediate endophenotype of laryngeal dystonia. Machine learning classified 95.2% of unaffected relatives as patients rather than healthy controls, substantiating that these neural alterations represent the endophenotypic marker of dystonia penetrance, independent of its symptomatology. Additional abnormalities in premotor-parietal-temporal cortical regions, caudate nucleus, and cerebellum were present only in patients but not their unaffected relatives, likely representing a secondary endophenotype of dystonia manifestation. Based on alterations in the parietal cortex and caudate nucleus, the machine learning categorized 28.6% of unaffected relative as patients, indicating their increased lifetime risk for developing clinical manifestation of dystonia. The identified endophenotypic neural markers may be implemented for screening of at-risk individuals for dystonia development, selection of families for genetic studies of novel variants based on their risk for disease penetrance, or stratification of patients who would respond differently to a particular treatment in clinical trials., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Published
2021
Full Text
View/download PDF

6. Seeding Brain Protein Aggregation by SARS-CoV-2 as a Possible Long-Term Complication of COVID-19 Infection.

Author

Tavassoly O, Safavi F, and Tavassoly I

Subjects
Brain pathology, Brain virology, COVID-19, Coronavirus Infections pathology, Humans, Pandemics, Pneumonia, Viral pathology, SARS-CoV-2, Time Factors, Betacoronavirus metabolism, Brain metabolism, Coronavirus Infections complications, Coronavirus Infections metabolism, Pneumonia, Viral complications, Pneumonia, Viral metabolism, Protein Aggregates physiology
Abstract

Postinfection complications of coronavirus disease 2019 (COVID-19) are still unknown, and one of the long-term concerns in infected people are brain pathologies. The question is that severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection may be an environmental factor in accelerating the sporadic neurodegeneration in the infected population. In this regard, induction of protein aggregation in the brain by SARS-CoV-2 intact structure or a peptide derived from spike protein subunits needs to be considered in futures studies. In this paper, we discuss these possibilities using pieces of evidence from other viruses.

Published
2020
Full Text
View/download PDF

7. Evaluation of chronic toxicity of cyclocreatine, a creatine analog, in Sprague Dawley rat after oral gavage administration for up to 26 weeks.

Author

Kale VP, Wallery J, Novak J, Gibbs S, Bourdi M, Do MT, McKew JC, and Terse PS

Subjects
Administration, Oral, Animals, Brain metabolism, Brain pathology, Creatine analogs & derivatives, Creatine blood, Creatine toxicity, Creatinine administration & dosage, Creatinine blood, Creatinine toxicity, Female, Male, Organ Size drug effects, Organ Size physiology, Rats, Rats, Sprague-Dawley, Testis drug effects, Testis metabolism, Testis pathology, Thyroid Gland drug effects, Thyroid Gland metabolism, Thyroid Gland pathology, Time Factors, Brain drug effects, Creatinine analogs & derivatives, Toxicity Tests, Chronic methods
Abstract

Cyclocreatine (LUM-001), a creatine analog, was evaluated for its nonclinical toxicity in Sprague Dawley (SD) rats. Deionized water as a vehicle control article or cyclocreatine was administered by oral gavage twice daily (approximately 12 ± 1 h apart) at 30, 100 and 300 mg/kg/dose levels in rats up to 26 weeks followed by a 28-day recovery period. Due to an increased incidence of seizures, the 600 mg/kg/day dose group males were dosed only for 16-weeks followed by a 14-week recovery period. Thirteen males and four females from 600 mg/kg/day dose group were sacrificed at interim on Day 113 to study plausible brain lesions and not due to moribundity. There was a dose dependent increase in the number of seizure incidences in ≥60 mg/kg/day males and 600 mg/kg/day females. Microscopically, higher incidences of vacuoles in the brain at 600 mg/kg/day in both sexes, thyroid follicular atrophy and follicular cell hypertrophy at ≥200 mg/kg/day in males and 600 mg/kg/day in females, and seminiferous tubular degeneration and/or interstitial edema in testes at ≥200 mg/kg/day were observed. Mean plasma half-life of cyclocreatine was between 3.5 and 6.5 h. In conclusion, chronic administration of cyclocreatine by oral gavage in Sprague Dawley rats induced the seizures and microscopic lesions in the brain, testes and thyroid. Based on the results of this study the highest tested dose of 600 mg/kg/day (mean C max of 151.5 μg/mL; AUC 0-24 of 1970 h*μg/mL) was considered the maximum tolerated dose (MTD) in SD rats., (Copyright © 2020. Published by Elsevier Inc.)

Published
2020
Full Text
View/download PDF

8. The Role of Mitochondria in Neurodegenerative Diseases: the Lesson from Alzheimer's Disease and Parkinson's Disease.

Author

Monzio Compagnoni G, Di Fonzo A, Corti S, Comi GP, Bresolin N, and Masliah E

Subjects
Alzheimer Disease pathology, Animals, Brain pathology, DNA, Mitochondrial, Electron Transport Complex I metabolism, Humans, Mitochondria pathology, Parkinson Disease pathology, Alzheimer Disease metabolism, Brain metabolism, Mitochondria metabolism, Parkinson Disease metabolism
Abstract

Although the pathogenesis of neurodegenerative diseases is still widely unclear, various mechanisms have been proposed and several pieces of evidence are supportive for an important role of mitochondrial dysfunction. The present review provides a comprehensive and up-to-date overview about the role of mitochondria in the two most common neurodegenerative disorders: Alzheimer's disease (AD) and Parkinson's disease (PD). Mitochondrial involvement in AD is supported by clinical features like reduced glucose and oxygen brain metabolism and by numerous microscopic and molecular findings, including altered mitochondrial morphology, impaired respiratory chain function, and altered mitochondrial DNA. Furthermore, amyloid pathology and mitochondrial dysfunction seem to be bi-directionally correlated. Mitochondria have an even more remarkable role in PD. Several hints show that respiratory chain activity, in particular complex I, is impaired in the disease. Mitochondrial DNA alterations, involving deletions, point mutations, depletion, and altered maintenance, have been described. Mutations in genes directly implicated in mitochondrial functioning (like Parkin and PINK1) are responsible for rare genetic forms of the disease. A close connection between alpha-synuclein accumulation and mitochondrial dysfunction has been observed. Finally, mitochondria are involved also in atypical parkinsonisms, in particular multiple system atrophy. The available knowledge is still not sufficient to clearly state whether mitochondrial dysfunction plays a primary role in the very initial stages of these diseases or is secondary to other phenomena. However, the presented data strongly support the hypothesis that whatever the initial cause of neurodegeneration is, mitochondrial impairment has a critical role in maintaining and fostering the neurodegenerative process.

Published
2020
Full Text
View/download PDF

9. Comparative meta-analyses of brain structural and functional abnormalities during cognitive control in attention-deficit/hyperactivity disorder and autism spectrum disorder.

Author

Lukito S, Norman L, Carlisi C, Radua J, Hart H, Simonoff E, and Rubia K

Subjects
Adolescent, Adult, Cerebral Cortex physiopathology, Child, Cognition physiology, Female, Gray Matter physiopathology, Humans, Magnetic Resonance Imaging, Male, Parietal Lobe physiopathology, Thalamus physiopathology, Young Adult, Attention Deficit Disorder with Hyperactivity physiopathology, Autism Spectrum Disorder physiopathology, Brain physiopathology
Abstract

Background: People with attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) have abnormalities in frontal, temporal, parietal and striato-thalamic networks. It is unclear to what extent these abnormalities are distinctive or shared. This comparative meta-analysis aimed to identify the most consistent disorder-differentiating and shared structural and functional abnormalities., Methods: Systematic literature search was conducted for whole-brain voxel-based morphometry (VBM) and functional magnetic resonance imaging (fMRI) studies of cognitive control comparing people with ASD or ADHD with typically developing controls. Regional gray matter volume (GMV) and fMRI abnormalities during cognitive control were compared in the overall sample and in age-, sex- and IQ-matched subgroups with seed-based d mapping meta-analytic methods., Results: Eighty-six independent VBM (1533 ADHD and 1295 controls; 1445 ASD and 1477 controls) and 60 fMRI datasets (1001 ADHD and 1004 controls; 335 ASD and 353 controls) were identified. The VBM meta-analyses revealed ADHD-differentiating decreased ventromedial orbitofrontal (z = 2.22, p < 0.0001) but ASD-differentiating increased bilateral temporal and right dorsolateral prefrontal GMV (zs ⩾ 1.64, ps ⩽ 0.002). The fMRI meta-analyses of cognitive control revealed ASD-differentiating medial prefrontal underactivation but overactivation in bilateral ventrolateral prefrontal cortices and precuneus (zs ⩾ 1.04, ps ⩽ 0.003). During motor response inhibition specifically, ADHD relative to ASD showed right inferior fronto-striatal underactivation (zs ⩾ 1.14, ps ⩽ 0.003) but shared right anterior insula underactivation., Conclusions: People with ADHD and ASD have mostly distinct structural abnormalities, with enlarged fronto-temporal GMV in ASD and reduced orbitofrontal GMV in ADHD; and mostly distinct functional abnormalities, which were more pronounced in ASD.

Published
2020
Full Text
View/download PDF

10. Human Herpesvirus 6 Detection in Alzheimer's Disease Cases and Controls across Multiple Cohorts.

Author

Allnutt MA, Johnson K, Bennett DA, Connor SM, Troncoso JC, Pletnikova O, Albert MS, Resnick SM, Scholz SW, De Jager PL, and Jacobson S

Subjects
Case-Control Studies, Cohort Studies, Female, Herpesvirus 6, Human genetics, Humans, Male, Sequence Analysis, DNA statistics & numerical data, Sequence Analysis, RNA statistics & numerical data, Alzheimer Disease virology, Brain virology, Herpesvirus 6, Human isolation & purification
Abstract

The interplay between viral infection and Alzheimer's disease (AD) has long been an area of interest, but proving causality has been elusive. Several recent studies have renewed the debate concerning the role of herpesviruses, and human herpesvirus 6 (HHV-6) in particular, in AD. We screened for HHV-6 detection across three independent AD brain repositories using (1) RNA sequencing (RNA-seq) datasets and (2) DNA samples extracted from AD and non-AD control brains. The RNA-seq data were screened for pathogens against taxon references from over 25,000 microbes, including 118 human viruses, whereas DNA samples were probed for PCR reactivity to HHV-6A and HHV-6B. HHV-6 demonstrated little specificity to AD brains over controls by either method, whereas other viruses, such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV), were detected at comparable levels. These direct methods of viral detection do not suggest an association between HHV-6 and AD., Competing Interests: Declaration of Interests The authors declare no competing interests., (Published by Elsevier Inc.)

Published
2020
Full Text
View/download PDF

11. A deconvolution algorithm for multi-echo functional MRI: Multi-echo Sparse Paradigm Free Mapping.

Author

Caballero-Gaudes C, Moia S, Panwar P, Bandettini PA, and Gonzalez-Castillo J

Subjects
Adult, Algorithms, Female, Humans, Male, ROC Curve, Young Adult, Brain physiology, Brain Mapping methods, Image Processing, Computer-Assisted methods, Magnetic Resonance Imaging, Signal Processing, Computer-Assisted
Abstract

This work introduces a novel algorithm for deconvolution of the BOLD signal in multi-echo fMRI data: Multi-echo Sparse Paradigm Free Mapping (ME-SPFM). Assuming a linear dependence of the BOLD percent signal change on the echo time (TE) and using sparsity-promoting regularized least squares estimation, ME-SPFM yields voxelwise time-varying estimates of the changes in the apparent transverse relaxation (ΔR 2 ) without prior knowledge of the timings of individual BOLD events. Our results in multi-echo fMRI data collected during a multi-task event-related paradigm at 3 Tesla demonstrate that the maps of R ⁎ changes obtained with ME-SPFM at the times of the stimulus trials show high spatial and temporal concordance with the activation maps and BOLD signals obtained with standard model-based analysis. This method yields estimates of ΔR 2 ⁎ associated with spontaneous, transient BOLD responses occurring between trials. This framework is a step towards deciphering the dynamic nature of brain activity in naturalistic paradigms, resting-state or experimental paradigms with unknown timing of the BOLD events.2 ⁎ having physiologically plausible values. Owing to its ability to blindly detect events, ME-SPFM also enables us to map ΔR 2 ⁎ associated with spontaneous, transient BOLD responses occurring between trials. This framework is a step towards deciphering the dynamic nature of brain activity in naturalistic paradigms, resting-state or experimental paradigms with unknown timing of the BOLD events., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Published
2019
Full Text
View/download PDF

12. Multisite reliability and repeatability of an advanced brain MRI protocol.

Author

Schwartz DL, Tagge I, Powers K, Ahn S, Bakshi R, Calabresi PA, Todd Constable R, Grinstead J, Henry RG, Nair G, Papinutto N, Pelletier D, Shinohara R, Oh J, Reich DS, Sicotte NL, and Rooney WD

Subjects
Brain pathology, Clinical Protocols, Diffusion Tensor Imaging methods, Humans, Male, Middle Aged, Multiple Sclerosis, Relapsing-Remitting pathology, Prospective Studies, Reproducibility of Results, Brain diagnostic imaging, Magnetic Resonance Imaging methods, Multiple Sclerosis, Relapsing-Remitting diagnosis
Abstract

Background: MRI is the imaging modality of choice for diagnosis and intervention assessment in neurological disease. Its full potential has not been realized due in part to challenges in harmonizing advanced techniques across multiple sites., Purpose: To develop a method for the assessment of reliability and repeatability of advanced multisite-multisession neuroimaging studies and specifically to assess the reliability of an advanced MRI protocol, including multiband fMRI and diffusion tensor MRI, in a multisite setting., Study Type: Prospective., Population: Twice repeated measurement of a single subject with stable relapsing-remitting multiple sclerosis (MS) at seven institutions., Field Strength/sequence: A 3 T MRI protocol included higher spatial resolution anatomical scans, a variable flip-angle longitudinal relaxation rate constant (R 1 ≡ 1/T 1 ) measurement, quantitative magnetization transfer imaging, diffusion tensor imaging, and a resting-state fMRI (rsFMRI) series., Assessment: Multiple methods of assessing intrasite repeatability and intersite reliability were evaluated for imaging metrics derived from each sequence., Statistical Tests: Student's t-test, Pearson's r, and intraclass correlation coefficient (ICC) (2,1) were employed to assess repeatability and reliability. Two new statistical metrics are introduced that frame reliability and repeatability in the respective units of the measurements themselves., Results: Intrasite repeatability was excellent for quantitative R 1 , magnetization transfer ratio (MTR), and diffusion-weighted imaging (DWI) based metrics (r > 0.95). rsFMRI metrics were less repeatable (r = 0.8). Intersite reliability was excellent for R 1 , MTR, and DWI (ICC >0.9), and moderate for rsFMRI metrics (ICC∼0.4)., Data Conclusion: From most reliable to least, using a new reliability metric introduced here, MTR > R 1 > DWI > rsFMRI; for repeatability, MTR > DWI > R 1 > rsFMRI. A graphical method for at-a-glance assessment of reliability and repeatability, effect sizes, and outlier identification in multisite-multisession neuroimaging studies is introduced., Level of Evidence: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:878-888., (© 2019 International Society for Magnetic Resonance in Medicine.)

Published
2019
Full Text
View/download PDF

13. Site-specific phosphorylation of Fbxw7 by Cdk5/p25 and its resulting decreased stability are linked to glutamate-induced excitotoxicity.

Author

Ko YU, Kim C, Lee J, Kim D, Kim Y, Yun N, and Oh YJ

Subjects
Animals, Brain growth & development, Brain pathology, Cell Death genetics, Cerebellar Cortex growth & development, Cerebellar Cortex metabolism, Cerebellar Cortex pathology, Gene Expression Regulation, Developmental genetics, Glutamic Acid metabolism, HEK293 Cells, Humans, Mice, Nerve Degeneration pathology, Nervous System growth & development, Nervous System metabolism, Neurons pathology, Phosphorylation genetics, Phosphotransferases genetics, Primary Cell Culture, Protein Stability, Brain metabolism, F-Box-WD Repeat-Containing Protein 7 genetics, Nerve Degeneration genetics, Neurons metabolism
Abstract

Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine protein kinase that regulates brain development and neurodegeneration. Cdk5 is activated by p25 that is generated from calpain-dependent cleavage of p35. The generation of p25 is responsible for the aberrant hyper-activation of Cdk5, which causes neurodegeneration. Using in vitro assays, we discovered that F-box/WD repeat-containing protein 7 (Fbxw7) is a new substrate of Cdk5. Additionally, Cdk5-dependent phosphorylation of Fbxw7 was detected in the presence of p25, and two amino acid residues (S349 and S372) were determined to be major phosphorylation sites. This phosphorylation was eventually linked to decreased stability of Fbxw7. Using a culture model of cortical neurons challenged with glutamate, we confirmed that decreased stability of Fbxw7 was indeed Cdk5-dependent. Furthermore, diminished levels of Fbxw7 led to increased levels of transcription factor AP-1 (c-Jun), a known substrate of Fbxw7. Given that previous reports demonstrate that c-Jun plays a role in accelerating neuronal apoptosis in these pathological models, our data support the concepts of a molecular cascade in which Cdk5-mediated phosphorylation of Fbxw7 negatively regulates Fbxw7 expression, thereby contributing to neuronal cell death following glutamate-mediated excitotoxicity.

Published
2019
Full Text
View/download PDF

14. DPTIP, a newly identified potent brain penetrant neutral sphingomyelinase 2 inhibitor, regulates astrocyte-peripheral immune communication following brain inflammation.

Author

Rojas C, Barnaeva E, Thomas AG, Hu X, Southall N, Marugan J, Chaudhuri AD, Yoo SW, Hin N, Stepanek O, Wu Y, Zimmermann SC, Gadiano AG, Tsukamoto T, Rais R, Haughey N, Ferrer M, and Slusher BS

Subjects
Animals, Astrocytes metabolism, Brain metabolism, Cell Line, Cytokines metabolism, Disease Models, Animal, Encephalitis metabolism, Extracellular Vesicles drug effects, Extracellular Vesicles metabolism, HEK293 Cells, Humans, Mice, Rats, Up-Regulation drug effects, Astrocytes drug effects, Brain drug effects, Encephalitis drug therapy, Enzyme Inhibitors pharmacology, Sphingomyelin Phosphodiesterase antagonists & inhibitors
Abstract

Brain injury and inflammation induces a local release of extracellular vesicles (EVs) from astrocytes carrying proteins, RNAs, and microRNAs into the circulation. When these vesicles reach the liver, they stimulate the secretion of cytokines that mobilize peripheral immune cell infiltration into the brain, which can cause secondary tissue damage and impair recovery. Recent studies suggest that suppression of EV biosynthesis through neutral sphingomyelinase 2 (nSMase2) inhibition may represent a new therapeutic strategy. Unfortunately, currently available nSMase2 inhibitors exhibit low potency (IC 50  ≥ 1 μM), poor solubility and/or limited brain penetration. Through a high throughput screening campaign of >365,000 compounds against human nSMase2 we identified 2,6-Dimethoxy-4-(5-Phenyl-4-Thiophen-2-yl-1H-Imidazol-2-yl)-Phenol (DPTIP), a potent (IC 50 30 nM), selective, metabolically stable, and brain penetrable (AUC brain /AUC plasma  = 0.26) nSMase2 inhibitor. DPTIP dose-dependently inhibited EV release in primary astrocyte cultures. In a mouse model of brain injury conducted in GFAP-GFP mice, DPTIP potently (10 mg/kg IP) inhibited IL-1β-induced astrocyte-derived EV release (51 ± 13%; p < 0.001). This inhibition led to a reduction of cytokine upregulation in liver and attenuation of the infiltration of immune cells into the brain (80 ± 23%; p < 0.01). A structurally similar but inactive analog had no effect in vitro or in vivo.

Published
2018
Full Text
View/download PDF

15. Decreased Brain pH as a Shared Endophenotype of Psychiatric Disorders.

Author

Hagihara H, Catts VS, Katayama Y, Shoji H, Takagi T, Huang FL, Nakao A, Mori Y, Huang KP, Ishii S, Graef IA, Nakayama KI, Shannon Weickert C, and Miyakawa T

Subjects
Animals, Brain Chemistry, Disease Models, Animal, Endophenotypes, Female, Humans, Hydrogen-Ion Concentration, Lactic Acid metabolism, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Brain metabolism, Mental Disorders metabolism
Abstract

Although the brains of patients with schizophrenia and bipolar disorder exhibit decreased brain pH relative to those of healthy controls upon postmortem examination, it remains controversial whether this finding reflects a primary feature of the diseases or is a result of confounding factors such as medication and agonal state. To date, systematic investigation of brain pH has not been undertaken using animal models that can be studied without confounds inherent in human studies. In the present study, we first reevaluated the pH of the postmortem brains of patients with schizophrenia and bipolar disorder by conducting a meta-analysis of existing data sets from 10 studies. We then measured pH, lactate levels, and related metabolite levels in brain homogenates from five neurodevelopmental mouse models of psychiatric disorders, including schizophrenia, bipolar disorder, and autism spectrum disorder. All mice were drug naive with the same agonal state, postmortem interval, and age within each strain. Our meta-analysis revealed that brain pH was significantly lower in patients with schizophrenia and bipolar disorder than in control participants, even when a few potential confounding factors (postmortem interval, age, and history of antipsychotic use) were considered. In animal experiments, we observed significantly lower pH and higher lactate levels in the brains of model mice relative to controls, as well as a significant negative correlation between pH and lactate levels. Our findings suggest that lower pH associated with increased lactate levels is not a mere artifact, but rather implicated in the underlying pathophysiology of schizophrenia and bipolar disorder.

Published
2018
Full Text
View/download PDF

16. Whole blood gene expression and white matter Hyperintensities.

Author

Lin H, Satizabal C, Xie Z, Yang Q, Huan T, Joehanes R, Wen C, Munson PJ, Beiser A, Levy D, and Seshadri S

Subjects
Adult, Aged, Female, Humans, Male, Middle Aged, Prospective Studies, Brain pathology, Transcriptome, White Matter pathology
Abstract

Background: White matter hyperintensities (WMH) are an important biomarker of cumulative vascular brain injury and have been associated with cognitive decline and an increased risk of dementia, stroke, depression, and gait impairments. The pathogenesis of white matter lesions however, remains uncertain. The characterization of gene expression profiles associated with WMH might help uncover molecular mechanisms underlying WMH., Methods: We performed a transcriptome-wide association study of gene expression profiles with WMH in 3248 participants from the Framingham Heart Study using the Affymetrix Human Exon 1.0 ST Array., Results: We identified 13 genes that were significantly associated with WMH (FDR < 0.05) after adjusting for age, sex and blood cell components. Many of these genes are involved in inflammation-related pathways., Conclusion: Thirteen genes were significantly associated with WMH. Our study confirms the hypothesis that inflammation might be an important factor contributing to white matter lesions. Future work is needed to explore if these gene products might serve as potential therapeutic targets.

Published
2017
Full Text
View/download PDF

17. Consequences of early adverse rearing experience(EARE) on development: insights from non-human primate studies.

Author

Zhang B

Subjects
Animals, Primates physiology, Stress, Psychological, Brain growth & development, Primates growth & development, Primates psychology, Social Behavior
Abstract

Early rearing experiences are important in one's whole life, whereas early adverse rearing experience(EARE) is usually related to various physical and mental disorders in later life. Although there were many studies on human and animals, regarding the effect of EARE on brain development, neuroendocrine systems, as well as the consequential mental disorders and behavioral abnormalities, the underlying mechanisms remain unclear. Due to the close genetic relationship and similarity in social organizations with humans, non-human primate(NHP) studies were performed for over 60 years. Various EARE models were developed to disrupt the early normal interactions between infants and mothers or peers. Those studies provided important insights of EARE induced effects on the physiological and behavioral systems of NHPs across life span, such as social behaviors(including disturbance behavior, social deficiency, sexual behavior, etc), learning and memory ability, brain structural and functional developments(including influences on neurons and glia cells, neuroendocrine systems, e.g., hypothalamic-pituitary-adrenal(HPA) axis, etc). In this review, the effects of EARE and the underlying epigenetic mechanisms were comprehensively summarized and the possibility of rehabilitation was discussed.

Published
2017
Full Text
View/download PDF

18. PREVAIL: Predicting Recovery through Estimation and Visualization of Active and Incident Lesions.

Author

Dworkin JD, Sweeney EM, Schindler MK, Chahin S, Reich DS, and Shinohara RT

Subjects
Adolescent, Adult, Brain diagnostic imaging, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, White Matter diagnostic imaging, Young Adult, Brain pathology, Disease Progression, Multiple Sclerosis diagnostic imaging, Multiple Sclerosis pathology, White Matter pathology
Abstract

Objective: The goal of this study was to develop a model that integrates imaging and clinical information observed at lesion incidence for predicting the recovery of white matter lesions in multiple sclerosis (MS) patients., Methods: Demographic, clinical, and magnetic resonance imaging (MRI) data were obtained from 60 subjects with MS as part of a natural history study at the National Institute of Neurological Disorders and Stroke. A total of 401 lesions met the inclusion criteria and were used in the study. Imaging features were extracted from the intensity-normalized T1-weighted (T1w) and T2-weighted sequences as well as magnetization transfer ratio (MTR) sequence acquired at lesion incidence. T1w and MTR signatures were also extracted from images acquired one-year post-incidence. Imaging features were integrated with clinical and demographic data observed at lesion incidence to create statistical prediction models for long-term damage within the lesion., Validation: The performance of the T1w and MTR predictions was assessed in two ways: first, the predictive accuracy was measured quantitatively using leave-one-lesion-out cross-validated (CV) mean-squared predictive error. Then, to assess the prediction performance from the perspective of expert clinicians, three board-certified MS clinicians were asked to individually score how similar the CV model-predicted one-year appearance was to the true one-year appearance for a random sample of 100 lesions., Results: The cross-validated root-mean-square predictive error was 0.95 for normalized T1w and 0.064 for MTR, compared to the estimated measurement errors of 0.48 and 0.078 respectively. The three expert raters agreed that T1w and MTR predictions closely resembled the true one-year follow-up appearance of the lesions in both degree and pattern of recovery within lesions., Conclusion: This study demonstrates that by using only information from a single visit at incidence, we can predict how a new lesion will recover using relatively simple statistical techniques. The potential to visualize the likely course of recovery has implications for clinical decision-making, as well as trial enrichment.

Published
2016
Full Text
View/download PDF

19. Relating multi-sequence longitudinal intensity profiles and clinical covariates in incident multiple sclerosis lesions.

Author

Sweeney EM, Shinohara RT, Dewey BE, Schindler MK, Muschelli J, Reich DS, Crainiceanu CM, and Eloyan A

Subjects
Adolescent, Adult, Biomarkers, Female, Humans, Longitudinal Studies, Male, Middle Aged, Multiple Sclerosis diagnosis, Multiple Sclerosis therapy, Principal Component Analysis, Regression Analysis, Reproducibility of Results, Steroids therapeutic use, Young Adult, Brain pathology, Magnetic Resonance Imaging methods, Multiple Sclerosis pathology
Abstract

The formation of multiple sclerosis (MS) lesions is a complex process involving inflammation, tissue damage, and tissue repair - all of which are visible on structural magnetic resonance imaging (MRI) and potentially modifiable by pharmacological therapy. In this paper, we introduce two statistical models for relating voxel-level, longitudinal, multi-sequence structural MRI intensities within MS lesions to clinical information and therapeutic interventions: (1) a principal component analysis (PCA) and regression model and (2) function-on-scalar regression models. To do so, we first characterize the post-lesion incidence repair process on longitudinal, multi-sequence structural MRI from 34 MS patients as voxel-level intensity profiles. For the PCA regression model, we perform PCA on the intensity profiles to develop a voxel-level biomarker for identifying slow and persistent, long-term intensity changes within lesion tissue voxels. The proposed biomarker's ability to identify such effects is validated by two experienced clinicians (a neuroradiologist and a neurologist). On a scale of 1 to 4, with 4 being the highest quality, the neuroradiologist gave the score on the first PC a median quality rating of 4 (95% CI: [4,4]), and the neurologist gave the score a median rating of 3 (95% CI: [3,3]). We then relate the biomarker to the clinical information in a mixed model framework. Treatment with disease-modifying therapies (p < 0.01), steroids (p < 0.01), and being closer to the boundary of abnormal signal intensity (p < 0.01) are all associated with return of a voxel to an intensity value closer to that of normal-appearing tissue. The function-on-scalar regression model allows for assessment of the post-incidence time points at which the covariates are associated with the profiles. In the function-on-scalar regression, both age and distance to the boundary were found to have a statistically significant association with the lesion intensities at some time point. The two models presented in this article show promise for understanding the mechanisms of tissue damage in MS and for evaluating the impact of treatments for the disease in clinical trials.

Published
2015
Full Text
View/download PDF

20. Alkaline Ceramidase 3 Deficiency Results in Purkinje Cell Degeneration and Cerebellar Ataxia Due to Dyshomeostasis of Sphingolipids in the Brain.

Author

Wang K, Xu R, Schrandt J, Shah P, Gong YZ, Preston C, Wang L, Yi JK, Lin CL, Sun W, Spyropoulos DD, Rhee S, Li M, Zhou J, Ge S, Zhang G, Snider AJ, Hannun YA, Obeid LM, and Mao C

Subjects
Aging metabolism, Aging pathology, Animals, Brain pathology, Ceramides genetics, Ceramides metabolism, Cerebellar Ataxia metabolism, Cerebellar Ataxia pathology, Homeostasis genetics, Humans, Lysophospholipids genetics, Lysophospholipids metabolism, Mice, Mice, Knockout, Purkinje Cells metabolism, Purkinje Cells pathology, Sphingolipids genetics, Sphingolipids metabolism, Sphingosine analogs & derivatives, Sphingosine genetics, Sphingosine metabolism, Aging genetics, Alkaline Ceramidase genetics, Brain metabolism, Cerebellar Ataxia genetics
Abstract

Dyshomeostasis of both ceramides and sphingosine-1-phosphate (S1P) in the brain has been implicated in aging-associated neurodegenerative disorders in humans. However, mechanisms that maintain the homeostasis of these bioactive sphingolipids in the brain remain unclear. Mouse alkaline ceramidase 3 (Acer3), which preferentially catalyzes the hydrolysis of C18:1-ceramide, a major unsaturated long-chain ceramide species in the brain, is upregulated with age in the mouse brain. Acer3 knockout causes an age-dependent accumulation of various ceramides and C18:1-monohexosylceramide and abolishes the age-related increase in the levels of sphingosine and S1P in the brain; thereby resulting in Purkinje cell degeneration in the cerebellum and deficits in motor coordination and balance. Our results indicate that Acer3 plays critically protective roles in controlling the homeostasis of various sphingolipids, including ceramides, sphingosine, S1P, and certain complex sphingolipids in the brain and protects Purkinje cells from premature degeneration.

Published
2015
Full Text
View/download PDF

21. Multimodal MRI markers support a model of small vessel ischemia for depressive symptoms in very old adults.

Author

Tudorascu DL, Rosano C, Venkatraman VK, MacCloud RL, Harris T, Yaffe K, Newman AB, and Aizenstein HJ

Subjects
Aged, 80 and over, Brain Mapping, Female, Humans, Image Processing, Computer-Assisted, Magnetic Resonance Imaging, Male, Microcirculation, Multimodal Imaging, Nerve Fibers, Myelinated, Quality of Life, Blood Vessels pathology, Brain pathology, Brain Ischemia pathology, Depressive Disorder pathology
Abstract

In older adults, depressive symptoms are associated with lower quality of life, high morbidity and mortality. This study aims to identify brain magnetic resonance imaging (MRI) features associated with late-life depressive symptoms in the population. Older community-dwelling adults (n=314) from the Health ABC study underwent brain MRI. Logistic regression was used to characterize the relationships between depressive symptoms (Center for Epidemiologic Studies of Depression scale, CES-D) and the following whole-brain variables: white matter hyperintensity (WMH) burden, fractional anisotropy (FA), and gray matter volume (GMV). Analyses examining possible regional differences between the CES-D groups controlled for Modified Mini-Mental State Examination score and diabetes status. The relative importance of localization of the markers was examined by comparing the distribution of significant peaks across the brain. Each whole-brain variable showed loss of integrity associated with high CES-D. For GMV, the odds ratio (OR)=0.84 (95% confidence interval (CI) 0.74, 0.96); for FA, OR=0.714 (95% CI 0.57, 0.88); for WMH, OR=1.89 (95%CI 1.33, 2.69). Voxel-wise analyses and patterns of peak significance showed non-specific patterns for white matter measures. Loss of GMV was most significant in the bilateral insula and anterior cingulate cortex. This study supports a cerebrovascular pattern for depressive symptoms in older adults. The localization of gray matter changes to the insula, a watershed area and a hub of affective circuits, suggests an etiological pathway from ischemia to increased depressive burden., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Published
2014
Full Text
View/download PDF

22. Individual differences in recovery from traumatic fear.

Author

Holmes A and Singewald N

Subjects
Animals, Fear physiology, Humans, Stress Disorders, Post-Traumatic psychology, Stress, Psychological physiopathology, Brain physiopathology, Extinction, Psychological physiology, Fear psychology, Individuality, Stress Disorders, Post-Traumatic physiopathology, Stress, Psychological psychology
Abstract

Although exposure to major psychological trauma is unfortunately common, risk for related neuropsychiatric conditions, such as post-traumatic stress disorder (PTSD), varies greatly among individuals. Fear extinction offers a tractable and translatable behavioral readout of individual differences in learned recovery from trauma. Studies in rodent substrains and subpopulations are providing new insights into neural system dysfunctions associated with impaired fear extinction. Rapid progress is also being made in identifying key molecular circuits, epigenetic mechanisms, and gene variants associated with differences in fear extinction. Here, we discuss how this research is informing understanding of the etiology and pathophysiology of individual differences in risk for trauma-related anxiety disorders, and how future work can help identify novel diagnostic biomarkers and pharmacotherapeutics for these disorders., (Published by Elsevier Ltd.)

Published
2013
Full Text
View/download PDF

23. Characteristic cortical thickness patterns in adolescents with autism spectrum disorders: interactions with age and intellectual ability revealed by canonical correlation analysis.

Author

Misaki M, Wallace GL, Dankner N, Martin A, and Bandettini PA

Subjects
Adolescent, Child, Female, Humans, Intelligence Tests, Male, Reproducibility of Results, Sensitivity and Specificity, Statistics as Topic, Young Adult, Aging pathology, Brain pathology, Cerebral Cortex pathology, Child Development Disorders, Pervasive diagnosis, Magnetic Resonance Imaging methods
Abstract

To investigate patterns and correlates of cortical thickness in adolescent males with autism spectrum disorders (ASD) versus matched typically developing controls, we applied kernel canonical correlation analysis to whole brain cortical thickness with the explaining variables of diagnosis, age, full-scale IQ, and their interactions. The analysis found that canonical variates (patterns of cortical thickness) correlated with each of these variables. The diagnosis- and age-by-diagnosis-related canonical variates showed thinner cortex for participants with ASD, which is consistent with previous studies using a univariate analysis. In addition, the multivariate statistics found larger affected regions with higher sensitivity than those found using univariate analysis. An IQ-related effect was also found with the multivariate analysis. The effects of IQ and age-by-IQ interaction on cortical thickness differed between the diagnostic groups. For typically developing adolescents, IQ was positively correlated with cortical thickness in orbitofrontal, postcentral and superior temporal regions, and greater thinning with age was seen in dorsal frontal areas in the superior IQ (>120) group. These associations between IQ and cortical thickness were not seen in the ASD group. Differing relationships between IQ and cortical thickness implies independent associations between measures of intelligence and brain structure in ASD versus typically developing controls. We discuss these findings vis-à-vis prior results obtained utilizing univariate methods., (Published by Elsevier Inc.)

Published
2012
Full Text
View/download PDF

24. Bone marrow-derived nonreactive astrocytes in the mouse brain after permanent middle cerebral artery occlusion.

Author

Tóth ZE, Leker RR, Shahar T, Bratincsak A, Szalayova I, Key S, Palkovits M, Cassiani-Ingoni R, and Mezey E

Subjects
Adult, Animals, Astrocytes metabolism, Brain physiopathology, Brain Ischemia pathology, Brain Ischemia therapy, Cell Count, Cell Differentiation, Disease Models, Animal, Female, Glial Fibrillary Acidic Protein metabolism, Humans, Infarction, Middle Cerebral Artery pathology, Male, Mice, Nerve Growth Factors metabolism, Regeneration, S100 Calcium Binding Protein beta Subunit, S100 Proteins metabolism, Transforming Growth Factor alpha pharmacology, Astrocytes cytology, Bone Marrow Cells cytology, Bone Marrow Transplantation, Brain pathology, Infarction, Middle Cerebral Artery therapy
Abstract

We studied the effect of permanent unilateral middle cerebral artery occlusion (PMCAO) on the generation of bone marrow (BM)-derived astrocytes in female mice previously transplanted with enhanced green fluorescent protein-expressing BM from male donors. In addition to an untreated PMCAO group, one group of mice also received intracerebral infusion of transforming growth factor-alpha, resulting in a decrease in the size of the infarct. Two months after PMCAO, we found a specific type of astrocyte of BM origin in the side of the injury, near the lesion. These astrocytes did not express glial fibrillary acidic protein (GFAP) by conventional fluorescence immunostaining; however, GFAP was easily detectable by tyramide signal amplification. These cells also expressed S100β, confirming their astrocytic character. Unlike the endogenous reactive astrocytes, these BM-derived astrocytes did not proliferate during the first week of ischemia and did not contribute to the glial scar formation. Transforming growth factor-alpha infusion increased the number of BM-derived astrocytes, without affecting their distribution. Interestingly, exclusively by tyramide signal amplification staining, we found that endogenous astrocytes displaying an identical morphology were also present in control mouse and human brains. Our data demonstrate that a subpopulation of nonreactive astrocytes expressing low levels of GFAP can originate from transplanted BM in the ischemic brain. We believe that these cells represent a subpopulation of astrocytes earlier considered to be GFAP negative. The high number of astrocytes with identical morphology and chemical character in control brains suggest that these type of astrocytes may have important functional role in the central nervous system that calls for further studies.

Published
2011
Full Text
View/download PDF

25. High-field MRI of brain iron.

Author

Duyn JH

Subjects
Computer Simulation, Humans, Image Interpretation, Computer-Assisted, Time Factors, Brain metabolism, Iron metabolism, Magnetic Resonance Imaging methods
Abstract

Recent developments in high-field MRI have provided opportunities to detect iron in human brain with much improved sensitivity. The combination of increased magnetic field strength with multi-channel detectors has made it possible to routinely obtain images at about 300 μm resolution. These images can be sensitized to tissue iron by exploiting the improved magnetic susceptibility contrast at high field. Together, these techniques have the potential to map the fine scale distribution of iron in human brain at the level of fiber bundles and cortical laminae, and may aid in the understanding of the role and transport of iron in normal brain and in disease. In this chapter, we will look at these techniques in detail and present some examples of high-field MRI data of human brain.

Published
2011
Full Text
View/download PDF

26. DiOLISTIC labeling of neurons from rodent and non-human primate brain slices.

Author

Seabold GK, Daunais JB, Rau A, Grant KA, and Alvarez VA

Subjects
Animals, Brain Chemistry, Dendrites chemistry, Haplorhini, Mice, Microscopy, Confocal methods, Neurons chemistry, Tungsten chemistry, Biolistics methods, Brain cytology, Neurons cytology
Abstract

DiOLISTIC staining uses the gene gun to introduce fluorescent dyes, such as DiI, into neurons of brain slices (Gan et al., 2009; O'Brien and Lummis, 2007; Gan et al., 2000). Here we provide a detailed description of each step required together with exemplary images of good and bad outcomes that will help when setting up the technique. In our experience, a few steps proved critical for the successful application of DiOLISTICS. These considerations include the quality of the DiI-coated bullets, the extent of fixative exposure, and the concentration of detergent used in the incubation solutions. Tips and solutions for common problems are provided. This is a versatile labeling technique that can be applied to multiple animal species at a wide range of ages. Unlike other fluorescent labeling techniques that are limited to preparations from young animals or restricted to mice because they rely on the expression of a fluorescent transgene, DiOLISTIC labeling can be applied to animals of all ages, species and genotypes and it can be used in combination with immunostaining to identify a specific subpopulation of cells. Here we demonstrate the use of DiOLISTICS to label neurons in brain slices from adult mice and adult non-human primates with the purpose of quantifying dendrite branching and dendritic spine morphology.

Published
2010
Full Text
View/download PDF

27. Normative data on development of neural and behavioral mechanisms underlying attention orienting toward social-emotional stimuli: an exploratory study.

Author

Lindstrom KM, Guyer AE, Mogg K, Bradley BP, Fox NA, Ernst M, Nelson EE, Leibenluft E, Britton JC, Monk CS, Pine DS, and Bar-Haim Y

Subjects
Adolescent, Adult, Aging physiology, Brain Mapping, Child, Cues, Facial Expression, Female, Humans, Magnetic Resonance Imaging, Male, Neuropsychological Tests, Photic Stimulation, Young Adult, Adolescent Development physiology, Attention physiology, Brain physiology, Child Development physiology, Emotions, Social Perception
Abstract

The ability of positive and negative facial signals to influence attention orienting is crucial to social functioning. Given the dramatic developmental change in neural architecture supporting social function, positive and negative facial cues may influence attention orienting differently in relatively young or old individuals. However, virtually no research examines such age-related differences in the neural circuitry supporting attention orienting to emotional faces. We examined age-related correlations in attention-orienting biases to positive and negative face emotions in a healthy sample (N=37; 9-40 years old) using functional magnetic resonance imaging and a dot-probe task. The dot-probe task in an fMRI setting yields both behavioral and neural indices of attention biases towards or away from an emotional cue (happy or angry face). In the full sample, angry-face attention bias scores did not correlate with age, and age did not correlate with brain activation to angry faces. However, age did positively correlate with attention bias towards happy faces; age also negatively correlated with left cuneus and left caudate activation to a happy bias fMRI contrast. Secondary analyses suggested age-related changes in attention bias to happy faces. The tendency in younger children to direct attention away from happy faces (relative to neutral faces) was diminished in the older age groups, in tandem with increasing neural deactivation. Implications for future work on developmental changes in attention-emotion processing are discussed.

Published
2009
Full Text
View/download PDF

28. Prefrontal cognitive systems in schizophrenia: towards human genetic brain mechanisms.

Author

Tan HY, Callicott JH, and Weinberger DR

Subjects
Animals, Diagnostic Imaging, Humans, Memory, Short-Term physiology, Models, Neurological, Phenotype, Signal Transduction genetics, Signal Transduction physiology, Brain physiopathology, Prefrontal Cortex physiopathology, Schizophrenia genetics, Schizophrenia physiopathology, Schizophrenic Psychology
Abstract

Schizophrenia has complex genetic heritability. It is also genetically heterogeneous. To the extent that genes are associated with symptom constellations in schizophrenia, they do so by affecting the development and function of neural systems that mediate the expression of such diverse behavioral, cognitive and perceptual phenomena. The genetic mechanisms of human brain dysfunction remain to be well understood. "Imaging genetics" is an emerging field that attempts to integrate the basic biology of putative disease mechanisms with physiological correlates from the live human brain. Here, we review recent imaging genetics work on prefrontal brain systems associated with working memory and executive function - heritable traits relevant to schizophrenia. Starting with genetic variation in dopaminergic systems (e.g., COMT), we examined the modulation of prefrontal brain networks during active cognitive processing; there is also evidence that variation in the expression of dopamine-related downstream intra-cellular signaling molecules (e.g., AKT1) are implicated. Moreover, these genetic variants evidence epistasis on neuroimaging measures, lending further support to the conceptualization that non-additive combinations of multiple genes modulate active human cognitive brain mechanisms. The imaging genetics platform therefore could extend understanding of genetic mechanisms of human cognitive brain processes relevant to neuropsychiatric disease.

Published
2009
Full Text
View/download PDF

29. Differences in EEG between gifted and average students: neural complexity and functional cluster analysis.

Author

Jin SH, Kim SY, Park KH, and Lee KJ

Subjects
Adolescent, Analysis of Variance, Case-Control Studies, Cluster Analysis, Cognition physiology, Female, Humans, Male, Neuropsychological Tests, ROC Curve, Brain physiology, Brain Mapping, Child, Gifted psychology, Electroencephalography
Abstract

The main aim of the present study was to assess the differences in EEG between gifted and average students. Another aim of the present study was to investigate which brain areas are related to a Rey-Osterrieth complex figure (ROCF) memorizing using a functional cluster (FC) analysis and how the complexity of cortical activities changes in both gifted and average students. The EEG was recorded from 16 electrodes in both 18 right-handed healthy gifted and age-matched average students before and during ROCF memorizing. FC was estimated to characterize the joint interactions among many brain regions and neural complexity. The study assessed the visuo-spatial memory abilities through examining EEG profiles using the measure of FC, and planning and executive function using recall score. The gifted students made a significantly high score compared to the average students during ROCF memorizing. Both groups showed very different FC patterns. ROCF memorizing is related to the visual mental process, thus simultaneous neuronal activities appears on the right central, temporal, occipital, and bilateral prefrontal regions. One of the notable characteristics of gifted students' FC map is the dominance of the right hemisphere compared with that of average students, and it is accordance with the characteristics of gifted brain.

Published
2007
Full Text
View/download PDF

30. Brain stimulation for epilepsy.

Author

Theodore WH

Subjects
Brain anatomy & histology, Clinical Trials as Topic statistics & numerical data, Deep Brain Stimulation instrumentation, Deep Brain Stimulation methods, Deep Brain Stimulation trends, Electric Stimulation Therapy instrumentation, Electrodes, Implanted standards, Electrodes, Implanted trends, Epilepsy physiopathology, Humans, Transcranial Magnetic Stimulation methods, Transcranial Magnetic Stimulation trends, Treatment Outcome, Vagus Nerve physiology, Brain physiopathology, Electric Stimulation Therapy methods, Electric Stimulation Therapy trends, Epilepsy therapy
Published
2005
Full Text
View/download PDF

31. High-resolution diffusion-weighted imaging with interleaved variable-density spiral acquisitions.

Author

Li TQ, Kim DH, and Moseley ME

Subjects
Adult, Algorithms, Gels, Humans, Phantoms, Imaging, Brain anatomy & histology, Diffusion Magnetic Resonance Imaging methods
Abstract

Purpose: To develop a multishot magnetic resonance imaging (MRI) pulse sequence and reconstruction algorithm for diffusion-weighted imaging (DWI) in the brain with submillimeter in-plane resolution., Materials and Methods: A self-navigated multishot acquisition technique based on variable-density spiral k-space trajectory design was implemented on clinical MRI scanners. The image reconstruction algorithm takes advantage of the oversampling of the center k-space and uses the densely sampled central portion of the k-space data for both imaging reconstruction and motion correction. The developed DWI technique was tested in an agar gel phantom and three healthy volunteers., Results: Motions result in phase and k-space shifts in the DWI data acquired using multishot spiral acquisitions. With the two-dimensional self-navigator correction, diffusion-weighted images with a resolution of 0.9 x 0.9 x 3 mm3 were successfully obtained using different interleaves ranging from 8-32. The measured apparent diffusion coefficient (ADC) in the homogenous gel phantom was (1.66 +/- 0.09) x 10(-3) mm2/second, which was the same as measured with single-shot methods. The intersubject average ADC from the brain parenchyma of normal adults was (0.91 +/- 0.01) x 10(-3) mm2/second, which was in a good agreement with the reported literature values., Conclusion: The self-navigated multishot variable-density spiral acquisition provides a time-efficient approach to acquire high-resolution diffusion-weighted images on a clinical scanner. The reconstruction algorithm based on motion correction in the k-space data is robust, and measured ADC values are accurate and reproducible.

Published
2005
Full Text
View/download PDF

32. Measurement and automatic correction of high-order B0 inhomogeneity in the rat brain at 11.7 Tesla.

Author

Chen Z, Li SS, Yang J, Letizia D, and Shen J

Subjects
Animals, Echo-Planar Imaging, Male, Models, Animal, Phantoms, Imaging, Rats, Rats, Sprague-Dawley, Brain physiology, Brain Mapping, Magnetic Resonance Spectroscopy methods
Abstract

In vivo B(0) inhomogeneity in the rat brain at 11.7 Tesla was measured and decomposed up to the fourth-order spherical harmonic terms using an automatic slice shimming routine derived from the FLATNESS method. In vivo shimming of horizontal slices showed that significant improvement in the T(2)*-weighted echo-planar imaging was achieved after correction of all first-, second- and third-order in-slice shims. For localized proton spectroscopy, reproducible, high quality data were obtained after correcting all first- and second-order shims. The measured high-order in vivo B(0) inhomogeneity in terms of spherical harmonic terms should provide a useful guide for designing shims to meet in vivo requirements.

Published
2004
Full Text
View/download PDF

33. Imaging brain phospholipase A2 activation in awake rats in response to the 5-HT2A/2C agonist (+/-)2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI).

Author

Qu Y, Chang L, Klaff J, Balbo A, and Rapoport SI

Subjects
Animals, Autoradiography, Enzyme Activation drug effects, Enzyme Activation physiology, Male, Phospholipases A2, Rats, Rats, Inbred F344, Receptor, Serotonin, 5-HT2A, Receptor, Serotonin, 5-HT2C, Wakefulness drug effects, Wakefulness physiology, Amphetamines pharmacology, Brain drug effects, Brain enzymology, Phospholipases A metabolism, Receptors, Serotonin metabolism, Serotonin Receptor Agonists pharmacology
Abstract

Incorporation coefficients k(*) of intravenously injected [(3)H]arachidonic acid from blood into brain reflect the release from phospholipids of arachidonic acid by receptor-initiated activation of phospholipase A(2) (PLA(2)). In unanesthetized adult rats, 2.5 mg/kg intraperitoneally (i.p.) (+/-)2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI), which is a 5-HT(2A/2C) receptor agonist, has been reported to produce the behavioral changes of what is known as the 5-HT(2) syndrome, but only a few small regional decrements in brain glucose metabolism. In this study, 2.5 mg/kg i.p. DOI, when administered to unanesthetized rats, produced widespread and significant increases, of the order of 60%, in k(*) for arachidonate, particularly in neocortical brain regions reported to have high densities of 5-HT(2A) receptors. The increases could be entirely blocked by chronic pretreatment with mianserin, a 5-HT(2) receptor antagonist. The results suggest that the 5-HT(2) syndrome involves widespread brain activation of PLA(2) via 5-HT(2A) receptors, leading to the release of the second messenger, arachidonic acid. Chronic mianserin, a 5-HT(2) antagonist, prevents this activation.

Published
2003
Full Text
View/download PDF

34. Effects of intrauterine inflammation on developing rat brain.

Author

Bell MJ and Hallenbeck JM

Subjects
2',3'-Cyclic-Nucleotide Phosphodiesterases biosynthesis, Animals, Apoptosis, Astrocytes metabolism, Astrocytes pathology, Brain embryology, Brain metabolism, Cell Count, Disease Models, Animal, Dose-Response Relationship, Drug, Female, Fetal Death chemically induced, Glial Fibrillary Acidic Protein biosynthesis, In Situ Nick-End Labeling, Inflammation chemically induced, Lipopolysaccharides, Myelin Proteolipid Protein biosynthesis, Pregnancy, Rats, Rats, Inbred F344, Rats, Inbred Lew, Tumor Necrosis Factor-alpha biosynthesis, Uterine Diseases chemically induced, Brain pathology, Inflammation complications, Uterine Diseases complications
Abstract

Damage to the white matter in the brain during development can lead to cerebral palsy (CP), a heterogeneous group of clinical syndromes that results in life-long disorders of movement and posture. Periventricular leukomalacia (PVL) is a pathological process within the white matter characterized by oligodendrocyte loss and is associated with the development of CP. Clinically, CP and PVL are associated with intrauterine infection and inflammation, but mechanisms involved are not well understood. We developed a model of intrauterine inflammation in Lewis and Fischer 344 rats to study the effects of intrauterine inflammation on developing glia. Pregnant rats were intracervically injected with lipopolysaccharide (LPS) at 15 days of gestation (E15) and a dose of LPS that caused low fetal mortality was determined. At E20, treated fetuses had increased TUNEL(+) nuclei and tumor necrosis factor (TNF)-alpha-immunoreactive areas within the brains. In a second series of animals allowed to survive until postnatal day 21 (PND 21), immunostaining was performed against several glial markers. Staining for the oligodendrocyte-specific proteins 2', 3'-cyclic nucleotide phosphodiesterase (CNP) and myelin proteolipid protein (PLP) was decreased in treated pups compared to shams within the corpus callosum, a white matter structure used as a representative area of developing white matter. Treated pups had activated astrocytes lining cerebral blood vessels, as observed by glial fibrillary acidic protein (GFAP) staining, while sham pups did not. Activated microglia were not detected using OX42 as a cell marker. Our model of intrauterine inflammation causes increased TUNEL and TNF-alpha staining early after injury, suggesting increased apoptotic cell death, possibly by cytokine-related mechanisms., (Copyright 2002 Wiley-Liss, Inc.)

Published
2002
Full Text
View/download PDF

35. Alternative splicing of brain-specific PTB defines a tissue-specific isoform pattern that predicts distinct functional roles.

Author

Rahman L, Bliskovski V, Reinhold W, and Zajac-Kaye M

Subjects
Animals, Fetus metabolism, HeLa Cells, Humans, Mice, Molecular Sequence Data, Organ Specificity genetics, Protein Isoforms genetics, Protein Isoforms metabolism, Alternative Splicing, Brain metabolism, Polypyrimidine Tract-Binding Protein genetics
Abstract

Splicing of neural-specific exons is differentially regulated in neuronal and non-neuronal cells. The polypyrimidine tract binding protein (PTB) has been implicated as a negative regulator for exon splicing, whereas the brain-specific homolog of PTB, termed nPTB, promotes exon splicing exclusively in neurons. We have now isolated a novel mRNA splice variant of nPTB from non-neuronal cells. In contrast to the neural nPTB transcript, the expression of this novel isoform was absent from brain tissue and was generated in non-neuronal cells by alternative splicing to include five additional amino acid residues encoded by exon 9. In addition, we identified a brain-specific transcript containing a novel, alternatively spliced, internal exon 10. The exclusion of this 34-nucleotide exon 10 in non-neuronal tissues generates a premature termination codon and results in the truncation of the open reading frame. Our findings suggest that alternative splicing of nPTB has an important role in regulation of tissue-specific gene expression and thus in the functional activity of nPTB in neuronal and non-neuronal cells.

Published
2002
Full Text
View/download PDF

36. Convection-enhanced delivery of AAV-2 combined with heparin increases TK gene transfer in the rat brain.

Author

Nguyen JB, Sanchez-Pernaute R, Cunningham J, and Bankiewicz KS

Subjects
Animals, Brain metabolism, Brain virology, Convection, Corpus Striatum drug effects, Corpus Striatum metabolism, Corpus Striatum virology, Dependovirus physiology, Drug Delivery Systems, Female, Functional Laterality drug effects, Functional Laterality physiology, Gene Expression Regulation, Viral drug effects, Gene Expression Regulation, Viral physiology, Genes, Reporter genetics, Genetic Vectors pharmacology, Glial Fibrillary Acidic Protein metabolism, Immunohistochemistry, Neurons drug effects, Neurons metabolism, Neurons virology, Rats, Rats, Sprague-Dawley, Thymidine Kinase genetics, Thymidine Kinase metabolism, Anticoagulants pharmacology, Brain drug effects, Dependovirus drug effects, Gene Transfer Techniques, Genetic Therapy methods, Genetic Vectors drug effects, Heparin pharmacology
Abstract

Adeno-associated virus type2 (AAV-2) binds to heparan-sulfate proteoglycans on the cell surface. In vivo, attachment of viral particles to cells adjacent to the injection tract limits the distribution of AAV-2 when infused into the CNS parenchyma and heparin co-infusion might decrease the binding of AAV-2 particles to cells in the vicinity of the infusion tract. We have previously shown that heparin co-infusion combined with convection enhanced delivery enhances distribution of the GDNF family trophic factors (heparin-binding proteins) in the rat brain. In this work we show that heparin co-infusion significantly increases the volume of distribution of AAV-2 as demonstrated by immunoreactivity to the transgene product 6 days after infusion into the rat striatum.

Published
2001
Full Text
View/download PDF

37. Opiate receptor avidity is reduced bilaterally in rhesus monkeys unilaterally lesioned with MPTP.

Author

Cohen RM, Carson RE, Wyatt RJ, and Doudet DJ

Subjects
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration & dosage, Animals, Basal Ganglia physiology, Brain diagnostic imaging, Brain drug effects, Cerebellum physiology, Cerebral Cortex physiology, Dihydroxyphenylalanine analogs & derivatives, Dihydroxyphenylalanine pharmacokinetics, Fluorine Radioisotopes, Functional Laterality, Infusions, Parenteral, Limbic System physiology, Macaca mulatta, Naltrexone pharmacokinetics, Narcotic Antagonists pharmacokinetics, Organ Specificity, Receptors, Opioid drug effects, Receptors, Opioid, kappa antagonists & inhibitors, Receptors, Opioid, kappa metabolism, Receptors, Opioid, mu antagonists & inhibitors, Receptors, Opioid, mu metabolism, Tomography, Emission-Computed, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine pharmacology, Brain physiology, Naltrexone analogs & derivatives, Receptors, Opioid metabolism
Abstract

Opiate receptor avidity (unoccupied receptor density / the receptor dissociation constant), was measured in four animals with unilateral parkinsonian symptoms following MPTP (1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine) infusions into the internal carotid of one side, and nine normal controls with positron emission tomography (PET) and 6-deoxy-6-beta-[(18)F]fluoronaltrexone (cyclofoxy, CF), a mu- and kappa-opiate receptor antagonist. PET studies of 6-[(18)F]-L-fluoro-L-3,4-dihydroxyphenylalanine ([(18)F]-DOPA) in these parkinsonian animals, although documenting the primarily unilateral nature of the lesion, also demonstrated a milder loss of dopaminergic on the side opposite the infusion. Opiate receptor avidity was found to be reduced by 20-34% in the caudate, anterior putamen, thalamus, and amygdala of these primarily unilaterally MPTP-exposed animals, bilaterally with no statistically significant differences between the two sides. The affected regions are the same as those previously demonstrated to have a 30-35% loss in clinically recovered bilaterally MPTP-lesioned animals. These findings confirm that the opiate pathway can change in response to modest decreases in basal ganglia dopamine innervation. Thus, opiate pathway adaptation is likely to contribute to the dynamic changes in basal ganglia circuits that forestall the initial clinical manifestations of Parkinson's disease. In addition, opiate pathway(s) may contribute to the treatment responsiveness and progression of the disease either directly through effects on basal ganglia function or indirectly through effects on basal ganglia plasticity., (Copyright 1999 Wiley-Liss, Inc.)

Published
1999
Full Text
View/download PDF

38. Adenosine A3 receptors: novel ligands and paradoxical effects.

Author

Jacobson KA

Subjects
Animals, Brain metabolism, CHO Cells, Cricetinae, Culture Techniques, Humans, Ligands, Purinergic P1 Receptor Antagonists, Rats, Receptor, Adenosine A3, Second Messenger Systems drug effects, Structure-Activity Relationship, Tumor Cells, Cultured, Brain drug effects, Cytokines antagonists & inhibitors, Heart drug effects, Purinergic P1 Receptor Agonists
Abstract

The physiological role of the adenosine A3 receptor is being investigated using newly synthesized, selective ligands. Recently, in addition to agonists, selective antagonists have been developed that belong to three distinct, non-purine chemical classes: flavonoids, 1,4-dihydropyridine derivatives (e.g. MRS1191, which is 1300-fold selective for human adenosine A3 vs A1/A2A receptors, with a Ki value of 31 nM) and the triazoloquinazolines (e.g. MRS1220, which has a Ki value of 0.65 nM). The A3 receptor has proven enigmatic in terms of antagonist ligand specificity, coupling to second messengers, and biological effects in the CNS, inflammatory system and cardiovascular system. A3 receptors are also potentially involved in apoptosis. It appears that intense, acute activation of A3 receptors acts as a lethal input to cells, while low concentrations of A3 receptor agonists protect against apoptosis. Here, Kenneth Jacobson describes how A3 receptor agonists might be useful in treating inflammatory conditions, possibly through their inhibition of tumour necrosis factor alpha (TNF-alpha) release, which has been shown in macrophages. A3 receptor antagonists might be useful in treating asthma or acute brain ischaemia. Recently, the versatility of A3 receptor agonists, administered either before or during ischaemia, in eliciting potent cardioprotection has been shown.

Published
1998
Full Text
View/download PDF

39. Gender differences in regional cerebral blood flow during transient self-induced sadness or happiness.

Author

George MS, Ketter TA, Parekh PI, Herscovitch P, and Post RM

Subjects
Adult, Arousal physiology, Brain Stem blood supply, Cerebral Cortex blood supply, Dominance, Cerebral physiology, Female, Gyrus Cinguli blood supply, Humans, Limbic System blood supply, Male, Middle Aged, Reference Values, Regional Blood Flow physiology, Sex Factors, Affect physiology, Brain blood supply, Happiness, Tomography, Emission-Computed
Abstract

Men, compared to women, are less likely to experience mood disorders. We wondered if gender differences exist in the ability to self-induce transient sadness and happiness, and in regional cerebral blood flow (rCBF) either at rest or during transient emotions. Ten adult men and 10 age-matched women, all healthy and never mentally ill, were scanned using H2(15)O positron emission tomography at rest and during happy, sad, and neutral states self-induced by recalling affect-appropriate life events and looking at happy, sad, or neutral human faces. At rest, women had decreased temporal and prefrontal cortex rCBF, and increased brainstem rCBF. There were no significant between-group differences in difficulty, effort required, or the degree of happiness or sadness induced. Women activated a significantly wider portion of their limbic system than did men during transient sadness, despite similar self-reported changes in mood. These findings may aid in understanding gender differences with respect to emotion and mood.

Published
1996
Full Text
View/download PDF

40. Melatonin synthesis: analysis of the more than 150-fold nocturnal increase in serotonin N-acetyltransferase messenger ribonucleic acid in the rat pineal gland.

Author

Roseboom PH, Coon SL, Baler R, McCune SK, Weller JL, and Klein DC

Subjects
Adrenergic beta-Agonists pharmacology, Adrenergic beta-Antagonists pharmacology, Amino Acid Sequence, Animals, Arylamine N-Acetyltransferase chemistry, Consensus Sequence, DNA, Complementary, Darkness, Light, Male, Molecular Sequence Data, Organ Specificity, Phenylephrine pharmacology, Pineal Gland physiology, Polymerase Chain Reaction, Propranolol pharmacology, RNA, Messenger analysis, RNA, Messenger biosynthesis, Rats, Rats, Sprague-Dawley, Receptors, Adrenergic, beta physiology, Sequence Homology, Amino Acid, Sheep, Arylamine N-Acetyltransferase biosynthesis, Brain enzymology, Circadian Rhythm, Melatonin biosynthesis, Pineal Gland enzymology, Transcription, Genetic
Abstract

In vertebrates, the circadian rhythm in the activity of serotonin N-acetyltransferase [arylalkylamine N-acetyltransferase (AA-NAT); EC 2.3.1.87] drives the daily rhythm in circulating melatonin. We have discovered that expression of the AA-NAT gene in the rat pineal gland is essentially turned off during the day and turned on at night, resulting in a more than 150-fold rhythm. Expression is regulated by a photoneural system that acts through an adrenergic-cAMP mechanism in pinealocytes, probably involving cAMP response element-binding protein phosphorylation. Turning off AA-NAT expression appears to involve de novo synthesis of a protein that attenuates transcription. A approximately 10-fold night/day rhythm in AA-NAT messenger RNA occurs in the retina, and AA-NAT messenger RNA is also detected at low levels in the brain.

Published
1996
Full Text
View/download PDF

41. Differential coexpression of genes encoding prothyrotropin-releasing hormone (pro-TRH) and prohormone convertases (PC1 and PC2) in rat brain neurons: implications for differential processing of pro-TRH.

Author

Pu LP, Ma W, Barker JL, and Loh YP

Subjects
Animals, Brain physiology, Brain Chemistry, Furin, Histocytochemistry, In Situ Hybridization, Male, Neurons physiology, Pyrrolidonecarboxylic Acid analogs & derivatives, RNA, Messenger metabolism, Rats, Rats, Sprague-Dawley, Brain cytology, Gene Expression, Protein Precursors genetics, Protein Processing, Post-Translational, Subtilisins genetics, Thyrotropin-Releasing Hormone genetics
Abstract

Pro-TRH is cleaved at paired basic residues to yield five copies of TRH and cryptic peptides. Recent studies have shown that the prohormone convertases, PC1 and PC2, can process pro-TRH correctly. To determine whether these two enzymes could play a role in pro-TRH processing in vivo, the regional and cellular colocalization of pro-TRH messenger RNA (mRNA) with the mRNAs encoding the prohormone convertases PC1 and PC2 was examined in rat brain, using in situ hybridization histochemistry. Differential regional distribution of pro-TRH mRNA with PC1 and/or PC2 mRNA was found in several brain regions. For example, in the olfactory regions, there was coexpression of pro-TRH mRNA in the glomerular layer with PC2 mRNA, but not PC1 mRNA, whereas in the tenia tecta, coexpression of pro-TRH and PC1 mRNAs was evident, but PC2 mRNA was absent. Pro-TRH mRNA in the paraventricular nucleus was coexpressed with both PC1 and PC2 mRNAs, whereas the basal lateral hypothalamus showed coexistence of pro-TRH mRNA with PC2 mRNA, but not PC1 mRNA. Interestingly, pro-TRH was expressed in the thalamic reticular nucleus, but neither PC1 nor PC2 was detectable in this region. Cellular colocalization studies using double in situ hybridization histochemistry showed the presence of PC2 mRNA in the pro-TRH neurons of the olfactory glomerular layer and basal lateral hypothalamus, and PC1 mRNA in the pro-TRH neurons in the paraventricular nucleus. These results suggest that PC1 and PC2 are enzyme candidates for the processing of pro-TRH in vivo. Moreover, the differential distribution of PC1 and PC2 mRNAs with pro-TRH mRNA may be responsible for the differential processing of this prohormone in the central nervous system. The absence of PC1 and PC2 mRNAs in certain TRH neurons raises the possibility that prohormone convertases other than PC1 and PC2 may be involved in the processing of brain pro-TRH.

Published
1996
Full Text
View/download PDF

42. Effect of anoxia and reoxygenation on antioxidant enzyme activities in immortalized brain endothelial cells.

Author

Rabin O, Piciotti M, Drieu K, Bourre JM, and Roux F

Subjects
Animals, Brain cytology, Catalase metabolism, Cell Hypoxia, Cells, Cultured, Cells, Immobilized, Endothelium, Vascular cytology, Glutathione Peroxidase metabolism, Glutathione Reductase metabolism, Rats, Superoxide Dismutase metabolism, Antioxidants metabolism, Brain enzymology, Endothelium, Vascular enzymology, Oxidoreductases metabolism, Oxygen metabolism
Abstract

The effects of anoxia and reoxygenation on major antioxidant enzyme activities were investigated in vitro in immortalized rat brain endothelial cells (RBE4 cells). A sublethal anoxic period of 12 h was assessed for RBE4 cells using the neutral red uptake test. Anoxia markedly influenced the specific activity of catalase and superoxide dismutase, with no major effect on glutathione peroxidase or glutathione reductase. After 24 h postanoxia, the superoxide dismutase activity modulated by the presence or absence of oxygen returned to control value. Damage and recovery of RBE4 immortalized rat brain endothelial cells in culture after exposure to free radicals and other oxygen-derived species provides a useful in vitro model to study anoxia-reoxygenation trauma at the cellular level.

Published
1996
Full Text
View/download PDF

43. IL-1-induced prostacyclin production by cerebral vascular endothelial cells inhibits myelin basic protein-specific lymphocyte proliferation.

Author

McCarron RM

Subjects
Animals, Cells, Cultured, Endothelium, Vascular drug effects, Mice, Brain blood supply, Endothelium, Vascular metabolism, Epoprostenol biosynthesis, Interleukin-1 pharmacology, Lymphocyte Activation, Myelin Basic Protein immunology
Abstract

Addition of cerebral vascular endothelial cells (EC) to myelin basic protein (MBP) immune lymph node cells (LNC) cultured in the presence of MBP resulted in the inhibition of MBP-specific proliferative responses. Proliferation was not inhibited in cultures containing indomethacin (IM), suggesting a possible role for prostaglandins. Significant levels of 6-KPGF1 alpha, the stable hydrolysate product of PGI2, but not PGE2 were observed in culture (LNC + EC) supernatants but not in supernatants from cultures containing only LNC or EC. The levels of PGI2 release were proportional to the concentration of exogenous EC present in culture and synthesis of PGI2 could be blocked by IM. These results indicate the requirement for coculture in the generation PGI2. Additional experiments indicated that EC were required for the generation of PGI2 and that either macrophages (M phi), or recombinant murine IL-1 were able to replace LNC in cocultures with EC in order to generate PGI2. The ability of IL-1 to stimulate EC-derived PGI2 synthesis was dose dependent with maximal stimulation observed at 50 U/ml IL-1. The IL-1-induced production of PGI2 by EC as well as PGI2 production in cultures containing EC and either LNC or M phi was inhibited by treatment with anti-IL-1 antibody. These results indicate that EC are capable of inhibiting antigen-specific lymphocyte proliferation by producing PGI2, which can be induced by the lymphokine, IL-1.

Published
1992
Full Text
View/download PDF

44. Magnetic resonance imaging of brain function.

Author

Turner R

Subjects
Animals, Cerebrovascular Circulation physiology, Contrast Media, Humans, Image Enhancement methods, Image Processing, Computer-Assisted, Brain anatomy & histology, Echo-Planar Imaging, Magnetic Resonance Imaging
Abstract

New techniques for imaging of brain function are described, which utilize magnetic resonance imaging. Echo-planar imaging (EPI), the preferred method, is introduced and technical issues are discussed. Two recent approaches for measurement of blood flow are explained: contrast agent bolus tracking and black blood perfusion. An intrinsic contrast technique, which utilizes the paramagnetism of deoxyhemoglobin, is presented. Results from experiments on functional imaging of the human brain are shown, and the specific advantages of MRI for this purpose are discussed.

Published
1992

45. Regional distribution of guanine nucleotide-sensitive and guanine nucleotide-insensitive vasoactive intestinal peptide receptors in rat brain.

Author

Hill JM, Harris A, and Hilton-Clarke DI

Subjects
Animals, Autoradiography, Brain cytology, Cell Membrane metabolism, Electrophoresis, Polyacrylamide Gel, Iodine Radioisotopes, Male, Molecular Weight, Organ Specificity, Rats, Rats, Inbred Strains, Receptors, Gastrointestinal Hormone drug effects, Receptors, Gastrointestinal Hormone isolation & purification, Receptors, Vasoactive Intestinal Peptide, Brain metabolism, Guanylyl Imidodiphosphate pharmacology, Receptors, Gastrointestinal Hormone metabolism, Vasoactive Intestinal Peptide metabolism
Abstract

Based on the ability of guanine nucleotides to inhibit the binding of vasoactive intestinal peptide to its receptors, a guanosine 5'-triphosphate analog, guanylyl-imidodiphosphate, was used to differentiate two subtypes (or different functional states of a single subtype) of vasoactive intestinal peptide receptor in brain with in vitro autoradiography. In most brain regions, guanylyl-imidodiphosphate reduced vasoactive intestinal peptide binding between 40 and 60%. However, in the supraoptic nucleus, locus coeruleus, interpeduncular nucleus, facial nucleus, olfactory tubercle and periventricular hypothalamic nucleus, 80% or more of vasoactive intestinal peptide binding was inhibited. In other brain regions, including the medial geniculate, olfactory bulbs, and ventral thalamic nuclei, guanylyl-imidodiphosphate had little effect on vasoactive intestinal peptide binding. In liver, lung and intestine it also partly inhibited vasoactive intestinal peptide binding. Electrophoretic analysis of vasoactive intestinal peptide, covalently cross-linked to its receptors in brain membranes, revealed a pair of bands between 44,000 and 52,000 mol. wt, a component at 64,000 mol. wt and another at 92,000 mol. wt. All were displaceable with vasoactive intestinal peptide but guanylyl-imidodiphosphate displaced only the 64,000 mol. wt band suggesting that the GTP-sensitive vasoactive intestinal peptide receptor seen in brain sections has a molecular weight of about 61,000. The differential sensitivity to guanylyl-imidodiphosphate suggests the existence of at least two vasoactive intestinal peptide receptor subtypes in brain, with distinct regional distribution, and may reflect differential coupling to second messenger systems.

Published
1992
Full Text
View/download PDF

47. Measuring random microscopic motion of water in tissues with MR imaging: a cat brain study.

Author

Le Bihan D, Moonen CT, van Zijl PC, Pekar J, and DesPres D

Subjects
Animals, Brain physiology, Cats, Cerebrospinal Fluid physiology, Movement, Body Water physiology, Brain anatomy & histology, Magnetic Resonance Imaging
Abstract

Cat brain images sensitized to incoherent motion by additional gradient pulses were obtained on a 4.7 T magnetic resonance unit equipped with shielded gradient coils. The apparent diffusion coefficient of water in gray and white matter was accurately determined and imaged from the signal attenuation curve obtained as a function of gradient strength. Contrast in calculated diffusion images differed from typical T2-weighted contrast. Furthermore, in gray matter and in areas containing flowing CSF the attenuation curve was found to be biexponential. These results are interpreted in terms of a simple voxel model with microcirculation and diffusion contributions.

Published
1991
Full Text
View/download PDF

48. Novel genetic loci underlying human intracranial volume identified through genome-wide association

Author

G. Bruce Pike, Marcel P. Zwiers, Andreas Meyer-Lindenberg, Jeroen van der Grond, Randy L. Gollub, Karen A. Mather, Andrew J. Schork, Vidar M. Steen, Marc M. Bohlken, Nhat Trung Doan, Derek W. Morris, John B.J. Kwok, Emma J. Rose, Johanna Hass, Andrew Simmons, Tian Ge, Reinhold Schmidt, Micael Andersson, Ian J. Deary, Christopher Chen, Derrek P. Hibar, Simon E. Fisher, Lucija Abramovic, Marcella Rietschel, Edith Hofer, Simon Lovestone, Clyde Francks, Christopher R.K. Ching, Srdjan Djurovic, Lachlan T. Strike, Lorna M. Lopez, Rene L. Olvera, Owen Carmichael, M. Arfan Ikram, Andre F. Marquand, Christine Macare, W.T. Longstreth, Philippe Amouyel, Aaron L. Goldman, Wolfgang Hoffmann, Philip L. De Jager, David C. Liewald, Harald H H Göring, Aad van der Lugt, David Ames, Neeltje E.M. van Haren, Lars Nyberg, Nina Romanczuk-Seiferth, Lukas Pirpamer, Stefan Ehrlich, Alexa S. Beiser, Lianne Schmaal, Hilkka Soininen, Mark Jenkinson, Kazima B. Bulayeva, Anderson M. Winkler, Mike A. Nalls, Diana Tordesillas-Gutiérrez, Martine Hoogman, Lars T. Westlye, Loes M. Olde Loohuis, Andrew Singleton, Gabriel Cuellar-Partida, Randy L. Buckner, Dorret I. Boomsma, Dena G. Hernandez, Steven G. Potkin, Sudha Seshadri, Bertram Müller-Myhsok, D. Hoehn, Gareth E. Davies, Chantal Depondt, Henrik Walter, Michael E. Weale, Deborah Janowitz, Susanne Erk, Iryna O. Fedko, Daniel R. Weinberger, Nic J A van der Wee, Jean-Luc Martinot, Jessica A. Turner, Marieke Klein, Sandra Barral, Sebastian Mohnke, Albert Hofman, Ingrid Melle, Saud Alhusaini, Vincent Chouraki, Stephen M. Lawrie, Mark E. Bastin, Juan C. Troncoso, Jean Shin, Wiro J. Niessen, Diane M. Becker, Laura Almasy, Anders M. Dale, Benjamin S. Aribisala, Dennis van 't Ent, Marco P. Boks, M. Mallar Chakravarty, Paul M. Thompson, David Reese McKay, Michael Griswold, John Blangero, Narelle K. Hansell, Eco J. C. de Geus, Paul A. Nyquist, Susana Muñoz Maniega, Sampath Arepalli, Tatjana Rundek, Dan L. Longo, Anton J. M. de Craen, Rebekah McWhirter, Nazanin Mirza-Schreiber, Henning Tiemeier, Girma Woldehawariat, Sven Cichon, Irene Pappa, Amelia A. Assareh, Sudheer Giddaluru, Pieter J. Hoekstra, Hieab H.H. Adams, Hilleke E. Hulshoff Pol, Grant W. Montgomery, Roel A. Ophoff, Markus M. Nöthen, Sara Pudas, Sigurdur Sigurdsson, Arthur W. Toga, Tien Yin Wong, Massimo Pandolfo, Corina U. Greven, Esther Walton, Tianye Jia, David J. Stott, Gunter Schumann, Marie-José van Tol, Dalia Kasperaviciute, Thomas Wolfers, Henry Völzke, Ian Ford, Shannon L. Risacher, Jessika E. Sussmann, Nicholas G. Martin, Wei Wen, Daniah Trabzuni, Iwona Kłoszewska, Kwangsik Nho, Gianpiero L. Cavalleri, Adam M. Brickman, Sungeun Kim, Andreas Heinz, Ralph L. Sacco, Neda Jahanshad, Velandai Srikanth, Elena Shumskaya, Susan H. Blanton, Katharina Wittfeld, Badri N. Vardarajan, Joshua C. Bis, Joanne E. Curran, Helena Schmidt, Peter T. Fox, Clifford R. Jack, Jason L. Stein, Laura M. E. Blanken, Thomas Espeseth, Dick J. Veltman, Sebastian Guelfi, Margaret J. Wright, Norman Delanty, Michael Czisch, Martina Papmeyer, Oscar L. Lopez, Marjolein M. J. Van Donkelaar, Bruce M. Psaty, Jan K. Buitelaar, Sven J. van der Lee, David A. Bennett, Beng-Choon Ho, Oliver Martinez, Wiepke Cahn, Li Shen, J. Wouter Jukema, Janita Bralten, Peter Kochunov, Greig I. Zubicaray, Marcel P. van der Brug, Ching-Yu Cheng, Philipp G. Sämann, Stella Trompet, Roberto Roiz-Santiañez, David C. Glahn, Allissa Dillman, Venkata S. Mattay, Dara M. Cannon, Michael W. Weiner, Christopher D. Whelan, Alexander Teumer, Sylvane Desrivières, Ole A. Andreassen, Thomas E. Nichols, Manuel Mattheisen, Matthias Nauck, René S. Kahn, Albert V. Smith, Colin Smith, Vilmundur Gudnason, Denis A. Evans, Anouk den Braber, Katie L. McMahon, Han G. Brunner, Florian Holsboer, Yuri Milaneschi, Andrew J. Saykin, Jiemin Liao, Vince D. Calhoun, Neelum T. Aggarwal, Dennis van der Meer, Hans J. Grabe, Anita L. DeStefano, Claudia L. Satizabal, Alan B. Zonderman, Alex P. Zijdenbos, Tulio Guadalupe, Ingrid Agartz, Jordan W. Smoller, Allison C. Nugent, Alejandro Arias-Vasquez, Masashi Ikeda, Avram J. Holmes, Brenda W.J.H. Penninx, John Hardy, Herve Lemaitre, Charles DeCarli, Patrizia Mecocci, Catharina A. Hartman, Tomas Axelsson, Oliver Grimm, Irina Filippi, Wayne C. Drevets, Hans van Bokhoven, Miguel E. Rentería, Aiden Corvin, Ryota Kanai, Kristel R. van Eijk, Andrew M. McIntosh, Jouke-Jan Hottenga, Roberto Toro, Lavinia Athanasiu, Joanna M. Wardlaw, Thomas H. Mosley, Mina Ryten, Meike W. Vernooij, Michelle Luciano, Joshua L. Roffman, Rebecca F. Gottesman, Dhananjay Vaidya, Ryota Hashimoto, Mar Matarin, Adaikalavan Ramasamy, Jerome I. Rotter, Ryan L. Muetzel, Konstantinos Arfanakis, Theo G.M. van Erp, Ganesh Chauhan, Xinmin Liu, Tomáš Paus, Emma Sprooten, Christiane Wolf, David S. Knopman, Manon Bernard, Zdenka Pausova, Bryan J. Traynor, Maria C. Valdés Hernández, Robert C. Green, Russell Thomson, Ravi Duggirala, Lisa R. Yanek, Luigi Ferrucci, Bing Xu, Thomas D. Dyer, Thomas H. Wassink, Eric Westman, Jennifer S. Richards, Phil H. Lee, Benno Pütz, Mark R. Cookson, Benedicto Crespo-Facorro, Natalie A. Royle, Bernd Kraemer, Katrin Hegenscheid, Francis J. McMahon, Tatiana Foroud, M. Kamran Ikram, Myriam Fornage, Nanda Rommelse, Saima Hilal, Perminder S. Sachdev, Qiang Chen, Najaf Amin, Lenore J. Launer, Norbert Hosten, Guillén Fernández, Simone Reppermund, Ashley Beecham, Dirk J. Heslenfeld, Masaki Fukunaga, Cornelia M. van Duijn, Clinton B. Wright, Erik G. Jönsson, Sanjay M. Sisodiya, Oliver Gruber, Christophe Tzourio, André G. Uitterlinden, Robert Johnson, Jaap Oosterlaan, Bernard Mazoyer, H. Ronald Zielke, Stephanie Le Hellard, Jingyun Yang, Georg Homuth, Stéphanie Debette, Nicola J. Armstrong, Sarah E. Medland, Henry Brodaty, Beverly G Windham, Gary Donohoe, Rachel M. Brouwer, James T. Becker, Kumar B. Rajan, Daan van Rooij, Thomas W. Mühleisen, Kazutaka Ohi, Peter R. Schofield, Tonya White, Barbara Franke, Unn K. Haukvik, Debra A. Fleischman, J. Raphael Gibbs, Colm McDonald, Anbupalam Thalamuthu, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Keck School of Medicine [Los Angeles], University of Southern California (USC), Boston University School of Medicine (BUSM), Boston University [Boston] (BU), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Johns Hopkins University (JHU), QIMR Berghofer Medical Research Institute, Leiden University Medical Center (LUMC), Radboud University Medical Center [Nijmegen], Institute of Psychiatry, Psychology & Neuroscience, King's College London, King‘s College London, University of Miami Leonard M. Miller School of Medicine (UMMSM), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Greifswald University Hospital, Department of Neurology and Neurosurgery [Montreal], Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada]-McGill University = Université McGill [Montréal, Canada], Royal College of Surgeons in Ireland (RCSI), Umeå University, Illinois Institute of Technology (IIT), Rush University Medical Center [Chicago], University of Edinburgh, Lagos State University (LASU), University of New South Wales [Sydney] (UNSW), Murdoch University, University of Oslo (UiO), Uppsala University, Framingham Heart Study, Boston University [Boston] (BU)-National Heart, Lung, and Blood Institute [Bethesda] (NHLBI), University of Toronto, University of Washington [Seattle], Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], Columbia University Medical Center (CUMC), Columbia University [New York], Pennington Biomedical Research Center, Louisiana State University (LSU), McGill University = Université McGill [Montréal, Canada], Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lieber Institute for Brain Development [Baltimore] (LIBD), University of California [Los Angeles] (UCLA), University of California, Vrije Universiteit Amsterdam [Amsterdam] (VU), Technische Universität Dresden = Dresden University of Technology (TU Dresden), Massachusetts General Hospital [Boston], Neuroimagerie en psychiatrie (U1000), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Sud - Paris 11 (UP11), Maison de Solenn [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], University of Bergen (UiB), Haukeland University Hospital, Johns Hopkins University School of Medicine [Baltimore], Universität Heidelberg [Heidelberg], University of Mississippi Medical Center (UMMC), International Max Planck Research School for Language Sciences (IMPRS ), Max Planck Institute for Psycholinguistics, Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, Language and Genetics Department [Nijmegen], National University of Singapore (NUS), Medical University Graz, Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, Yale University [New Haven], University College of London [London] (UCL), Imperial College London, Structure et Réactivité des Systèmes Moléculaires Complexes (SRSMC), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Center for Translational Research in Systems Neuroscience and Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center, Goettingen 37075, Germany, Medstar Research Institute, Clinical And Experimental Epilepsy, Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia, Department of Biomedicine and the Centre for Integrative Sequencing, Aarhus University [Aarhus], Institute of Human Genetics, University of Bonn, Department of Genomics, Life and Brain Center, Groupe d'imagerie neurofonctionnelle (GIN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Dpt of Psychiatry [New Haven], Yale University School of Medicine, Department of Psychiatry, VU University Medical Center [Amsterdam], Department of Psychology [Minneapolis], University of Minnesota [Twin Cities] (UMN), University of Minnesota System-University of Minnesota System, Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indiana University System-Indiana University System, Indiana University System, Institute of Food & Health, University College Dublin, University College Dublin [Dublin] (UCD), Statistical Genetics Group, Respiratory Epidemiology and Public Health, Imperial College London-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU)-MRC-HPA Centre for Environment and Health, Centro de Investigación Biomédica en Red Salud Mental [Madrid] (CIBER-SAM), Karakter Child and Adolescent Psychiatry University Centre [Nijmegen], Institut Parisien de Chimie Moléculaire (IPCM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), INSERM, Neuroepidemiology U708, Bordeaux, France, Department of Cognitive Sciences [San Diego], University of California [San Diego] (UC San Diego), University of California-University of California, Department of Neurosciences [San Diego], Centre for Advanced Imaging, University of Queensland, Brisbane 4072, Australia, School of Psychology, University of Queensland, Brisbane 4072, Australia, University of Queensland [Brisbane], Queensland Institute of Medical Research, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Department of Genetics, King Faisal Specialist Hospital and Research Centre, Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL, Institute of Neurology [London], Depts of Radiology, University of Twente [Netherlands], Department of Psychiatry and Human Behavior [Irvine], University of California [Irvine] (UCI), Donders Center for Cognitive Neuroimaging, Donders Centre for Cognitive Neuroimaging, Radboud university [Nijmegen]-Radboud university [Nijmegen], Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Department of Psychology [Oslo], Faculty of Social Sciences [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Deutsche Bundesbank, National Institutes of Health [Bethesda] (NIH), General Internal Medicine, Johns Hopkins School of Medicine, Biospective [Montréal], KG Jebsen Centre for Psychosis Research, University of Oslo (UiO)-Institute of Clinical Medicine-Oslo University Hospital [Oslo], Southwest Foundation for Biomedical Research, Department of Psychiatry and National Ageing Research Institute, University of Melbourne, Department of Clinical Genetics, Department of Medical Parasitology and Mycology, School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU)-Tehran University of Medical Siences, Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Departments of Psychiatry, Neurology, and Psychology, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE)-Pennsylvania Commonwealth System of Higher Education (PCSHE), The University of Texas Health Science Center at Houston (UTHealth), Texas Biomedical Research Institute [San Antonio, TX], 849 Department of Human Genetics, Dementia Collaborative Research Centre, Centre for Healthy Brain Ageing, Brain Center Rudolf Magnus, Department of Psychiatry, UMC Utrecht, Utrecht 3584 CX, The Netherlands, Université de Lausanne (UNIL), Department of Psychiatry [Boston], N.I. Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow 119333, Russia, Icahn School of Medicine at Mount Sinai [New York] (MSSM), The Mind Research Network, Department of Electrical and Computer Engineering [Albuquerque] (ECE Department), The University of New Mexico [Albuquerque], Human Genetics Branch, National Institutes of Health [Bethesda] (NIH)-National Institute of Mental Health (NIMH), Division of Molecular and Cellular Therapeutics, Metacohorts Consortium, Division of Medical Genetics, University of Basel (Unibas), Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Cell Biology and Gene Expression Section, National Institute of Health, Bethesda, Neuropsychiatric Genetics Research Group, Trinity College Dublin, Trinity College Dublin-St. James's Hospital, Department of Materials Science & Metallurgy, University of Cambridge [UK] (CAM), Bijvoet Center of Biomolecular Research [Utrecht], Utrecht University [Utrecht], VU University Amsterdam, Program in Translational NeuroPsychiatric Genomics, Brigham and Women's Hospital [Boston], Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA, Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Harvard Medical School [Boston] (HMS), School of Psychology, University of Queensland, Neurology Division, Beaumont Hospital, Dublin 9, Ireland, Beaumont Hospital, Molecular and Cellular Therapeutics, Department of Neurology, Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Laboratory of Neurogenetics, Department of Genomics, Biological Psychology, Neuroscience Campus Amsterdam & EMGO Institute for Health and Care Research, VU University & VU Medical Center, Amsterdam 1081 BT, The Netherlands, Department of Radiology, Mayo Clinic, Department of Medical and Molecular Genetics, South Texas Veterans Health Care System, San Antonio, Texas 78229, USA, Department of Physics, Okayama University, Okayama University, National Institute of Aging, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS), Public Health Genomics Unit, Department of Psychiatry and Psychotherapy, HELIOS Klinikum Stralsund Hanseatic-Greifswald University Hospital, Department of Mathematics, University of Colorado, University of Colorado [Boulder], Icelandic Heart Association, Kopavogur, Iceland., Faculty of Medicine, University of Iceland [Reykjavik], Department of Molecular Neurosciences, Institute of Neurology, UCL, Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University [Osaka], Department of Psychiatry, University of Iowa, University of Iowa [Iowa City], University Medical Center Groningen [Groningen] (UMCG), Neuronal Plasticity / Mouse Behaviour, Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, Tohoku University [Sendai], Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Stony Brook University [SUNY] (SBU), State University of New York (SUNY), Department of Medicine, Clinical Pharmacology Unit, Karolinska University Hospital [Stockholm], Centre for Allergy Research, Karolinska Institutet [Stockholm], Interuniversity Cardiology Institute Netherlands, Institute of Cognitive Neuroscience, School of Psychology, University of Sussex, Brighton BN1 9QH, UK, University of Sussex, Medical University of Łódź (MUL), Mayo Clinic [Rochester], University of Maryland School of Medicine, University of Maryland System-University of Maryland System-University of Maryland [Baltimore County] (UMBC), University of Maryland System, Department of Civil and Structural Engineering, The Hong Kong Polytechnic University [Hong Kong] (POLYU)-The Hong Kong Polytechnic University [Hong Kong] (POLYU), Université de Cergy Pontoise (UCP), Université Paris-Seine, Lymphocyte Cell Biology Unit, Laboratory of Genetics, Laboratoire de Statistique Théorique et Appliquée (LSTA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Psychiatry Institute, Department of Health and Human Services, Department of Life Sciences, Mathematical Sciences Institute (MSI), Australian National University (ANU), Centre for Advanced Imaging, Institute of Gerontology and Geriatrics, Università degli Studi di Perugia (UNIPG), Division of Mental Health and Addiction, Oslo University Hospital [Oslo], Institute of Clinical Medicine [Oslo], Faculty of Medicine [Oslo], Medical Faculty [Mannheim], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Genetic Epidemiology Unit, Université de Toulon - UFR Lettres et Sciences Humaines (UTLN UFR LSH), Université de Toulon (UTLN), Translational Centre for Regenerative Medicine (TRM), Department of Cell Therapy, Universität Leipzig [Leipzig]-Universität Leipzig [Leipzig], Institute of Clinical Chemistry and Laboratory Medicine, Warwick Manufacturing Group [Coventry] (WMG), University of Warwick [Coventry], Department of Statistics [Warwick], Delft University of Technology (TU Delft), Rheinische Friedrich-Wilhelms-Universität Bonn, Department of Health Science, Division of Health and Rehabilitation, Luleå University of Technology (LUT), University Medical Center [Utrecht]-Brain Center Rudolf Magnus, McConnell Brain Imaging Centre (MNI), Departments of Physiology and Nutritional Sciences, University of Toronto, Toronto, Canada, Psychiatry and Human Behavior, University of California, Irvine, California 92617, USA, Group Health Research Institute, Group Health Cooperative, Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health [Mannheim], Medical Faculty [Mannheim]-Medical Faculty [Mannheim], Cedars-Sinai Medical Center, Centre for Healthy Brain Ageing [Sydney], The University of Sydney, Genetics of Mental Illness and Brain Function, Neuroscience Research Australia, Broad Institute [Cambridge], Harvard University [Cambridge]-Massachusetts Institute of Technology (MIT), Department of Medical Biochemistry and Microbiology, Department of Clinical and Experimental Epilepsy, Department of neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland, Department of neurology, University of Eastern Finland-University Hospital of Kuopio-University of Eastern Finland-University Hospital of Kuopio, Stroke and Ageing Research Centre, Southern Clinical School, Department of Medicine, Monash University, Monash University [Melbourne], Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia, University of Tasmania [Hobart, Australia] (UTAS), Institute of Cardiovascular and Medical Sciences [Glasgow], University of Glasgow, Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney 2052, Australia, Department of Epidemiology, Laboratory of Neuro Imaging [Los Angeles] (LONI), University of York [York, UK], Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Genentech, Inc. [San Francisco], Departments of Radiology and of Epidemiology [Rotterdam], Psychiatry and Leiden Institute for Brain and Cognition, Department of Neurology [Rotterdam], Institute for Community Medicine, Berlin School of Mind and Brain [Berlin], Humboldt-Universität zu Berlin, Carver College of Medicine [Iowa City], University of Iowa [Iowa City]-University of Iowa [Iowa City], Centre for Population Health Sciences, Department of Physics [Hong Kong University of Science and Technology], Hong Kong University of Science and Technology (HKUST), Department of Neurobiology, Care Sciences and Society, Research Laboratory for Archaeology & the History of Art, Singapore Eye Research Institute, Singapore National Eye Centre, School of Life Sciences, Arizona State University [Tempe] (ASU), Department of Neurology and Center for Neuroscience, University of California at Davis, Sacramento, University of California [Davis] (UC Davis), Dpt of Pharmacology and Personalised Medicine [Maastricht], Maastricht University [Maastricht], University of Missouri [Columbia] (Mizzou), University of Missouri System, Göttingen Zentrum Geowissenschaften, Georg-August-University [Göttingen], Human Genetics Center, Psychiatry, EMGO - Mental health, Amsterdam Neuroscience - Complex Trait Genetics, Anatomy and neurosciences, Klinische Genetica, MUMC+: DA Klinische Genetica (5), RS: FHML non-thematic output, RS: GROW - School for Oncology and Reproduction, RS: GROW - R4 - Reproductive and Perinatal Medicine, Genetica & Celbiologie, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Chimie du CNRS (INC)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Institut de Chimie du CNRS (INC)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), University of Maryland [Baltimore County] (UMBC), University of Maryland System-University of Maryland System-University of Maryland School of Medicine, Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Universidad de Cantabria, Universiteit Leiden, Radboud University [Nijmegen], University of California (UC), Universität Heidelberg [Heidelberg] = Heidelberg University, Universität Bonn = University of Bonn, [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Yale School of Medicine [New Haven, Connecticut] (YSM), Department of Cognitive Sciences [Univ California San Diego] (CogSci - UC San Diego), University of California (UC)-University of California (UC), Department of Neurosciences [Univ California San Diego] (Neuro - UC San Diego), School of Medicine [Univ California San Diego] (UC San Diego), University of California (UC)-University of California (UC)-University of California [San Diego] (UC San Diego), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), King Faisal Specialist Hospital and Research Centre (KFSH & RC), Universiteit Leiden-Universiteit Leiden, University of Twente, University of California [Irvine] (UC Irvine), Radboud University [Nijmegen]-Radboud University [Nijmegen], Centre épigénétique et destin cellulaire (EDC), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Université de Lausanne = University of Lausanne (UNIL), Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Università degli Studi di Perugia = University of Perugia (UNIPG), University Hospital Mannheim | Universitätsmedizin Mannheim, Universität Leipzig-Universität Leipzig, University Hospital Mannheim | Universitätsmedizin Mannheim-University Hospital Mannheim | Universitätsmedizin Mannheim, Harvard University-Massachusetts Institute of Technology (MIT), University of Eastern Finland, Humboldt University Of Berlin, Georg-August-University = Georg-August-Universität Göttingen, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Epidemiology, Child and Adolescent Psychiatry / Psychology, Ophthalmology, Radiology & Nuclear Medicine, Internal Medicine, Neurosciences, Obstetrics & Gynecology, Neurology, EMGO+ - Mental Health, Biological Psychology, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement (Inserm U1167 - RID-AGE - Institut Pasteur), McGill University-McGill University, National Heart, Lung, and Blood Institute [Bethesda] (NHLBI)-Boston University [Boston] (BU), McGill University, Technische Universität Dresden (TUD), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], University of Bergen (UIB), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), University of Minnesota [Twin Cities], Karakter Child and Adolescent Psychiatry University Center Nijmegen, Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut Pasteur [Paris], Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Texas Biomedical Research Institute [San Antonio, Texas], Bijvoet Center of Biomolecular Research, Université Libre de Bruxelles [Bruxelles] (ULB)-Hôpital Erasme (Bruxelles), Okayama University [Okayama], Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Massachusetts Institute of Technology (MIT)-Harvard University [Cambridge], University of Tasmania (UTAS), Humboldt Universität zu Berlin, Department of Physics [Kowloon], University of Missouri [Columbia], Georg-August-Universität Göttingen, and the Alzheimer's Disease Neuroimaging Initiative, EPIGEN, IMAGEN, SYS

Subjects
0301 basic medicine, Netherlands Twin Register (NTR), Genome-wide association study, Disease, methods [Genome-Wide Association Study], Genome-wide association studies, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, Cognition, PARKINSONS-DISEASE, pathology [Brain], genetics [Parkinson Disease], 610 Medicine & health, General Neuroscience, growth & development [Brain], physiology [Cognition], 220 Statistical Imaging Neuroscience, COMMON VARIANTS, Brain, Parkinson Disease, Phenotype, 17Q21.31 MICRODELETION, IGF-I, genetics [Oncogene Protein v-akt], Oncogene Protein v-akt, ALZHEIMERS-DISEASE, HEAD CIRCUMFERENCE, Brain size, genetics [Polymorphism, Single Nucleotide], Medical genetics, GROWTH, Neuroinformatics, medicine.medical_specialty, Neuroscience(all), European Continental Ancestry Group, genetics [Genetic Loci], Biology, Genetic correlation, Polymorphism, Single Nucleotide, 150 000 MR Techniques in Brain Function, Article, White People, 03 medical and health sciences, Image processing, SDG 3 - Good Health and Well-being, ddc:570, medicine, Journal Article, Humans, Genetic Predisposition to Disease, Gene, METAANALYSIS, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Neurology & Neurosurgery, Neuroscience (all), Height, [SCCO.NEUR]Cognitive science/Neuroscience, CONSORTIUM, Development of the nervous system, 1702 Cognitive Science, 030104 developmental biology, Genetic Loci, Human genome, BRAIN SIZE, 1109 Neurosciences, genetics [Phosphatidylinositol 3-Kinases], Neuroscience, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract

Contains fulltext : 165723pub.pdf (Publisher’s version ) (Closed access) Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (rhogenetic = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.

Published
2016
Full Text
View/download PDF

49. Common genetic variants influence human subcortical brain structures

Author

Hibar, Derrek P, Stein, Jason L, Aribisala, Benjamin S, de Zubicaray, Greig I, Dillman, Allissa, Duggirala, Ravi, Dyer, Thomas D, Erk, Susanne, Fedko, Iryna O, Ferrucci, Luigi, Foroud, Tatiana M, Fox, Peter T, Fukunaga, Masaki, Armstrong, Nicola J, Gibbs, J Raphael, Göring, Harald H H, Green, Robert C, Guelfi, Sebastian, Hansell, Narelle K, Hartman, Catharina A, Hegenscheid, Katrin, Heinz, Andreas, Hernandez, Dena G, Heslenfeld, Dirk J, Bernard, Manon, Hoekstra, Pieter J, Holsboer, Florian, Homuth, Georg, Hottenga, Jouke-Jan, Ikeda, Masashi, Jack, Clifford R, Jenkinson, Mark, Johnson, Robert, Kanai, Ryota, Keil, Maria, Bohlken, Marc M, Kent, Jack W, Kochunov, Peter, Kwok, John B, Lawrie, Stephen M, Liu, Xinmin, Longo, Dan L, McMahon, Katie L, Meisenzahl, Eva, Melle, Ingrid, Mohnke, Sebastian, Boks, Marco P, Montgomery, Grant W, Mostert, Jeanette C, Mühleisen, Thomas W, Nalls, Michael A, Nichols, Thomas E, Nilsson, Lars G, Nöthen, Markus M, Ohi, Kazutaka, Olvera, Rene L, Perez-Iglesias, Rocio, Bralten, Janita, Pike, G Bruce, Potkin, Steven G, Reinvang, Ivar, Reppermund, Simone, Rietschel, Marcella, Romanczuk-Seiferth, Nina, Rosen, Glenn D, Rujescu, Dan, Schnell, Knut, Schofield, Peter R, Brown, Andrew A, Smith, Colin, Steen, Vidar M, Sussmann, Jessika E, Thalamuthu, Anbupalam, Toga, Arthur W, Traynor, Bryan J, Troncoso, Juan, Turner, Jessica A, Valdés Hernández, Maria C, van 't Ent, Dennis, Chakravarty, M Mallar, van der Brug, Marcel, van der Wee, Nic J A, van Tol, Marie-Jose, Veltman, Dick J, Wassink, Thomas H, Westman, Eric, Zielke, Ronald H, Zonderman, Alan B, Ashbrook, David G, Hager, Reinmar, Chen, Qiang, Lu, Lu, McMahon, Francis J, Morris, Derek W, Williams, Robert W, Brunner, Han G, Buckner, Randy L, Buitelaar, Jan K, Cahn, Wiepke, Calhoun, Vince D, Cavalleri, Gianpiero L, Ching, Christopher R K, Crespo-Facorro, Benedicto, Dale, Anders M, Davies, Gareth E, Delanty, Norman, Depondt, Chantal, Djurovic, Srdjan, Drevets, Wayne C, Espeseth, Thomas, Gollub, Randy L, Ho, Beng-Choon, Renteria, Miguel E, Cuellar-Partida, Gabriel, Hoffmann, Wolfgang, Hosten, Norbert, Kahn, René S, Le Hellard, Stephanie, Meyer-Lindenberg, Andreas, Müller-Myhsok, Bertram, Nauck, Matthias, Nyberg, Lars, Pandolfo, Massimo, Penninx, Brenda W J H, den Braber, Anouk, Roffman, Joshua L, Sisodiya, Sanjay M, Smoller, Jordan W, van Bokhoven, Hans, van Haren, Neeltje E M, Völzke, Henry, Walter, Henrik, Weiner, Michael W, Wen, Wei, White, Tonya, Giddaluru, Sudheer, Agartz, Ingrid, Andreassen, Ole A, Blangero, John, Boomsma, Dorret I, Brouwer, Rachel M, Cannon, Dara M, Cookson, Mark R, de Geus, Eco J C, Deary, Ian J, Donohoe, Gary, Goldman, Aaron L, Fernández, Guillén, Fisher, Simon E, Francks, Clyde, Glahn, David C, Grabe, Hans J, Gruber, Oliver, Hardy, John, Hashimoto, Ryota, Hulshoff Pol, Hilleke E, Jönsson, Erik G, Grimm, Oliver, Kloszewska, Iwona, Lovestone, Simon, Mattay, Venkata S, Mecocci, Patrizia, McDonald, Colm, McIntosh, Andrew M, Ophoff, Roel A, Paus, Tomas, Pausova, Zdenka, Ryten, Mina, Guadalupe, Tulio, Sachdev, Perminder S, Saykin, Andrew J, Simmons, Andy, Singleton, Andrew, Soininen, Hilkka, Wardlaw, Joanna M, Weale, Michael E, Weinberger, Daniel R, Adams, Hieab H H, Launer, Lenore J, Hass, Johanna, Seiler, Stephan, Schmidt, Reinhold, Chauhan, Ganesh, Satizabal, Claudia L, Becker, James T, Yanek, Lisa, van der Lee, Sven J, Ebling, Maritza, Fischl, Bruce, Longstreth, W. T., Woldehawariat, Girma, Greve, Douglas, Schmidt, Helena, Nyquist, Paul, Vinke, Louis N, van Duijn, Cornelia M, Xue, Luting, Mazoyer, Bernard, Bis, Joshua C, Gudnason, Vilmundur, Seshadri, Sudha, Holmes, Avram J, Ikram, M Arfan, Initiative, Alzheimer’s Disease Neuroimaging, Consortium, CHARGE, EPIGEN, IMAGEN, SYS, Martin, Nicholas G, Wright, Margaret J, Schumann, Gunter, Franke, Barbara, Hoogman, Martine, Thompson, Paul M, Medland, Sarah E, Weiner, Michael, Aisen, Paul, Petersen, Ronald, Jagust, William, Trojanowki, John Q, Beckett, Laurel, Arias-Vasquez, Alejandro, Janowitz, Deborah, Morris, John, Shaw, Leslie M, Khachaturian, Zaven, Sorensen, Greg, Carrillo, Maria, Kuller, Lew, Raichle, Marc, Paul, Steven, Jia, Tianye, Davies, Peter, Fillit, Howard, Hefti, Franz, Holtzman, Davie, Mesulman, M Marcel, Potter, William, Snyder, Peter, Schwartz, Adam, Montine, Tom, Kim, Sungeun, Thomas, Ronald G, Donohue, Michael, Walter, Sarah, Gessert, Devon, Sather, Tamie, Jiminez, Gus, Harvey, Danielle, Klein, Marieke, Bernstein, Matthew, Fox, Nick, Thompson, Paul, Schuff, Norbert, DeCarli, Charles, Borowski, Bret, Gunter, Jeff, Senjem, Matt, Kraemer, Bernd, Vemuri, Prashanthi, Jones, David, Kantarci, Kejal, Ward, Chad, Koeppe, Robert A, Foster, Norm, Reiman, Eric M, Chen, Kewei, Mathis, Chet, Lee, Phil H, Landau, Susan, Cairns, Nigel J, Householder, Erin, Taylor-Reinwald, Lisa, Trojanowki, J. Q., Shaw, Les, Lee, Virginia M Y, Korecka, Magdalena, Figurski, Michal, Olde Loohuis, Loes M, Crawford, Karen, Neu, Scott, Potkin, Steven, Shen, Li, Faber, Kelley, Nho, Kwangsik, Luciano, Michelle, Thal, Leon, Frank, Richard, Snyder, Peter J, Buckholtz, Neil, Macare, Christine, Albert, Marilyn, Hsiao, John, Kaye, Jeffrey, Quinn, Joseph, Lind, Betty, Carter, Raina, Dolen, Sara, Gutman, Boris A, Schneider, Lon S, Mather, Karen A, Pawluczyk, Sonia, Beccera, Mauricio, Teodoro, Liberty, Spann, Bryan M, Brewer, James, Vanderswag, Helen, Fleisher, Adam, Heidebrink, Judith L, Lord, Joanne L, Desrivières, Sylvane, Mattheisen, Manuel, Mason, Sara S, Albers, Colleen S, Knopman, David, Johnson, Kris, Doody, Rachelle S, Villanueva-Meyer, Javier, Chowdhury, Munir, Rountree, Susan, Dang, Mimi, Stern, Yaakov, Milaneschi, Yuri, Honig, Lawrence S, Bell, Karen L, Ances, Beau, Morris, John C, Carroll, Maria, Leon, Sue, Mintun, Mark A, Schneider, Stacy, Oliver, Angela, Marson, Daniel, Griffith, Randall, Clark, David, Geldmacher, David, Brockington, John, Roberson, Erik, Grossman, Hillel, Mitsis, Effie, deToledo-Morrell, Leyla, Shah, Raj C, Papmeyer, Martina, Duara, Ranjan, Varon, Daniel, Greig, Maria T, Roberts, Peggy, Onyike, Chiadi, D'Agostino, Daniel, Kielb, Stephanie, Galvin, James E, Pogorelec, Dana M, Ramasamy, Adaikalavan, Cerbone, Brittany, Michel, Christina A, Rusinek, Henry, de Leon, Mony J, Glodzik, Lidia, De Santi, Susan, Doraiswamy, P Murali, Petrella, Jeffrey R, Wong, Terence Z, Arnold, Steven E, Risacher, Shannon L, Karlawish, Jason H, Wolk, David, Smith, Charles D, Jicha, Greg, Hardy, Peter, Sinha, Partha, Oates, Elizabeth, Conrad, Gary, Lopez, Oscar L, Oakley, MaryAnn, Roiz-Santiañez, Roberto, Simpson, Donna M, Porsteinsson, Anton P, Goldstein, Bonnie S, Martin, Kim, Makino, Kelly M, Ismail, M Saleem, Brand, Connie, Mulnard, Ruth A, Thai, Gaby, Mc-Adams-Ortiz, Catherine, Rose, Emma J, Womack, Kyle, Mathews, Dana, Quiceno, Mary, Diaz-Arrastia, Ramon, King, Richard, Weiner, Myron, Martin-Cook, Kristen, DeVous, Michael, Levey, Allan I, Lah, James J, Salami, Alireza, Cellar, Janet S, Burns, Jeffrey M, Anderson, Heather S, Swerdlow, Russell H, Apostolova, Liana, Tingus, Kathleen, Woo, Ellen, Silverman, Daniel H S, Lu, Po H, Bartzokis, George, Sämann, Philipp G, Graff-Radford, Neill R, Parfitt, Francine, Kendall, Tracy, Johnson, Heather, Farlow, Martin R, Hake, Ann Marie, Matthews, Brandy R, Herring, Scott, Hunt, Cynthia, van Dyck, Christopher H, Jahanshad, Neda, Schmaal, Lianne, Carson, Richard E, MacAvoy, Martha G, Chertkow, Howard, Bergman, Howard, Hosein, Chris, Black, Sandra, Stefanovic, Bojana, Caldwell, Curtis, Hsiung, Yuek Robin, Feldman, Howard, Schork, Andrew J, Mudge, Benita, Assaly, Michele, Kertesz, Andrew, Rogers, John, Trost, Dick, Bernick, Charles, Munic, Donna, Kerwin, Diana, Mesulam, Marek-Marsel, Lipowski, Kristine, Shin, Jean, Wu, Chuang-Kuo, Johnson, Nancy, Sadowsky, Carl, Martinez, Walter, Villena, Teresa, Turner, Raymond Scott, Johnson, Kathleen, Reynolds, Brigid, Sperling, Reisa A, Johnson, Keith A, Strike, Lachlan T, Marshall, Gad, Frey, Meghan, Yesavage, Jerome, Taylor, Joy L, Lane, Barton, Rosen, Allyson, Tinklenberg, Jared, Sabbagh, Marwan N, Belden, Christine M, Jacobson, Sandra A, Teumer, Alexander, Sirrel, Sherye A, Kowall, Neil, Killiany, Ronald, Budson, Andrew E, Norbash, Alexander, Johnson, Patricia Lynn, Obisesan, Thomas O, Wolday, Saba, Allard, Joanne, Lerner, Alan, van Donkelaar, Marjolein M J, Ogrocki, Paula, Hudson, Leon, Fletcher, Evan, Carmichael, Owen, Olichney, John, Kittur, Smita, Borrie, Michael, Lee, T-Y, Bartha, Rob, van Eijk, Kristel R, Johnson, Sterling, Asthana, Sanjay, Carlsson, Cynthia M, Preda, Adrian, Nguyen, Dana, Tariot, Pierre, Reeder, Stephanie, Bates, Vernice, Walters, Raymond K, Capote, Horacio, Rainka, Michelle, Scharre, Douglas W, Kataki, Maria, Adeli, Anahita, Zimmerman, Earl A, Celmins, Dzintra, Brown, Alice D, Pearlson, Godfrey D, Blank, Karen, Westlye, Lars T, Anderson, Karen, Santulli, Robert B, Kitzmiller, Tamar J, Schwartz, Eben S, Sink, Kaycee M, Williamson, Jeff D, Garg, Pradeep, Watkins, Franklin, Ott, Brian R, Querfurth, Henry, Whelan, Christopher D, Tremont, Geoffrey, Salloway, Stephen, Malloy, Paul, Correia, Stephen, Rosen, Howard J, Miller, Bruce L, Mintzer, Jacobo, Spicer, Kenneth, Bachman, David, Finger, Elizabether, Toro, Roberto, Winkler, Anderson M, Pasternak, Stephen, Rachinsky, Irina, Drost, Dick, Pomara, Nunzio, Hernando, Raymundo, Sarrael, Antero, Schultz, Susan K, Ponto, Laura L Boles, Zwiers, Marcel P, Shim, Hyungsub, Smith, Karen Elizabeth, Relkin, Norman, Chaing, Gloria, Raudin, Lisa, Smith, Amanda, Fargher, Kristin, Raj, Balebail Ashok, Amin, Najaf, Becker, Diane, Alhusaini, Saud, Beiser, Alexa, Debette, Stéphanie, DeStefano, Anita, Hofer, Edith, Hofman, Albert, Niessen, Wiro J, Smith, Albert, Tzourio, Christophe, Vaidya, Dhananjay, Athanasiu, Lavinia, Vernooij, Meike W, Goldstein, David B, Heinzen, Erin L, Shianna, Kevin, Radtke, Rodney, Ottmann, Ruth, Albrecht, Lisa, Andrew, Chris, Arroyo, Mercedes, Artiges, Eric, Ehrlich, Stefan, Aydin, Semiha, Bach, Christine, Banaschewski, Tobias, Barbot, Alexis, Barker, Gareth, Boddaert, Nathalie, Bokde, Arun, Bricaud, Zuleima, Bromberg, Uli, Bruehl, Ruediger, Hakobjan, Marina M H, Büchel, Christian, Cachia, Arnaud, Cattrell, Anna, Conrod, Patricia, Constant, Patrick, Crombag, Hans, Czech, Katharina, Dalley, Jeffrey, Decideur, Benjamin, Desrivieres, Sylvane, Hartberg, Cecilie B, Fadai, Tahmine, Flor, Herta, Frouin, Vincent, Fuchs, Birgit, Gallinat, Jürgen, Garavan, Hugh, Briand, Fanny Gollier, Gowland, Penny, Head, Kay, Heinrichs, Bert, Haukvik, Unn K, Heym, Nadja, Hübner, Thomas, Ihlenfeld, Albrecht, Ireland, James, Ittermann, Bernd, Ivanov, Nikolay, Jones, Jennifer, Klaassen, Arno, Heister, Angelien J G A M, Lalanne, Christophe, Lathrop, Mark, Lanzerath, Dirk, Lemaitre, Hervé, Lüdemann, Katharina, Mallik, Catherine, Mangin, Jean-François, Mann, Karl, Mar, Adam, Hoehn, David, Martinot, Jean-Luc, Massicotte, Jessica, Mennigen, Eva, Mesquita de Carvahlo, Fabiana, Mignon, Xavier, Miranda, Ruben, Müller, Kathrin, Nees, Frauke, Nymberg, Charlotte, Paillere, Marie-Laure, Wittfeld, Katharina, Kasperaviciute, Dalia, Pena-Oliver, Yolanda, Poline, Jean-Baptiste, Poustka, Luise, Rapp, Michael, Reed, Laurence, Robert, Gabriel, Reuter, Jan, Liewald, David C M, Ripke, Stephan, Ripley, Tamzin, Robbins, Trevor, Rodehacke, Sarah, Romanowski, Alexander, Ruggeri, Barbara, Schilling, Christina, Schmäl, Christine, Schmidt, Dirk, Lopez, Lorna M, Schneider, Sophia, Schroeder, Markus, Schubert, Florian, Schwartz, Yannick, Smolka, Michael, Sommer, Wolfgang, Spanagel, Rainer, Speiser, Claudia, Spranger, Tade, Stedman, Alicia, Makkinje, Remco R R, Steiner, Sabina, Stephens, Dai, Strache, Nicole, Ströhle, Andreas, Struve, Maren, Subramaniam, Naresh, Theobald, David, Topper, Lauren, Vollstaedt-Klein, Sabine, Walaszek, Bernadeta, Matarin, Mar, Weiß, Katharina, Werts, Helen, Whelan, Robert, Williams, Steve, Yacubian, Juliana, Ziesch, Veronika, Zilbovicius, Monica, Wong, C Peng, Lubbe, Steven, Naber, Marlies A M, Martinez-Medina, Lourdes, Kepa, Agnes, Fernandes, Alinda, Tahmasebi, Amir, Abrahamowicz, Michal, Gaudet, Daniel, Leonard, Gabriel, Perron, Michel, Richer, Louis, Seguin, Jean, McKay, D Reese, Veillette, Suzanne, Needham, Margaret, Nugent, Allison C, Pütz, Benno, Abramovic, Lucija, Royle, Natalie A, Sprooten, Emma, Trabzuni, Daniah, van der Marel, Saskia S L, van Hulzen, Kimm J E, Walton, Esther, Wolf, Christiane, Almasy, Laura, Ames, David, Andersson, Micael, Arepalli, Sampath, Assareh, Amelia A, Bastin, Mark E, Brodaty, Henry, Bulayeva, Kazima B, Carless, Melanie A, Cichon, Sven, Corvin, Aiden, Curran, Joanne E, Czisch, Michael, MUMC+: DA Klinische Genetica (5), RS: GROW - Developmental Biology, RS: GROW - R4 - Reproductive and Perinatal Medicine, Université de Montréal. Faculté de médecine. Département de psychiatrie et d'addictologie, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California (UC)-University of California (UC), QIMR Berghofer Medical Research Institute, Department of Psychiatry, Donders Centre for Neuroscience, Radboud University [Nijmegen]-Radboud University Medical Center [Nijmegen]-Radboud University [Nijmegen]-Radboud University Medical Center [Nijmegen], Department of Human Genetics, Radboud University Medical Center [Nijmegen], Institute of Psychiatry, Psychology & Neuroscience, King's College London, King‘s College London, PRES Sorbonne Paris Cité, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Gènes, Synapses et Cognition (CNRS - UMR3571 ), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Greifswald University Hospital, University Medical Center [Utrecht], European Commission, University of Edinburgh, Lagos State University (LASU), Heriot-Watt University [Edinburgh] (HWU), Unité d'expérimentation sur les Ruminants de Theix, Institut National de la Recherche Agronomique (INRA), Donders Institute for Brain, Cognition and Behaviour, Radboud University [Nijmegen], University of Oslo (UiO), Montreal Neurological Institute and Hospital, McGill University = Université McGill [Montréal, Canada], School of Technical Physics, Xidian University, Dept. of Mechanical Engineering, McMaster University [Hamilton, Ontario], Biological Psychology, Neuroscience Campus Amsterdam & EMGO Institute for Health and Care Research, VU University & VU Medical Center, Amsterdam 1081 BT, The Netherlands, Haukeland University Hospital, University of Bergen (UiB), Physicochimie des Processus de Combustion et de l’Atmosphère - UMR 8522 (PC2A), Université de Lille-Centre National de la Recherche Scientifique (CNRS), Department of Geriatric Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Universität Heidelberg [Heidelberg] = Heidelberg University, Language and Genetics Department [Nijmegen], Max Planck Institute for Psycholinguistics, Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, International Max Planck Research School for Language Sciences (IMPRS ), Georgia Institute of Technology [Atlanta], National Institutes of Health [Bethesda] (NIH), Yale University [New Haven], Massachusetts General Hospital [Boston], Mental Health Sciences Unit, University College of London [London] (UCL), Beijing Normal University (BNU), Indiana University School of Medicine, Indiana University System, Indiana Alzheimer Disease Center, Indiana University System-Indiana University System, Center for Translational Research in Systems Neuroscience and Psychiatry, Department of Psychiatry and Psychotherapy, University Medical Center, Goettingen 37075, Germany, Scottish Fish Immunology Research Centre, School of Biological Sciences, University of Aberdeen, University of California (UC), Medstar Research Institute, Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia, Department of Genomics, Life and Brain Center, Universität Bonn = University of Bonn, Institute of Human Genetics, Department of Biomedicine and the Centre for Integrative Sequencing, Aarhus University [Aarhus], VU University Medical Center [Amsterdam], Respiratory Epidemiology and Public Health, Imperial College London-School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU)-MRC-HPA Centre for Environment and Health, Centro de Investigación Biomédica en Red Salud Mental [Madrid] (CIBER-SAM), Institut Parisien de Chimie Moléculaire (IPCM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Umeå Centre for Functional Brain Imaging (UFBI), Umeå University, Umeå 901 87, Sweden, Aging Research Center [Karolinska Institutet] (ARC ), Stockholm University-Karolinska Institutet [Stockholm], Max Planck Institute of Psychiatry, Max-Planck-Gesellschaft, Department of Neurosciences [Univ California San Diego] (Neuro - UC San Diego), School of Medicine [Univ California San Diego] (UC San Diego), University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC)-University of California [San Diego] (UC San Diego), Department of Cognitive Sciences [Univ California San Diego] (CogSci - UC San Diego), The Hospital for sick children [Toronto] (SickKids), Queensland Institute of Medical Research, School of Psychology, University of Queensland, Brisbane 4072, Australia, University of Queensland [Brisbane], Centre for Advanced Imaging, University of Queensland, Brisbane 4072, Australia, Department of Genomics of Common Disease, Imperial College London, Department of Psychology [Oslo], Faculty of Social Sciences [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Deutsche Bundesbank, Department of Neurology and Neurosurgery [Montreal], McGill University = Université McGill [Montréal, Canada]-McGill University = Université McGill [Montréal, Canada], Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland (RCSI), MetaGenoPolis, Department of Psychiatric Research and Development, Diakonhjemmet Hospital, Oslo 0319, Norway, UCL Institute of Neurology and Epilepsy Society, Department of Medicine, Clinical And Experimental Epilepsy, Dpt of Psychiatry [New Haven], Yale School of Medicine [New Haven, Connecticut] (YSM), Hartford Hospital, Neuropsychiatric Genetics Research Group and Department of Psychiatry, Trinity College Institute of Psychiatry, Trinity College Dublin, Dublin 2, Ireland, Institute of Food & Health, University College Dublin, University College Dublin [Dublin] (UCD), Statistical Genetics Group, State Key Laboratory of Lead Compound Research, WuXi AppTec, Co., Ltd, Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL, Institute of Neurology [London], Department of Genetics, King Faisal Specialist Hospital and Research Centre (KFSH & RC), Centre épigénétique et destin cellulaire (EDC), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Dundee Technopole, CXR Biosciences Ltd, Ninewells Hospital and Medical School, Biomedical Research Centre, University of Dundee, Southwest Foundation for Biomedical Research, Department of Psychiatry and National Ageing Research Institute, University of Melbourne, Department of Clinical Genetics, Department of Medical Parasitology and Mycology, School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU)-Tehran University of Medical Siences, Centre for Healthy Brain Ageing, University of New South Wales [Sydney] (UNSW), Dementia Collaborative Research Centre, N.I. Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow 119333, Russia, Texas Biomedical Research Institute [San Antonio, TX], Institute of Neuroscience and Medicine (INM-1), Research Center Juelich, Division of Medical Genetics, University of Basel (Unibas), Trinity College Dublin-St. James's Hospital, Neuropsychiatric Genetics Research Group, Trinity College Dublin, Department of Materials Science & Metallurgy, University of Cambridge [UK] (CAM), Bijvoet Center of Biomolecular Research [Utrecht], Utrecht University [Utrecht], School of Psychology, University of Queensland, Laboratory of Neurogenetics, The University of Texas Health Science Center at Houston (UTHealth), Department of Genomics, Department of Medical and Molecular Genetics, South Texas Veterans Health Care System, San Antonio, Texas 78229, USA, Biofunctional Imaging, Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan, Public Health Genomics Unit, Department of Biomolecular Engineering, Rheinische Friedrich-Wilhelms-Universität Bonn, Estación Experimental de Pastos y Forrajes 'Indio Hatuey', University Medical Center Groningen [Groningen] (UMCG), Neuronal Plasticity / Mouse Behaviour, Interfaculty Institute for Genetics and Functional Genomics, Universität Greifswald - University of Greifswald, Department of Psychiatry, Fujita Health University School of Medicine, Toyoake 470-1192, Japan, Department of Radiology, Mayo Clinic, Department of Clinical Neurology [Oxford], University of Oxford-FMRIB Centre- John Radcliffe Hospital [Oxford University Hospital], University of Maryland School of Medicine, University of Maryland System, University of Sussex, Institute of Cognitive Neuroscience, United Kingdom Met Office [Exeter], University of Maryland [Baltimore County] (UMBC), University of Maryland System-University of Maryland System-University of Maryland School of Medicine, Department of Civil and Structural Engineering, The Hong Kong Polytechnic University [Hong Kong] (POLYU)-The Hong Kong Polytechnic University [Hong Kong] (POLYU), Columbia University Irving Medical Center (CUIMC), Lymphocyte Cell Biology Unit, Laboratory of Genetics, Centre for Advanced Imaging, Psychiatry and Psychotherapy, KG Jebsen Centre for Psychosis Research, University of Oslo (UiO)-Institute of Clinical Medicine-Oslo University Hospital [Oslo], Division of Mental Health and Addiction, Oslo University Hospital [Oslo], Institute of Clinical Medicine [Oslo], Faculty of Medicine [Oslo], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Genetic Epidemiology Unit, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Department of Statistics [Warwick], University of Warwick [Coventry], Osaka University [Osaka], Institute of Psychiatry, King’s College London, London SE5 8AF, UK, University of Calgary, Psychiatry and Human Behavior, University of California, Irvine, California 92617, USA, University of California [Irvine] (UC Irvine), Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health [Mannheim], University Hospital Mannheim | Universitätsmedizin Mannheim-University Hospital Mannheim | Universitätsmedizin Mannheim, Space and Naval Warfare Systems Center, Klinik für Psychiatrie, Martin-Luther-University Halle-Wittenberg, Department of Psychiatry, Division of Medical Psychology, Genetics of Mental Illness and Brain Function, Neuroscience Research Australia, Développement et amélioration des plantes (UMR DAP), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Centre for Healthy Brain Ageing, School of Psychiatry, University of New South Wales, Sydney 2052, Australia, Laboratory of Neuro Imaging [Los Angeles] (LONI), Departamento de Física Aplicada, Universidade de Vigo, Georgia State University, University System of Georgia (USG), Genentech, Inc. [San Francisco], Psychiatry and Leiden Institute for Brain and Cognition, Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Universiteit Leiden, Carver College of Medicine [Iowa City], University of Iowa [Iowa City]-University of Iowa [Iowa City], Department of Neurobiology, Care Sciences and Society, Karolinska Institutet [Stockholm], University of Manchester [Manchester], The University of Tennessee Health Science Center [Memphis] (UTHSC), iangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Medical College of Nantong University, Nantong 226001, China, Centre for Ultrahigh Bandwidth Devices for Optical Systems (CUDOS), Macquarie University, Cognitive Neuroscience Laboratory (CNL), Harvard University, Donders Center for Cognitive Neuroimaging, Donders Centre for Cognitive Neuroimaging, Radboud University [Nijmegen]-Radboud University [Nijmegen], Icahn School of Medicine at Mount Sinai [New York] (MSSM), The Mind Research Network, Department of Electrical and Computer Engineering [Albuquerque] (ECE Department), The University of New Mexico [Albuquerque], Division of Molecular and Cellular Therapeutics, Scottish Association for Marine Science (SAMS), Structural Biology Laboratory, Department of Chemistry, University of York, Neurology Division, Beaumont Hospital, Dublin 9, Ireland, Beaumont Hospital, Department of Neurology, Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB)-Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Deparment of Medical Genetics, Human Genetics Branch, National Institutes of Health [Bethesda] (NIH)-National Institute of Mental Health (NIMH), Athinoula A. Martinos Center for Biomedical Imaging, Harvard Medical School [Boston] (HMS)-Massachusetts General Hospital [Boston], Department of Psychiatry, University of Iowa, University of Iowa [Iowa City], Institute for Community Medicine, Department Epidemiology of Health Care and Community Health, Translational Centre for Regenerative Medicine (TRM), Department of Cell Therapy, Universität Leipzig-Universität Leipzig, Institute of Clinical Chemistry and Laboratory Medicine, Department of Health Science, Division of Health and Rehabilitation, Luleå University of Technology (LUT), Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Psychiatric and Neurodevelopmental Genetics Unit, 849 Department of Human Genetics, Institute for Community Medicine, Institute for Energy Systems and Thermodynamics, Renyi Institute, Neuropsychiatric Institute, Prince of Wales Hospital, Randwick, NSW, Department of Child and Adolescent Psychiatry, Erasmus University Medical Centre, Rotterdam 3000 CB, The Netherlands, Department of Radiology, Erasmus University Medical Centre, Rotterdam 3015 CN, The Netherlands, Vrije Universiteit Amsterdam [Amsterdam] (VU), Cell Biology and Gene Expression Section, National Institute of Health, Bethesda, Dept of Psychology, Laboratoire de Recherche Magellan, Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon-Institut d'Administration des Entreprises (IAE) - Lyon, Institut de Socio-économie des Entreprises et des ORganisations (ISEOR), Institut de socio-économie des entreprises et des organisations, Department of Psychiatry and Psychotherapy, HELIOS Klinikum Stralsund Hanseatic-Greifswald University Hospital, Laboratoire d'Informatique de Grenoble (LIG), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS), Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Centre for Allergy Research, Department of Medicine, Clinical Pharmacology Unit, Karolinska University Hospital [Stockholm], Medical University of Łódź (MUL), Psychiatry Institute, Department of Health and Human Services, Institute of Gerontology and Geriatrics, Università degli Studi di Perugia = University of Perugia (UNIPG), Commonwealth Scientific and Industrial Research Organisation [Canberra] (CSIRO), Australian Centre for Research into Injury in Sport and its Prevention, Monash University [Clayton], University Medical Center [Utrecht]-Brain Center Rudolf Magnus, School of Psychology [Nottingham], University of Nottingham, UK (UON), McConnell Brain Imaging Centre (MNI), SickKids - The Hospital for sick children, European Centre for Medium-Range Weather Forecasts (ECMWF), University of Eastern Finland, Centre for Population Health Sciences, Lieber Institute for Brain Development [Baltimore] (LIBD), Johns Hopkins University (JHU), Institut Gilbert-Laustriat : Biomolécules, Biotechnologie, Innovation Thérapeutique, Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique (CNRS), Department of Neurology, Clinical Division of Neurogeriatrics, Medical University Graz, Graz 8010, Austria, Austrian Institute of Technology [Vienna] (AIT), INSERM Research Center for Epidemiology and Biostatistics (U897) Team Neuroepidemiology, Bordeaux, France College of Health Sciences, University of Bordeaux, Bordeaux, France, INSERM, Neuroepidemiology U708, Bordeaux, France, Karlsruhe Institute of Technology (KIT), General Internal Medicine, Johns Hopkins School of Medicine, Johns Hopkins University School of Medicine [Baltimore], Harvard Medical School [Boston] (HMS), Computer Science and Artificial Intelligence Laboratory [Cambridge] (CSAIL), Massachusetts Institute of Technology (MIT), University of Washington [Seattle], Department of Physics [Stockholm], Stockholm University, Center for Medical Systems Biology, Netherlands Genomics Initiative, Leiden University Medical Center, Leiden, The Netherlands, Netherlands Consortium for Healthy Ageing, Leiden, The Netherlands, Boston University [Boston] (BU), Groupe d'Imagerie Neurofonctionnelle (GIN - UMR 5296), Service NEUROSPIN (NEUROSPIN), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Faculty of Medicine, University of Iceland [Reykjavik], Icelandic Heart Association, Kopavogur, Iceland., Boston University School of Medicine (BUSM), Laboratoire d'Ingénierie des Matériaux de Bretagne (LIMATB), Université de Bretagne Sud (UBS)-Université de Brest (UBO)-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université de Brest (UBO), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], University of California-University of California, Radboud university [Nijmegen]-Radboud University Medical Center [Nijmegen]-Radboud university [Nijmegen]-Radboud University Medical Center [Nijmegen], Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Gènes, Synapses et Cognition, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), UE 1354 Unité d'expérimentation sur les Ruminants de Theix, Institut National de la Recherche Agronomique (INRA)-Physiologie Animale et Systèmes d'Elevage (PHASE), Institut National de la Recherche Agronomique (INRA)-Unité d'expérimentation sur les Ruminants de Theix (UE RT), Radboud university [Nijmegen], McGill University, University of Bergen (UIB), Universität Heidelberg [Heidelberg], Beijing Normal University, University of California, University of Bonn, Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC), Department of Neurosciences [San Diego], Department of Cognitive Sciences [San Diego], The Hospital for Sick Children, University of Toronto, Toronto M5G 1X8, Canada, McGill University-McGill University, US 1367 MetaGénoPolis, Institut National de la Recherche Agronomique (INRA)-Département Microbiologie et Chaîne Alimentaire (MICA), Institut National de la Recherche Agronomique (INRA)-MetaGénoPolis (MGP), Yale University School of Medicine, King Faisal Specialist Hospital and Research Centre, Centre épigénétique et destin cellulaire (EDC (UMR_7216)), Texas Biomedical Research Institute [San Antonio, Texas], Bijvoet Center of Biomolecular Research, Academic Unit for Psychiatry of Old Age, University of Melbourne, Melbourne 3101, Australia, Department of Genomics, Life & Brain Center, University of Bonn, Bonn D-53127, Germany, University of Oxford [Oxford]-FMRIB Centre- John Radcliffe Hospital [Oxford University Hospital], School of Psychology, University of Sussex, Brighton BN1 9QH, UK, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Department of Neurology [University of Calgary], Department of Clinical Neuroscience [University of Calgary], University of California [Irvine] (UCI), Medical Faculty [Mannheim]-Medical Faculty [Mannheim], Centre National de la Recherche Scientifique (CNRS)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Recherche Agronomique (INRA)-Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), Universidate de Vigo, Harvard University [Cambridge], Radboud university [Nijmegen]-Radboud university [Nijmegen], Université Libre de Bruxelles [Bruxelles] (ULB)-Hôpital Erasme (Bruxelles), Universität Leipzig [Leipzig]-Universität Leipzig [Leipzig], Centre de Recherche Magellan, Institut d'Administration des Entreprises (IAE) - Lyon-Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon, Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP)-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Università degli Studi di Perugia (UNIPG), Department of neurology, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland, Department of neurology, University of Eastern Finland-University Hospital of Kuopio-University of Eastern Finland-University Hospital of Kuopio, Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS)-Service NEUROSPIN (NEUROSPIN), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université de Bretagne Sud (UBS)-Institut Brestois du Numérique et des Mathématiques (IBNM), Université de Brest (UBO)-Université de Brest (UBO)-Université de Brest (UBO), The Alzheimer’s Disease Neuroimaging Initiative, The CHARGE Consortium, EPIGEN, IMAGEN, SYS, Radboud University Medical Center [Nijmegen]-Radboud university [Nijmegen]-Radboud University Medical Center [Nijmegen]-Radboud university [Nijmegen], Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), FMRIB Centre- John Radcliffe Hospital [Oxford University Hospital]-University of Oxford [Oxford], Massachusetts General Hospital [Boston]-Harvard Medical School [Boston] (HMS), Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP )-Institut National Polytechnique de Grenoble (INPG)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Life Course Epidemiology (LCE), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut Pasteur [Paris], Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), University of Oxford [Oxford]- John Radcliffe Hospital [Oxford University Hospital]-FMRIB Centre, Neurology, Psychiatry, Anatomy and neurosciences, NCA - Neurobiology of mental health, EMGO - Mental health, NCA - Brain imaging technology, Biological Psychology, Cognitive Psychology, Neuroscience Campus Amsterdam - Neurobiology of Mental Health, Neuroscience Campus Amsterdam - Brain Imaging Technology, EMGO+ - Mental Health, Child and Adolescent Psychiatry / Psychology, Epidemiology, Radiology & Nuclear Medicine, Laboratory of Neuro Imaging, David Geffen School of Medicine, University of California, Los Angeles, California, USA, Donders Centre for Neuroscience, Radboud University Nijmegen Medical Centre, MRC- SGDP Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London SE5 8AF, UK, Génétique humaine et Fonctions cognitives - Human Genetics and Cognitive Functions, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), German Center for Neurodegenerative Diseases (DZNE) Rostock/Greifswald, Greifswald 17487, Germany, Department of Psychiatry, University Medicine Greifswald, Greifswald 17489, Germany, Brain Center Rudolf Magnus, Department of Psychiatry, University Medical Center Utrecht, Utrecht, 3584 CX, The Netherlands, Brain Research Imaging Centre, University of Edinburgh, Edinburgh EH4 2XU, UK, Department of Computer Science, Lagos State University, Lagos, Nigeria, Scottish Imaging Network, A Platform for Scientific Excellence (SINAPSE) Collaboration, Department of Neuroimaging Sciences, University of Edinburgh, Edinburgh EH4 2XU, UK, Heriot-Watt University [Edinburgh] ( HWU ), Institut National de la Recherche Agronomique ( INRA ) -Physiologie Animale et Systèmes d'Elevage ( PHASE ) -Unité d'expérimentation sur les Ruminants de Theix ( UE RT ), Department of Human Genetics, Radboud university medical center, Nijmegen 6500 HB, The Netherlands, Department of Cognitive Neuroscience, Radboud university medical center, Nijmegen 6500 HB, The Netherlands, NORMENT - KG Jebsen Centre, Institute of Clinical Medicine, University of Oslo, Oslo N-0316, Norway, NORMENT - KG Jebsen Centre, Division of Mental Health and Addiction, Oslo University Hospital, Oslo 0424, Norway, Montreal Neurological Institute [Montréal], NORMENT - KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway, Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen 5021, Norway, Physicochimie des Processus de Combustion et de l’Atmosphère - UMR 8522 ( PC2A ), Université de Lille-Centre National de la Recherche Scientifique ( CNRS ), Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen 6525 XD, The Netherlands, International Max Planck Research School for Language Sciences, Nijmegen 6525 XD, The Netherlands, Human Genetics Branch and Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health Intramural Research Program, Bethesda, Maryland 20892, USA, Department of Psychology, Yale University, New Haven, Connecticut 06511, USA, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02115, USA, University College of London [London] ( UCL ), Center for Neuroimaging, Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA, Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA, Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA, Center for Neurobehavioral Genetics, University of California, Los Angeles, California 90095, USA, Université de Bonn, Department of Psychiatry, Neuroscience Campus Amsterdam, VU University Medical Center/GGZ inGeest, Amsterdam 1081 HL, The Netherlands, Division of Psychiatry, Royal Edinburgh Hospital, University of Edinburgh, Edinburgh EH10 5HF, UK, Imperial College London-School of public health-MRC-HPA Centre for Environment and Health, Cibersam (Centro Investigación Biomédica en Red Salud Mental), Madrid 28029, Spain, Institut Parisien de Chimie Moléculaire ( IPCM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Centre National de la Recherche Scientifique ( CNRS ), Aging Research Center [Karolinska Institutet] ( ARC ), Max Planck Institute of Psychiatry, Munich 80804, Germany, Multimodal Imaging Laboratory, Department of Neurosciences, University of California, San Diego, California 92093, USA, Department of Cognitive Sciences, University of California, San Diego, California 92161, USA, Genetic Epidemiology Laboratory, Queensland Institute of Medical Research, Brisbane, Queensland, Australia, Department of Psychology, University of Oslo, Oslo 0373, Norway, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal H3A 2B4, Canada, Molecular and Cellular Therapeutics, The Royal College of Surgeons, Dublin 2, Ireland, Institut National de la Recherche Agronomique ( INRA ) -MetaGénoPolis ( MGP ) -Microbiologie et Chaîne Alimentaire ( MICA ), UCL Institute of Neurology, London, United Kingdom and Epilepsy Society, London WC1N 3BG, UK, Department of Medicine, Imperial College London, London W12 0NN, UK, Centre for Cognitive Ageing and Cognitive Epidemiology, Psychology, University of Edinburgh, Edinburgh EH8 9JZ, UK, Yale School of Medicine, Olin Neuropsychiatric Research Center, Institute of Living, Hartford Hospital, Hartford, Connecticut 06106, USA, University College Dublin [Dublin] ( UCD ), Reta Lila Weston Institute and Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3BG, UK, Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia, Centre épigénétique et destin cellulaire ( EDC ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), School of public health-Tehran University of Medical Siences, University of New South Wales [Sydney] ( UNSW ), Texas Biomedical Research Institute, San Antonio, Texas 78245, USA, Institute of Neuroscience and Medicine ( INM-1 ), University of Basel ( Unibas ), Cambridge University, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA, University of Texas Health Science Center, San Antonio, Texas 78229, USA, Clinical Research Branch, National Institute on Aging, Baltimore, Maryland 20892, USA, Institute of Diagnostic Radiology and Neuroradiology, University Medicine Greifswald, Greifswald 17475, Germany, University Medical Center Groningen, University of Groningen, University of Greifswald, Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA, NICHD Brain and Tissue Bank for Developmental Disorders, University of Maryland Medical School, Baltimore, Maryland 21201, USA, nstitute of Cognitive Neuroscience, University College London, London WC1N 3AR, UK, Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland, Baltimore, Maryland 21201, USA, Department of Pathology and Cell Biology, Columbia University Medical Center, New York 10032, USA, Lymphocyte Cell Biology Unit, Laboratory of Genetics, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA, University of Oslo ( UiO ) -Institute of Clinical Medicine-Oslo University Hospital, Oslo University Hospital, Institute of Clinical Medicine, University of Oslo ( UiO ) -European Network of Bipolar Research Expert Centers (ENBREC) Group, Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, CCM, Berlin 10117, Germany, Erasmus MC, Laboratory of Neurogenetics, Intramural Research Program, National Institute on Aging, National Institutes of Health (NIH), Bethesda, Maryland, USA, Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA, Central Institute of Mental Health, UMR 1098 Développement et Amélioration des Plantes, Institut National de la Recherche Agronomique ( INRA ) -Université Montpellier 2 - Sciences et Techniques ( UM2 ) -MontpellierSupAgro ( MontpellierSupAgro ) -Génétique et amélioration des plantes ( G.A.P. ) -Développement et Amélioration des Plantes ( DAP ), Laboratory of Neuro Imaging [Los Angeles] ( LONI ), University of California at Los Angeles [Los Angeles] ( UCLA ), Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh EH4 2XU, UK, Genentech, South San Francisco, California 94080, USA, Psychiatry and Leiden Institute for Brain and Cognition, Leiden University Medical Center, Leiden 2333 ZA, The Netherlands, LUMC, Carver College of Medicine, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm SE-141 83, Sweden, Behavioral Epidemiology Section, National Institute on Aging Intramural Research Program, Baltimore, Maryland 20892, USA, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, UK, Center for Integrative and Translational Genomics, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA, Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA, Centre Interlangues - Texte, Image, Langage ( TIL ), Université de Bourgogne ( UB ), Centre for Ultrahigh Bandwidth Devices for Optical Systems ( CUDOS ), Icahn School of Medicine at Mount Sinai [New York], The Mind Research Network & LBERI, Albuquerque, New Mexico 87106, USA, Department of ECE, University of New Mexico, Albuquerque, New Mexico 87131, USA, Scottish Association for Marine Science ( SAMS ), Department of Neurology, Hopital Erasme, Universite Libre de Bruxelles, Brussels 1070, Belgium, National Institutes of Health ( NIH ) -National Institute of Mental Health (NIMH), Harvard Medical School [Boston] ( HMS ) -Massachusetts General Hospital [Boston], Department of Psychiatry, University of Iowa, Iowa City, Iowa 52242, USA, Luleå University of Technology ( LUT ), Broad Institute of MIT and Harvard, Massachusetts General Hospital, Vrije Universiteit Amsterdam [Amsterdam] ( VU ), Université Jean Moulin - Lyon III-Institut d'Administration des Entreprises (IAE) - Lyon, Institut de Socio-économie des Entreprises et des ORganisations ( ISEOR ), University Medicine Greifswald,-HELIOS Hospital Stralsund, Laboratoire d'Informatique de Grenoble ( LIG ), Université Pierre Mendès France - Grenoble 2 ( UPMF ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Institut National Polytechnique de Grenoble ( INPG ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Molecular Research Center for Children’s Mental Development, United Graduate School of Child Development, Osaka University, Osaka 565-0871, Japan, Karolinska University Hospital (Solna), Medical University of Łódź ( MUL ), National Institutes of Health ( NIH ), University of Perugia, Commonwealth Scientific and Industrial Research Organisation, University Medical Center Utrecht-Brain Center Rudolf Magnus, University of Nottingham, UK ( UON ), McConnell Brain Imaging Centre ( MNI ), The Hospital for sick children [Toronto] ( SickKids ), Department of Medical and Molecular Genetics, King’s College London, London SE1 9RT, UK, European Centre for Medium-Range Weather Forecasts ( ECMWF ), Lieber Institute for Brain Development, Baltimore, Maryland 21205, USA, Departments of Psychiatry, Neurology, Neuroscience and the Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA, Université Louis Pasteur - Strasbourg I-Centre National de la Recherche Scientifique ( CNRS ), Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands, Austrian Institute of Technology [Vienna] ( AIT ), Karlsruhe Institute of Technology ( KIT ), General Internal Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA, Department of Radiology, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA, Computer Science and Artificial Intelligence Laboratory [Cambridge] ( CSAIL ), Massachusetts Institute of Technology ( MIT ), Department of Epidemiology, University of Washington, Seattle, Washington, USA, Department of Neurology, University of Washington, Seattle, Washington, USA, Department of Physics, Stockholm University ( Department of Physics, Stockholm University ), Université de Lille, Sciences Humaines et Sociales, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA, Genetic Epidemiology Unit, Department of Epidemiology, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands, Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA, Groupe d'Imagerie Neurofonctionnelle ( GIN - UMR 5296 ), Service NEUROSPIN ( NEUROSPIN ), Direction de Recherche Fondamentale (CEA) ( DRF (CEA) ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) ( DRF (CEA) ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ) -Université de Bordeaux ( UB ), Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, Washington, USA, Faculty of Medicine, University of Iceland, Reykjavik, Iceland, Department of Neurology, Boston University School of Medicine, Framingham Heart Study, Boston, MA, Department of Neurology, Erasmus Medical Center University Medical Center, Rotterdam, The Netherlands, Laboratoire d'Ingénierie des Matériaux de Bretagne ( LIMATB ), Université de Bretagne Sud ( UBS ) -Institut Brestois du Numérique et des Mathématiques ( IBNM ), Université de Brest ( UBO ) -Université de Brest ( UBO ) -Université de Brest ( UBO ), King's College, Department of Psychiatry, Radboud university medical center, Nijmegen 6500 HB, The Netherlands, and Broad Institute of © 2012 Nature America, Inc. All rights reserved. Nature Ge N etics aDV a NCE ONLINE PUBLIC a TION 7 l e t t e r s Harvard and MIT, Cambridge, Massachusetts, US

Subjects
CHROMATIN, Male, Netherlands Twin Register (NTR), Aging, Identification, nervous-system, human geography, SEGMENTATION, Caudate nucleus, Apoptosis, Expression, Genome-wide association study, Striatum, Hippocampal formation, Hippocampus, BASAL GANGLIA, 130 000 Cognitive Neurology & Memory, Basal ganglia, genetics [Gene Expression Regulation, Developmental], Hippocampal, Child, anatomy & histology [Skull], Aged, 80 and over, Genetics, Sex Characteristics, KINECTIN, Genome-wide association, Multidisciplinary, Putamen, Brain, Gene Expression Regulation, Developmental, blood, brain, disease incidence, genetic variation, neurology, Organ Size, Human brain, Middle Aged, organization, Magnetic Resonance Imaging, genetics [Genetic Variation], Chromatin, Dynamics, genetics [Membrane Proteins], medicine.anatomical_structure, genetics [Aging], Anatomy & histology, [ SCCO.NEUR ] Cognitive science/Neuroscience, Female, ddc:500, anatomy & histology [Caudate Nucleus], Neuroinformatics, EXPRESSION, Adult, Adolescent, Evolution, anatomy & histology [Hippocampus], ORGANIZATION, genetics [Genetic Loci], Biology, Article, Young Adult, SDG 3 - Good Health and Well-being, Journal Article, medicine, Humans, GENOME-WIDE ASSOCIATION, General, genetics [Apoptosis], Kinectin, Aged, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], HIPPOCAMPAL, IDENTIFICATION, genetics [Organ Size], [SCCO.NEUR]Cognitive science/Neuroscience, Skull, segmentation, Genetic Variation, Membrane Proteins, NERVOUS-SYSTEM, anatomy & histology [Putamen], Genetic Loci, KTN1 protein, human, Caudate Nucleus, anatomy & histology [Brain], Neuroscience, Genome-Wide Association Study
Abstract

Contains fulltext : 144426.pdf (Publisher’s version ) (Closed access) Contains fulltext : 144426pre.pdf (Author’s version preprint ) (Open Access) The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 x 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction. 6 p.

Published
2015
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results