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Publisher: Oxford University Press   (Total: 370 journals)

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Showing 1 - 200 of 370 Journals sorted alphabetically
Acta Biochimica et Biophysica Sinica     Hybrid Journal   (Followers: 6, SJR: 0.881, h-index: 38)
Adaptation     Hybrid Journal   (Followers: 8, SJR: 0.111, h-index: 4)
Aesthetic Surgery J.     Hybrid Journal   (Followers: 6, SJR: 1.538, h-index: 35)
African Affairs     Hybrid Journal   (Followers: 57, SJR: 1.512, h-index: 46)
Age and Ageing     Hybrid Journal   (Followers: 82, SJR: 1.611, h-index: 107)
Alcohol and Alcoholism     Hybrid Journal   (Followers: 15, SJR: 0.935, h-index: 80)
American Entomologist     Full-text available via subscription   (Followers: 6)
American Historical Review     Hybrid Journal   (Followers: 129, SJR: 0.652, h-index: 43)
American J. of Agricultural Economics     Hybrid Journal   (Followers: 41, SJR: 1.441, h-index: 77)
American J. of Epidemiology     Hybrid Journal   (Followers: 157, SJR: 3.047, h-index: 201)
American J. of Hypertension     Hybrid Journal   (Followers: 18, SJR: 1.397, h-index: 111)
American J. of Jurisprudence     Hybrid Journal   (Followers: 15)
American J. of Legal History     Full-text available via subscription   (Followers: 4, SJR: 0.151, h-index: 7)
American Law and Economics Review     Hybrid Journal   (Followers: 26, SJR: 0.824, h-index: 23)
American Literary History     Hybrid Journal   (Followers: 12, SJR: 0.185, h-index: 22)
Analysis     Hybrid Journal   (Followers: 24)
Annals of Botany     Hybrid Journal   (Followers: 35, SJR: 1.912, h-index: 124)
Annals of Occupational Hygiene     Hybrid Journal   (Followers: 26, SJR: 0.837, h-index: 57)
Annals of Oncology     Hybrid Journal   (Followers: 47, SJR: 4.362, h-index: 173)
Annals of the Entomological Society of America     Full-text available via subscription   (Followers: 8, SJR: 0.642, h-index: 53)
Annals of Work Exposures and Health     Hybrid Journal  
AoB Plants     Open Access   (Followers: 4, SJR: 0.78, h-index: 10)
Applied Economic Perspectives and Policy     Hybrid Journal   (Followers: 19, SJR: 0.884, h-index: 31)
Applied Linguistics     Hybrid Journal   (Followers: 51, SJR: 1.749, h-index: 63)
Applied Mathematics Research eXpress     Hybrid Journal   (Followers: 1, SJR: 0.779, h-index: 11)
Arbitration Intl.     Full-text available via subscription   (Followers: 21)
Arbitration Law Reports and Review     Hybrid Journal   (Followers: 12)
Archives of Clinical Neuropsychology     Hybrid Journal   (Followers: 27, SJR: 0.96, h-index: 71)
Aristotelian Society Supplementary Volume     Hybrid Journal   (Followers: 2, SJR: 0.102, h-index: 20)
Arthropod Management Tests     Hybrid Journal   (Followers: 2)
Astronomy & Geophysics     Hybrid Journal   (Followers: 47, SJR: 0.144, h-index: 15)
Behavioral Ecology     Hybrid Journal   (Followers: 47, SJR: 1.698, h-index: 92)
Bioinformatics     Hybrid Journal   (Followers: 236, SJR: 4.643, h-index: 271)
Biology Methods and Protocols     Hybrid Journal  
Biology of Reproduction     Full-text available via subscription   (Followers: 9, SJR: 1.646, h-index: 149)
Biometrika     Hybrid Journal   (Followers: 19, SJR: 2.801, h-index: 90)
BioScience     Hybrid Journal   (Followers: 28, SJR: 2.374, h-index: 154)
Bioscience Horizons : The National Undergraduate Research J.     Open Access   (Followers: 1, SJR: 0.213, h-index: 9)
Biostatistics     Hybrid Journal   (Followers: 16, SJR: 1.955, h-index: 55)
BJA : British J. of Anaesthesia     Hybrid Journal   (Followers: 141, SJR: 2.314, h-index: 133)
BJA Education     Hybrid Journal   (Followers: 66, SJR: 0.272, h-index: 20)
Brain     Hybrid Journal   (Followers: 61, SJR: 6.097, h-index: 264)
Briefings in Bioinformatics     Hybrid Journal   (Followers: 45, SJR: 4.086, h-index: 73)
Briefings in Functional Genomics     Hybrid Journal   (Followers: 4, SJR: 1.771, h-index: 50)
British J. for the Philosophy of Science     Hybrid Journal   (Followers: 33, SJR: 1.267, h-index: 38)
British J. of Aesthetics     Hybrid Journal   (Followers: 25, SJR: 0.217, h-index: 18)
British J. of Criminology     Hybrid Journal   (Followers: 510, SJR: 1.373, h-index: 62)
British J. of Social Work     Hybrid Journal   (Followers: 79, SJR: 0.771, h-index: 53)
British Medical Bulletin     Hybrid Journal   (Followers: 7, SJR: 1.391, h-index: 84)
British Yearbook of Intl. Law     Hybrid Journal   (Followers: 27)
Bulletin of the London Mathematical Society     Hybrid Journal   (Followers: 3, SJR: 1.474, h-index: 31)
Cambridge J. of Economics     Hybrid Journal   (Followers: 56, SJR: 0.957, h-index: 59)
Cambridge J. of Regions, Economy and Society     Hybrid Journal   (Followers: 9, SJR: 1.067, h-index: 22)
Cambridge Quarterly     Hybrid Journal   (Followers: 10, SJR: 0.1, h-index: 7)
Capital Markets Law J.     Hybrid Journal  
Carcinogenesis     Hybrid Journal   (Followers: 2, SJR: 2.439, h-index: 167)
Cardiovascular Research     Hybrid Journal   (Followers: 11, SJR: 2.897, h-index: 175)
Cerebral Cortex     Hybrid Journal   (Followers: 39, SJR: 4.827, h-index: 192)
CESifo Economic Studies     Hybrid Journal   (Followers: 16, SJR: 0.501, h-index: 19)
Chemical Senses     Hybrid Journal   (Followers: 1, SJR: 1.436, h-index: 76)
Children and Schools     Hybrid Journal   (Followers: 6, SJR: 0.211, h-index: 18)
Chinese J. of Comparative Law     Hybrid Journal   (Followers: 3)
Chinese J. of Intl. Law     Hybrid Journal   (Followers: 21, SJR: 0.737, h-index: 11)
Chinese J. of Intl. Politics     Hybrid Journal   (Followers: 8, SJR: 1.238, h-index: 15)
Christian Bioethics: Non-Ecumenical Studies in Medical Morality     Hybrid Journal   (Followers: 11, SJR: 0.191, h-index: 8)
Classical Receptions J.     Hybrid Journal   (Followers: 17, SJR: 0.1, h-index: 3)
Clinical Infectious Diseases     Hybrid Journal   (Followers: 58, SJR: 4.742, h-index: 261)
Clinical Kidney J.     Open Access   (Followers: 4, SJR: 0.338, h-index: 19)
Community Development J.     Hybrid Journal   (Followers: 24, SJR: 0.47, h-index: 28)
Computer J.     Hybrid Journal   (Followers: 7, SJR: 0.371, h-index: 47)
Conservation Physiology     Open Access   (Followers: 2)
Contemporary Women's Writing     Hybrid Journal   (Followers: 11, SJR: 0.111, h-index: 3)
Contributions to Political Economy     Hybrid Journal   (Followers: 6, SJR: 0.313, h-index: 10)
Critical Values     Full-text available via subscription  
Current Legal Problems     Hybrid Journal   (Followers: 25)
Current Zoology     Full-text available via subscription   (SJR: 0.999, h-index: 20)
Database : The J. of Biological Databases and Curation     Open Access   (Followers: 11, SJR: 1.068, h-index: 24)
Digital Scholarship in the Humanities     Hybrid Journal   (Followers: 12)
Diplomatic History     Hybrid Journal   (Followers: 18, SJR: 0.296, h-index: 22)
DNA Research     Open Access   (Followers: 4, SJR: 2.42, h-index: 77)
Dynamics and Statistics of the Climate System     Open Access   (Followers: 3)
Early Music     Hybrid Journal   (Followers: 14, SJR: 0.124, h-index: 11)
Economic Policy     Hybrid Journal   (Followers: 54, SJR: 2.052, h-index: 52)
ELT J.     Hybrid Journal   (Followers: 25, SJR: 1.26, h-index: 23)
English Historical Review     Hybrid Journal   (Followers: 46, SJR: 0.311, h-index: 10)
English: J. of the English Association     Hybrid Journal   (Followers: 13, SJR: 0.144, h-index: 3)
Environmental Entomology     Full-text available via subscription   (Followers: 11, SJR: 0.791, h-index: 66)
Environmental Epigenetics     Open Access   (Followers: 1)
Environmental History     Hybrid Journal   (Followers: 25, SJR: 0.197, h-index: 25)
EP-Europace     Hybrid Journal   (Followers: 2, SJR: 2.201, h-index: 71)
Epidemiologic Reviews     Hybrid Journal   (Followers: 10, SJR: 3.917, h-index: 81)
ESHRE Monographs     Hybrid Journal  
Essays in Criticism     Hybrid Journal   (Followers: 15, SJR: 0.1, h-index: 6)
European Heart J.     Hybrid Journal   (Followers: 47, SJR: 6.997, h-index: 227)
European Heart J. - Cardiovascular Imaging     Hybrid Journal   (Followers: 9, SJR: 2.044, h-index: 58)
European Heart J. - Cardiovascular Pharmacotherapy     Full-text available via subscription   (Followers: 1)
European Heart J. - Quality of Care and Clinical Outcomes     Hybrid Journal  
European Heart J. Supplements     Hybrid Journal   (Followers: 8, SJR: 0.152, h-index: 31)
European J. of Cardio-Thoracic Surgery     Hybrid Journal   (Followers: 8, SJR: 1.568, h-index: 104)
European J. of Intl. Law     Hybrid Journal   (Followers: 149, SJR: 0.722, h-index: 38)
European J. of Orthodontics     Hybrid Journal   (Followers: 4, SJR: 1.09, h-index: 60)
European J. of Public Health     Hybrid Journal   (Followers: 22, SJR: 1.284, h-index: 64)
European Review of Agricultural Economics     Hybrid Journal   (Followers: 12, SJR: 1.549, h-index: 42)
European Review of Economic History     Hybrid Journal   (Followers: 27, SJR: 0.628, h-index: 24)
European Sociological Review     Hybrid Journal   (Followers: 39, SJR: 2.061, h-index: 53)
Evolution, Medicine, and Public Health     Open Access   (Followers: 11)
Family Practice     Hybrid Journal   (Followers: 12, SJR: 1.048, h-index: 77)
Fems Microbiology Ecology     Hybrid Journal   (Followers: 8, SJR: 1.687, h-index: 115)
Fems Microbiology Letters     Hybrid Journal   (Followers: 20, SJR: 1.126, h-index: 118)
Fems Microbiology Reviews     Hybrid Journal   (Followers: 25, SJR: 7.587, h-index: 150)
Fems Yeast Research     Hybrid Journal   (Followers: 13, SJR: 1.213, h-index: 66)
Foreign Policy Analysis     Hybrid Journal   (Followers: 21, SJR: 0.859, h-index: 10)
Forestry: An Intl. J. of Forest Research     Hybrid Journal   (Followers: 16, SJR: 0.903, h-index: 44)
Forum for Modern Language Studies     Hybrid Journal   (Followers: 6, SJR: 0.108, h-index: 6)
French History     Hybrid Journal   (Followers: 30, SJR: 0.123, h-index: 10)
French Studies     Hybrid Journal   (Followers: 19, SJR: 0.119, h-index: 7)
French Studies Bulletin     Hybrid Journal   (Followers: 10, SJR: 0.102, h-index: 3)
Gastroenterology Report     Open Access   (Followers: 2)
Genome Biology and Evolution     Open Access   (Followers: 10, SJR: 3.22, h-index: 39)
Geophysical J. Intl.     Hybrid Journal   (Followers: 31, SJR: 1.839, h-index: 119)
German History     Hybrid Journal   (Followers: 25, SJR: 0.437, h-index: 13)
GigaScience     Open Access   (Followers: 3)
Global Summitry     Hybrid Journal  
Glycobiology     Hybrid Journal   (Followers: 14, SJR: 1.692, h-index: 101)
Health and Social Work     Hybrid Journal   (Followers: 46, SJR: 0.505, h-index: 40)
Health Education Research     Hybrid Journal   (Followers: 12, SJR: 0.814, h-index: 80)
Health Policy and Planning     Hybrid Journal   (Followers: 21, SJR: 1.628, h-index: 66)
Health Promotion Intl.     Hybrid Journal   (Followers: 20, SJR: 0.664, h-index: 60)
History Workshop J.     Hybrid Journal   (Followers: 27, SJR: 0.313, h-index: 20)
Holocaust and Genocide Studies     Hybrid Journal   (Followers: 23, SJR: 0.115, h-index: 13)
Human Molecular Genetics     Hybrid Journal   (Followers: 9, SJR: 4.288, h-index: 233)
Human Reproduction     Hybrid Journal   (Followers: 79, SJR: 2.271, h-index: 179)
Human Reproduction Update     Hybrid Journal   (Followers: 19, SJR: 4.678, h-index: 128)
Human Rights Law Review     Hybrid Journal   (Followers: 58, SJR: 0.7, h-index: 21)
ICES J. of Marine Science: J. du Conseil     Hybrid Journal   (Followers: 54, SJR: 1.233, h-index: 88)
ICSID Review     Hybrid Journal   (Followers: 9)
ILAR J.     Hybrid Journal   (Followers: 1, SJR: 1.099, h-index: 51)
IMA J. of Applied Mathematics     Hybrid Journal   (SJR: 0.329, h-index: 26)
IMA J. of Management Mathematics     Hybrid Journal   (Followers: 2, SJR: 0.351, h-index: 20)
IMA J. of Mathematical Control and Information     Hybrid Journal   (Followers: 2, SJR: 0.661, h-index: 28)
IMA J. of Numerical Analysis - advance access     Hybrid Journal   (SJR: 2.032, h-index: 44)
Industrial and Corporate Change     Hybrid Journal   (Followers: 8, SJR: 1.37, h-index: 81)
Industrial Law J.     Hybrid Journal   (Followers: 29, SJR: 0.184, h-index: 15)
Information and Inference     Free  
Integrative and Comparative Biology     Hybrid Journal   (Followers: 8, SJR: 1.911, h-index: 90)
Interacting with Computers     Hybrid Journal   (Followers: 10, SJR: 0.529, h-index: 59)
Interactive CardioVascular and Thoracic Surgery     Hybrid Journal   (Followers: 4, SJR: 0.743, h-index: 35)
Intl. Affairs     Hybrid Journal   (Followers: 51, SJR: 1.264, h-index: 53)
Intl. Data Privacy Law     Hybrid Journal   (Followers: 27)
Intl. Health     Hybrid Journal   (Followers: 4, SJR: 0.835, h-index: 15)
Intl. Immunology     Hybrid Journal   (Followers: 3, SJR: 1.613, h-index: 111)
Intl. J. for Quality in Health Care     Hybrid Journal   (Followers: 32, SJR: 1.593, h-index: 69)
Intl. J. of Constitutional Law     Hybrid Journal   (Followers: 59, SJR: 0.613, h-index: 19)
Intl. J. of Epidemiology     Hybrid Journal   (Followers: 126, SJR: 4.381, h-index: 145)
Intl. J. of Law and Information Technology     Hybrid Journal   (Followers: 3, SJR: 0.247, h-index: 8)
Intl. J. of Law, Policy and the Family     Hybrid Journal   (Followers: 28, SJR: 0.307, h-index: 15)
Intl. J. of Lexicography     Hybrid Journal   (Followers: 8, SJR: 0.404, h-index: 18)
Intl. J. of Low-Carbon Technologies     Open Access   (Followers: 1, SJR: 0.457, h-index: 12)
Intl. J. of Neuropsychopharmacology     Open Access   (Followers: 3, SJR: 1.69, h-index: 79)
Intl. J. of Public Opinion Research     Hybrid Journal   (Followers: 8, SJR: 0.906, h-index: 33)
Intl. J. of Refugee Law     Hybrid Journal   (Followers: 32, SJR: 0.231, h-index: 21)
Intl. J. of Transitional Justice     Hybrid Journal   (Followers: 13, SJR: 0.833, h-index: 12)
Intl. Mathematics Research Notices     Hybrid Journal   (Followers: 1, SJR: 2.052, h-index: 42)
Intl. Political Sociology     Hybrid Journal   (Followers: 30, SJR: 1.339, h-index: 19)
Intl. Relations of the Asia-Pacific     Hybrid Journal   (Followers: 17, SJR: 0.539, h-index: 17)
Intl. Studies Perspectives     Hybrid Journal   (Followers: 7, SJR: 0.998, h-index: 28)
Intl. Studies Quarterly     Hybrid Journal   (Followers: 36, SJR: 2.184, h-index: 68)
Intl. Studies Review     Hybrid Journal   (Followers: 17, SJR: 0.783, h-index: 38)
ISLE: Interdisciplinary Studies in Literature and Environment     Hybrid Journal   (Followers: 1, SJR: 0.155, h-index: 4)
ITNOW     Hybrid Journal   (Followers: 2, SJR: 0.102, h-index: 4)
J. of African Economies     Hybrid Journal   (Followers: 15, SJR: 0.647, h-index: 30)
J. of American History     Hybrid Journal   (Followers: 39, SJR: 0.286, h-index: 34)
J. of Analytical Toxicology     Hybrid Journal   (Followers: 13, SJR: 1.038, h-index: 60)
J. of Antimicrobial Chemotherapy     Hybrid Journal   (Followers: 17, SJR: 2.157, h-index: 149)
J. of Antitrust Enforcement     Hybrid Journal   (Followers: 1)
J. of Applied Poultry Research     Hybrid Journal   (Followers: 3, SJR: 0.563, h-index: 43)
J. of Biochemistry     Hybrid Journal   (Followers: 43, SJR: 1.341, h-index: 96)
J. of Chromatographic Science     Hybrid Journal   (Followers: 16, SJR: 0.448, h-index: 42)
J. of Church and State     Hybrid Journal   (Followers: 11, SJR: 0.167, h-index: 11)
J. of Competition Law and Economics     Hybrid Journal   (Followers: 34, SJR: 0.442, h-index: 16)
J. of Complex Networks     Hybrid Journal   (Followers: 1, SJR: 1.165, h-index: 5)
J. of Conflict and Security Law     Hybrid Journal   (Followers: 12, SJR: 0.196, h-index: 15)
J. of Consumer Research     Full-text available via subscription   (Followers: 41, SJR: 4.896, h-index: 121)
J. of Crohn's and Colitis     Hybrid Journal   (Followers: 9, SJR: 1.543, h-index: 37)
J. of Cybersecurity     Hybrid Journal   (Followers: 3)
J. of Deaf Studies and Deaf Education     Hybrid Journal   (Followers: 8, SJR: 0.69, h-index: 36)
J. of Design History     Hybrid Journal   (Followers: 15, SJR: 0.166, h-index: 14)
J. of Economic Entomology     Full-text available via subscription   (Followers: 6, SJR: 0.894, h-index: 76)
J. of Economic Geography     Hybrid Journal   (Followers: 34, SJR: 2.909, h-index: 69)
J. of Environmental Law     Hybrid Journal   (Followers: 23, SJR: 0.457, h-index: 20)
J. of European Competition Law & Practice     Hybrid Journal   (Followers: 19)
J. of Experimental Botany     Hybrid Journal   (Followers: 14, SJR: 2.798, h-index: 163)
J. of Financial Econometrics     Hybrid Journal   (Followers: 21, SJR: 1.314, h-index: 27)
J. of Global Security Studies     Hybrid Journal   (Followers: 2)
J. of Heredity     Hybrid Journal   (Followers: 3, SJR: 1.024, h-index: 76)
J. of Hindu Studies     Hybrid Journal   (Followers: 7, SJR: 0.186, h-index: 3)
J. of Hip Preservation Surgery     Open Access  
J. of Human Rights Practice     Hybrid Journal   (Followers: 20, SJR: 0.399, h-index: 10)
J. of Infectious Diseases     Hybrid Journal   (Followers: 40, SJR: 4, h-index: 209)
J. of Insect Science     Open Access   (Followers: 9, SJR: 0.388, h-index: 31)

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Journal Cover Brain
  [SJR: 6.097]   [H-I: 264]   [61 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0006-8950 - ISSN (Online) 1460-2156
   Published by Oxford University Press Homepage  [370 journals]
  • Potential mechanisms of white matter injury in the acute phase of
           experimental subarachnoid haemorrhage
    • Authors: Wu Y; Peng J, Pang J, et al.
      PubDate: 2017-04-18
      DOI: 10.1093/brain/awx084
       
  • De novo p.T362R mutation in MORC2 causes early onset cerebellar ataxia,
           axonal polyneuropathy and nocturnal hypoventilation
    • Authors: Zanni G; Nardella M, Barresi S, et al.
      Abstract: Sir,
      PubDate: 2017-04-10
      DOI: 10.1093/brain/awx083
       
  • Serotonergic modulation as a pharmacological modality in the treatment of
           Dravet syndrome
    • Authors: de Witte P; Lagae L.
      PubDate: 2017-04-10
      DOI: 10.1093/brain/awx090
       
  • Heterozygous PINK1 p.G411S in rapid eye movement sleep behaviour disorder
    • Authors: Gan-Or Z; Ruskey JA, Spiegelman D, et al.
      Abstract: Sir,
      PubDate: 2017-03-29
      DOI: 10.1093/brain/awx076
       
  • Reply: Heterozygous PINK1 p.G411S in rapid eye movement sleep behaviour
           disorder
    • Authors: Puschmann A; Fiesel FC, Caulfield TR, et al.
      Abstract: Sir,
      PubDate: 2017-03-29
      DOI: 10.1093/brain/awx077
       
  • Corrigendum
    • Abstract: Andreas Puschmann, Fabienne C. Fiesel, Thomas R. Caulfield, Roman Hudec, Maya Ando, Dominika Truban, Xu Hou, Kotaro Ogaki, Michael G. Heckman, Elle D. James, Maria Swanberg, Itzia Jimenez-Ferrer, Oskar Hansson, Grzegorz Opala, Joanna Siuda, Magdalena Boczarska-Jedynak, Andrzej Friedman, Dariusz Koziorowski, Monika Rudzińska-Bar jan, O. Aasly, Timothy Lynch, George D. Mellick, Megha Mohan, Peter A. Silburn, Yanosh Sanotsky, Carles Vilariño-Güell, Matthew J. Farrer, Li Chen, Valina L. Dawson, Ted M. Dawson, Zbigniew K. Wszolek, Owen A. Ross, Wolfdieter Springer. Heterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanism. Brain 2017; 140: 98–117; 10.1093/brain/aww261.
      PubDate: 2017-03-22
      DOI: 10.1093/brain/awx055
       
  • Transdiagnostic neurology: neuropsychiatric symptoms in neurodegenerative
           diseases
    • Authors: Husain M.
      First page: 1535
      Abstract: The development of neurology over the last two decades has been characterized by a trend towards increasing hyper-specialization. Whereas many clinicians in the past felt comfortable dealing with the entire range of neurological disorders, this has now become extremely difficult—most might say, impossible—to achieve with the array of diagnostic and treatment options that have become established in many areas. For patients too, specialist clinics and expert advice have become crucial for their ongoing care. But it is also worth considering the possibility that hyper-specialism comes at a potential cost: loss of the ability to perceive, or even care about, the significance of common symptoms that cross conventional disease boundaries.
      PubDate: 2017-05-24
      DOI: 10.1093/brain/awx115
       
  • Holes in the leaky migraine blood–brain barrier hypothesis?
    • Authors: Moskowitz MA.
      First page: 1537
      Abstract: This scientific commentary refers to ‘Increased brainstem perfusion, but no blood-brain barrier disruption, during attacks of migraine with aura’, by Hougaard et al.. (doi:10.1093/brain/awx089).
      PubDate: 2017-05-24
      DOI: 10.1093/brain/awx099
       
  • Cortical areas needed for choosing actions based on desires
    • Authors: Manohar SG; Akam T.
      First page: 1539
      Abstract: This scientific commentary refers to ‘Selective impairment of goal-directed decision-making following lesions to the human ventromedial prefrontal cortex’, by Reber et al. 2017 (doi:10.1093/brain/awx105).
      PubDate: 2017-05-24
      DOI: 10.1093/brain/awx119
       
  • In vivo imaging of retinal neurodegeneration at the single cell level in
           humans
    • Authors: Herms J; Schön C.
      First page: 1542
      Abstract: This scientific commentary refers to ‘Real-time imaging of single neuronal cell apoptosis in patients with glaucoma’, by Cordeiro et al. (doi:10.1093/brain/awx088).
      PubDate: 2017-05-24
      DOI: 10.1093/brain/awx100
       
  • Drug repurposing to target proteostasis and prevent neurodegeneration:
           accelerating translational efforts
    • Authors: Mercado G; Hetz C.
      First page: 1544
      Abstract: This scientific commentary refers to ‘Repurposed drugs targeting eIF2α-P-mediated translational repression prevent neurodegeneration in mice’, by Halliday et al.. (doi:10.1093/brain/awx074).
      PubDate: 2017-05-24
      DOI: 10.1093/brain/awx107
       
  • Glioblastoma-associated microglia and macrophages: targets for therapies
           to improve prognosis
    • Authors: Poon CC; Sarkar S, Yong V, et al.
      First page: 1548
      Abstract: Glioblastoma is the most common and most malignant primary adult human brain tumour. Diagnosis of glioblastoma carries a dismal prognosis. Treatment resistance and tumour recurrence are the result of both cancer cell proliferation and their interaction with the tumour microenvironment. A large proportion of the tumour microenvironment consists of an inflammatory infiltrate predominated by microglia and macrophages, which are thought to be subverted by glioblastoma cells for tumour growth. Thus, glioblastoma-associated microglia and macrophages are logical therapeutic targets. Their emerging roles in glioblastoma progression are reflected in the burgeoning research into therapeutics directed at their modification or elimination. Here, we review the biology of glioblastoma-associated microglia and macrophages, and model systems used to study these cells in vitro and in vivo. We discuss translation of results using these model systems and review recent advances in immunotherapies targeting microglia and macrophages in glioblastoma. Significant challenges remain but medications that affect glioblastoma-associated microglia and macrophages hold considerable promise to improve the prognosis for patients with this disease.
      PubDate: 2017-02-04
      DOI: 10.1093/brain/aww355
       
  • Hypomorphic mutations in POLR3A are a frequent cause of sporadic and
           recessive spastic ataxia
    • Authors: Minnerop M; Kurzwelly D, Wagner H, et al.
      First page: 1561
      Abstract: Despite extensive efforts, half of patients with rare movement disorders such as hereditary spastic paraplegias and cerebellar ataxias remain genetically unexplained, implicating novel genes and unrecognized mutations in known genes. Non-coding DNA variants are suspected to account for a substantial part of undiscovered causes of rare diseases. Here we identified mutations located deep in introns of POLR3A to be a frequent cause of hereditary spastic paraplegia and cerebellar ataxia. First, whole-exome sequencing findings in a recessive spastic ataxia family turned our attention to intronic variants in POLR3A, a gene previously associated with hypomyelinating leukodystrophy type 7. Next, we screened a cohort of hereditary spastic paraplegia and cerebellar ataxia cases (n = 618) for mutations in POLR3A and identified compound heterozygous POLR3A mutations in ∼3.1% of index cases. Interestingly, >80% of POLR3A mutation carriers presented the same deep-intronic mutation (c.1909+22G>A), which activates a cryptic splice site in a tissue and stage of development-specific manner and leads to a novel distinct and uniform phenotype. The phenotype is characterized by adolescent-onset progressive spastic ataxia with frequent occurrence of tremor, involvement of the central sensory tracts and dental problems (hypodontia, early onset of severe and aggressive periodontal disease). Instead of the typical hypomyelination magnetic resonance imaging pattern associated with classical POLR3A mutations, cases carrying c.1909+22G>A demonstrated hyperintensities along the superior cerebellar peduncles. These hyperintensities may represent the structural correlate to the cerebellar symptoms observed in these patients. The associated c.1909+22G>A variant was significantly enriched in 1139 cases with spastic ataxia-related phenotypes as compared to unrelated neurological and non-neurological phenotypes and healthy controls (P = 1.3 × 10−4). In this study we demonstrate that (i) autosomal-recessive mutations in POLR3A are a frequent cause of hereditary spastic ataxias, accounting for about 3% of hitherto genetically unclassified autosomal recessive and sporadic cases; and (ii) hypomyelination is frequently absent in POLR3A-related syndromes, especially when intronic mutations are present, and thus can no longer be considered as the unifying feature of POLR3A disease. Furthermore, our results demonstrate that substantial progress in revealing the causes of Mendelian diseases can be made by exploring the non-coding sequences of the human genome.
      PubDate: 2017-04-27
      DOI: 10.1093/brain/awx095
       
  • A panel study on patients with dominant cerebellar ataxia highlights the
           frequency of channelopathies
    • Authors: Coutelier M; Coarelli G, Monin M, et al.
      First page: 1579
      Abstract: Autosomal dominant cerebellar ataxias have a marked heterogeneous genetic background, with mutations in 34 genes identified so far. This large amount of implicated genes accounts for heterogeneous clinical presentations, making genotype–phenotype correlations a major challenge in the field. While polyglutamine ataxias, linked to CAG repeat expansions in genes such as ATXN1, ATXN2, ATXN3, ATXN7, CACNA1A and TBP, have been extensively characterized in large cohorts, there is a need for comprehensive assessment of frequency and phenotype of more ‘conventional’ ataxias. After exclusion of CAG/polyglutamine expansions in spinocerebellar ataxia genes in 412 index cases with dominantly inherited cerebellar ataxias, we aimed to establish the relative frequencies of mutations in other genes, with an approach combining panel sequencing and TaqMan® polymerase chain reaction assay. We found relevant genetic variants in 59 patients (14.3%). The most frequently mutated were channel genes [CACNA1A (n = 16), KCND3 (n = 4), KCNC3 (n = 2) and KCNA1 (n = 2)]. Deletions in ITPR1 (n = 11) were followed by biallelic variants in SPG7 (n = 9). Variants in AFG3L2 (n = 7) came next in frequency, and variants were rarely found in STBN2 (n = 2), ELOVL5, FGF14, STUB1 and TTBK2 (n = 1 each). Interestingly, possible risk factor variants were detected in SPG7 and POLG. Clinical comparisons showed that ataxias due to channelopathies had a significantly earlier age at onset with an average of 24.6 years, versus 40.9 years for polyglutamine expansion spinocerebellar ataxias and 37.8 years for SPG7-related forms (P = 0.001). In contrast, disease duration was significantly longer in the former (20.5 years versus 9.3 and 13.7, P=0.001), though for similar functional stages, indicating slower progression of the disease. Of interest, intellectual deficiency was more frequent in channel spinocerebellar ataxias, while cognitive impairment in adulthood was similar among the three groups. Similar differences were found among a single gene group, comparing 23 patients with CACNA1A expansions (spinocerebellar ataxia 6) to 22 patients with CACNA1A point mutations, which had lower average age at onset (25.2 versus 47.3 years) with longer disease duration (18.7 versus 10.9), but lower severity indexes (0.39 versus 0.44), indicating slower progression of the disease. In conclusion, we identified relevant genetic variations in up to 15% of cases after exclusion of polyglutamine expansion spinocerebellar ataxias, and confirmed CACNA1A and SPG7 as major ataxia genes. We could delineate firm genotype–phenotype correlations that are important for genetic counselling and of possible prognostic value.
      PubDate: 2017-04-21
      DOI: 10.1093/brain/awx081
       
  • ATAD3 gene cluster deletions cause cerebellar dysfunction associated with
           altered mitochondrial DNA and cholesterol metabolism
    • Authors: Desai R; Frazier AE, Durigon R, et al.
      First page: 1595
      Abstract: Although mitochondrial disorders are clinically heterogeneous, they frequently involve the central nervous system and are among the most common neurogenetic disorders. Identifying the causal genes has benefited enormously from advances in high-throughput sequencing technologies; however, once the defect is known, researchers face the challenge of deciphering the underlying disease mechanism. Here we characterize large biallelic deletions in the region encoding the ATAD3C, ATAD3B and ATAD3A genes. Although high homology complicates genomic analysis of the ATAD3 defects, they can be identified by targeted analysis of standard single nucleotide polymorphism array and whole exome sequencing data. We report deletions that generate chimeric ATAD3B/ATAD3A fusion genes in individuals from four unrelated families with fatal congenital pontocerebellar hypoplasia, whereas a case with genomic rearrangements affecting the ATAD3C/ATAD3B genes on one allele and ATAD3B/ATAD3A genes on the other displays later-onset encephalopathy with cerebellar atrophy, ataxia and dystonia. Fibroblasts from affected individuals display mitochondrial DNA abnormalities, associated with multiple indicators of altered cholesterol metabolism. Moreover, drug-induced perturbations of cholesterol homeostasis cause mitochondrial DNA disorganization in control cells, while mitochondrial DNA aggregation in the genetic cholesterol trafficking disorder Niemann-Pick type C disease further corroborates the interdependence of mitochondrial DNA organization and cholesterol. These data demonstrate the integration of mitochondria in cellular cholesterol homeostasis, in which ATAD3 plays a critical role. The dual problem of perturbed cholesterol metabolism and mitochondrial dysfunction could be widespread in neurological and neurodegenerative diseases.
      PubDate: 2017-05-24
      DOI: 10.1093/brain/awx094
       
  • A comprehensive analysis of rare genetic variation in amyotrophic lateral
           sclerosis in the UK
    • Authors: Morgan S; Shatunov A, Sproviero W, et al.
      First page: 1611
      Abstract: Amyotrophic lateral sclerosis is a progressive neurodegenerative disease of motor neurons. About 25 genes have been verified as relevant to the disease process, with rare and common variation implicated. We used next generation sequencing and repeat sizing to comprehensively assay genetic variation in a panel of known amyotrophic lateral sclerosis genes in 1126 patient samples and 613 controls. About 10% of patients were predicted to carry a pathological expansion of the C9orf72 gene. We found an increased burden of rare variants in patients within the untranslated regions of known disease-causing genes, driven by SOD1, TARDBP, FUS, VCP, OPTN and UBQLN2. We found 11 patients (1%) carried more than one pathogenic variant (P = 0.001) consistent with an oligogenic basis of amyotrophic lateral sclerosis. These findings show that the genetic architecture of amyotrophic lateral sclerosis is complex and that variation in the regulatory regions of associated genes may be important in disease pathogenesis.
      PubDate: 2017-04-18
      DOI: 10.1093/brain/awx082
       
  • A novel cortical target to enhance hand motor output in humans with spinal
           cord injury
    • Authors: Long J; Federico P, Perez MA.
      First page: 1619
      Abstract: A main goal of rehabilitation strategies in humans with spinal cord injury is to strengthen transmission in spared neural networks. Although neuromodulatory strategies have targeted different sites within the central nervous system to restore motor function following spinal cord injury, the role of cortical targets remain poorly understood. Here, we use 180 pairs of transcranial magnetic stimulation for ∼30 min over the hand representation of the motor cortex at an interstimulus interval mimicking the rhythmicity of descending late indirect (I) waves in corticospinal neurons (4.3 ms; I-wave protocol) or at an interstimulus interval in-between I-waves (3.5 ms; control protocol) on separate days in a randomized order. Late I-waves are thought to arise from trans-synaptic cortical inputs and have a crucial role in the recruitment of spinal motor neurons following spinal cord injury. Motor evoked potentials elicited by transcranial magnetic stimulation, paired-pulse intracortical inhibition, spinal motor neuron excitability (F-waves), index finger abduction force and electromyographic activity as well as a hand dexterity task were measured before and after both protocols in 15 individuals with chronic incomplete cervical spinal cord injury and 17 uninjured participants. We found that motor evoked potentials size increased in spinal cord injury and uninjured participants after the I-wave but not the control protocol for ∼30 to 60 min after the stimulation. Intracortical inhibition decreased and F-wave amplitude and persistence increased after the I-wave but not the control protocol, suggesting that cortical and subcortical networks contributed to changes in corticospinal excitability. Importantly, hand motor output and hand dexterity increased in individuals with spinal cord injury after the I-wave protocol. These results provide the first evidence that late synaptic input to corticospinal neurons may represent a novel therapeutic target for improving motor function in humans with paralysis due to spinal cord injury.
      PubDate: 2017-05-24
      DOI: 10.1093/brain/awx102
       
  • Increased brainstem perfusion, but no blood-brain barrier disruption,
           during attacks of migraine with aura
    • Authors: Hougaard A; Amin FM, Christensen CE, et al.
      First page: 1633
      Abstract: See Moskowitz (doi:10.1093/brain/awx099) for a scientific commentary on this article.The migraine aura is characterized by transient focal cortical disturbances causing dramatic neurological symptoms that are usually followed by migraine headache. It is currently not understood how the aura symptoms are related to the headache phase of migraine. Animal studies suggest that cortical spreading depression, the likely mechanism of migraine aura, causes disruption of the blood–brain barrier and noxious stimulation of trigeminal afferents leading to activation of brainstem nuclei and triggering of migraine headache. We used the sensitive and validated technique of dynamic contrast-enhanced high-field magnetic resonance imaging to simultaneously investigate blood–brain barrier permeability and tissue perfusion in the brainstem (at the level of the lower pons), visual cortex, and brain areas of the anterior, middle and posterior circulation during spontaneous attacks of migraine with aura. Patients reported to our institution to undergo magnetic resonance imaging during the headache phase after presenting with typical visual aura. Nineteen patients were scanned during attacks and on an attack-free day. The mean time from attack onset to scanning was 7.6 h. We found increased brainstem perfusion bilaterally during migraine with aura attacks. Perfusion also increased in the visual cortex and posterior white matter following migraine aura. We found no increase in blood–brain barrier permeability in any of the investigated regions. There was no correlation between blood–brain barrier permeability, brain perfusion, and time from symptom onset to examination or pain intensity. Our findings demonstrate hyperperfusion in brainstem during the headache phase of migraine with aura, while the blood–brain barrier remains intact during attacks of migraine with aura. These data thus contradict the preclinical hypothesis of cortical spreading depression-induced blood–brain barrier disruption as a possible mechanism linking aura and headache.
      PubDate: 2017-04-18
      DOI: 10.1093/brain/awx089
       
  • Inhibition of the P2X7–PANX1 complex suppresses spreading
           depolarization and neuroinflammation
    • Authors: Chen S; Qin T, Seidel JL, et al.
      First page: 1643
      Abstract: Spreading depolarization is a wave of neuronal and glial depolarization. Within minutes after spreading depolarization, the neuronal hemichannel pannexin 1 (PANX1) opens and forms a pore complex with the ligand-gated cation channel P2X7, allowing the release of excitatory neurotransmitters to sustain spreading depolarization and activate neuroinflammation. Here, we explore the hypothesis that the P2X7–PANX1 pore complex is a critical determinant of spreading depolarization susceptibility with important consequences for neuroinflammation and trigeminovascular activation. We found that genetic loss of function or ablation of the P2x7 gene inhibits spreading depolarization. Moreover, pharmacological suppression of the P2X7–PANX1 pore complex inhibits spreading depolarization in mice carrying the human familial hemiplegic migraine type 1 R192Q missense mutation as well as in wild-type mice and rats. Pore inhibitors elevate the electrical threshold for spreading depolarization, and reduce spreading depolarization frequency and amplitude. Pore inhibitors also suppress downstream consequences of spreading depolarization such as upregulation of interleukin-1 beta, inducible nitric oxide synthase and cyclooxygenase-2 in the cortex after spreading depolarization. In addition, they inhibit surrogates for trigeminovascular activation, including expression of calcitonin gene-related peptide in the trigeminal ganglion and c-Fos in the trigeminal nucleus caudalis. Our results are consistent with the hypothesis that the P2X7–PANX1 pore complex is a critical determinant of spreading depolarization susceptibility and its downstream consequences, of potential relevance to its signature disorders such as migraine.
      PubDate: 2017-04-20
      DOI: 10.1093/brain/awx085
       
  • Rare missense mutations in P2RY11 in narcolepsy with cataplexy
    • Authors: Degn M; Dauvilliers Y, Dreisig K, et al.
      First page: 1657
      Abstract: The sleep disorder narcolepsy with cataplexy is characterized by a highly specific loss of hypocretin (orexin) neurons, leading to the hypothesis that the condition is caused by an immune or autoimmune mechanism. All genetic variants associated with narcolepsy are immune-related. Among these are single nucleotide polymorphisms in the P2RY11–EIF3G locus. It is unknown how these genetic variants affect narcolepsy pathogenesis and whether the effect is directly related to P2Y11 signalling or EIF3G function. Exome sequencing in 18 families with at least two affected narcolepsy with cataplexy subjects revealed non-synonymous mutations in the second exon of P2RY11 in two families, and P2RY11 re-sequencing in 250 non-familial cases and 135 healthy control subjects revealed further six different non-synonymous mutations in the second exon of P2RY11 in seven patients. No mutations were found in healthy controls. Six of the eight narcolepsy-associated P2Y11 mutations resulted in significant functional deficits in P2Y11 signalling through both Ca2+ and cAMP signalling pathways. In conclusion, our data show that decreased P2Y11 signalling plays an important role in the development of narcolepsy with cataplexy.
      PubDate: 2017-04-27
      DOI: 10.1093/brain/awx093
       
  • The spectrum of REM sleep-related episodes in children with type 1
           narcolepsy
    • Authors: Antelmi E; Pizza F, Vandi S, et al.
      First page: 1669
      Abstract: Type 1 narcolepsy is a central hypersomnia due to the loss of hypocretin-producing neurons and characterized by cataplexy, excessive daytime sleepiness, sleep paralysis, hypnagogic hallucinations and disturbed nocturnal sleep. In children, close to the disease onset, type 1 narcolepsy has peculiar clinical features with severe cataplexy and a complex admixture of movement disorders occurring while awake. Motor dyscontrol during sleep has never been systematically investigated. Suspecting that abnormal motor control might affect also sleep, we systematically analysed motor events recorded by means of video polysomnography in 40 children with type 1 narcolepsy (20 females; mean age 11.8 ± 2.6 years) and compared these data with those recorded in 22 age- and sex-matched healthy controls. Motor events were classified as elementary movements, if brief and non-purposeful and complex behaviours, if simulating purposeful behaviours. Complex behaviours occurring during REM sleep were further classified as ‘classically-defined’ and ‘pantomime-like’ REM sleep behaviour disorder episodes, based on their duration and on their pattern (i.e. brief and vivid-energetic in the first case, longer and with subcontinuous gesturing mimicking daily life activity in the second case). Elementary movements emerging either from non-REM or REM sleep were present in both groups, even if those emerging from REM sleep were more numerous in the group of patients. Conversely, complex behaviours could be detected only in children with type 1 narcolepsy and were observed in 13 patients, with six having ‘classically-defined’ REM sleep behaviour disorder episodes and seven having ‘pantomime-like’ REM sleep behaviour disorder episodes. Complex behaviours during REM sleep tended to recur in a stereotyped fashion for several times during the night, up to be almost continuous. Patients displaying a more severe motor dyscontrol during REM sleep had also more severe motor disorder during daytime (i.e. status cataplecticus) and more complaints of disrupted nocturnal sleep and of excessive daytime sleepiness. The neurophysiological hallmark of this severe motor dyscontrol during REM sleep was a decreased atonia index. The present study reports for the first time the occurrence of a severe and peculiar motor disorder during REM sleep in paediatric type 1 narcolepsy and confirms the presence of a severe motor dyscontrol in these patients, emerging not only from wakefulness (i.e. status cataplecticus), but also from sleep (i.e. complex behaviours during REM sleep). This is probably related to the acute imbalance of the hypocretinergic system, which physiologically acts by promoting movements during wakefulness and suppressing them during sleep.
      PubDate: 2017-05-01
      DOI: 10.1093/brain/awx096
       
  • Crowdsourcing seizure detection: algorithm development and validation on
           human implanted device recordings
    • Authors: Baldassano SN; Brinkmann BH, Ung H, et al.
      First page: 1680
      Abstract: There exist significant clinical and basic research needs for accurate, automated seizure detection algorithms. These algorithms have translational potential in responsive neurostimulation devices and in automatic parsing of continuous intracranial electroencephalography data. An important barrier to developing accurate, validated algorithms for seizure detection is limited access to high-quality, expertly annotated seizure data from prolonged recordings. To overcome this, we hosted a kaggle.com competition to crowdsource the development of seizure detection algorithms using intracranial electroencephalography from canines and humans with epilepsy. The top three performing algorithms from the contest were then validated on out-of-sample patient data including standard clinical data and continuous ambulatory human data obtained over several years using the implantable NeuroVista seizure advisory system. Two hundred teams of data scientists from all over the world participated in the kaggle.com competition. The top performing teams submitted highly accurate algorithms with consistent performance in the out-of-sample validation study. The performance of these seizure detection algorithms, achieved using freely available code and data, sets a new reproducible benchmark for personalized seizure detection. We have also shared a ‘plug and play’ pipeline to allow other researchers to easily use these algorithms on their own datasets. The success of this competition demonstrates how sharing code and high quality data results in the creation of powerful translational tools with significant potential to impact patient care.
      PubDate: 2017-04-27
      DOI: 10.1093/brain/awx098
       
  • Imaging blood–brain barrier dysfunction as a biomarker for
           epileptogenesis
    • Authors: Bar-Klein G; Lublinsky S, Kamintsky L, et al.
      First page: 1692
      Abstract: A biomarker that will enable the identification of patients at high-risk for developing post-injury epilepsy is critically required. Microvascular pathology and related blood–brain barrier dysfunction and neuroinflammation were shown to be associated with epileptogenesis after injury. Here we used prospective, longitudinal magnetic resonance imaging to quantitatively follow blood–brain barrier pathology in rats following status epilepticus, late electrocorticography to identify epileptic animals and post-mortem immunohistochemistry to confirm blood–brain barrier dysfunction and neuroinflammation. Finally, to test the pharmacodynamic relevance of the proposed biomarker, two anti-epileptogenic interventions were used; isoflurane anaesthesia and losartan. Our results show that early blood–brain barrier pathology in the piriform network is a sensitive and specific predictor (area under the curve of 0.96, P < 0.0001) for epilepsy, while diffused pathology is associated with a lower risk. Early treatments with either isoflurane anaesthesia or losartan prevented early microvascular damage and late epilepsy. We suggest quantitative assessment of blood–brain barrier pathology as a clinically relevant predictive, diagnostic and pharmaco!dynamics biomarker for acquired epilepsy.
      PubDate: 2017-04-23
      DOI: 10.1093/brain/awx073
       
  • Lesion mapping of stroke-related erectile dysfunction
    • Authors: Winder K; Seifert F, Köhrmann M, et al.
      First page: 1706
      Abstract: Acute ischaemic stroke in brain areas contributing to male sexual function may impair erectile function depending on the lesion site. This study intended to determine associations between stroke-related erectile dysfunction and cerebral ischaemic lesion sites using voxel-based lesion mapping. In 52 males (mean age 60.5 ± 10.5 years) with first-ever ischaemic strokes, we assessed erectile function after and retrospectively 3 months prior to the stroke using scores of the 5-item International Index of Erectile Function-5 questionnaire. We assessed cardiovascular risk factors and determined clinical stroke severity and infarct volumes as well as total brain volume by neuroimaging. We calculated correlations between patient age, clinical stroke severity, infarct volumes as well as brain volumes and the difference between erectile dysfunction scores before and after stroke. Moreover, we compared patient age, prevalence of cardiovascular risk factors, clinical stroke severity, infarct volumes and brain volumes of patients with unchanged and deteriorated erectile function after stroke. The infarcts were manually outlined and transformed into stereotaxic space. We determined the lesion overlap and performed subtraction analyses of lesions. In a voxel-based lesion analysis, the difference between erectile dysfunction scores before and after stroke was correlated with the lesion site using t-test statistics. Finally, we conducted a region of interest-based multivariate linear regression analysis that was adjusted for potential confounding factors including patient age, clinical stroke severity, imaging modality, lesion size and brain volume. In 32 patients (61.5%) erectile dysfunction scores declined after the stroke and therefore had stroke-related erectile dysfunction. Deterioration of erectile dysfunction scores was not associated with patient age, clinical stroke severity, infarct volume, brain volume, and cardiovascular risk factors. The voxel-wise subtraction analysis showed associations between stroke-related erectile dysfunction and lesion sites in the right occipito-parietal cortex and thalamus, as well as in the left insula and adjacent temporo-parietal areas. Using voxel-wise t-test statistics, we showed associations between deterioration of erectile function and lesion sites in the right occipital and thalamic region, and the left parietal association area. The linear regression analysis showed that stroke-related erectile dysfunction remained associated with lesions of the right occipital and left parietal association areas after adjusting for confounding factors. In conclusion, our voxel-wise analysis indicates that deteriorating erectile function after stroke is associated with lesions in the right occipito-parietal and thalamic areas integrating visual and somatosensory information, as well as lesions in the left insular and adjacent parieto-temporal areas contributing to generating and mapping visceral arousal states.
      PubDate: 2017-04-18
      DOI: 10.1093/brain/awx080
       
  • Right hemisphere structural adaptation and changing language skills years
           after left hemisphere stroke
    • Authors: Hope TH; Leff AP, Prejawa S, et al.
      First page: 1718
      Abstract: Stroke survivors with acquired language deficits are commonly thought to reach a ‘plateau’ within a year of stroke onset, after which their residual language skills will remain stable. Nevertheless, there have been reports of patients who appear to recover over years. Here, we analysed longitudinal change in 28 left-hemisphere stroke patients, each more than a year post-stroke when first assessed—testing each patient’s spoken object naming skills and acquiring structural brain scans twice. Some of the patients appeared to improve over time while others declined; both directions of change were associated with, and predictable given, structural adaptation in the intact right hemisphere of the brain. Contrary to the prevailing view that these patients’ language skills are stable, these results imply that real change continues over years. The strongest brain–behaviour associations (the ‘peak clusters’) were in the anterior temporal lobe and the precentral gyrus. Using functional magnetic resonance imaging, we confirmed that both regions are actively involved when neurologically normal control subjects name visually presented objects, but neither appeared to be involved when the same participants used a finger press to make semantic association decisions on the same stimuli. This suggests that these regions serve word-retrieval or articulatory functions in the undamaged brain. We teased these interpretations apart by reference to change in other tasks. Consistent with the claim that the real change is occurring here, change in spoken object naming was correlated with change in two other similar tasks, spoken action naming and written object naming, each of which was independently associated with structural adaptation in similar (overlapping) right hemisphere regions. Change in written object naming, which requires word-retrieval but not articulation, was also significantly more correlated with both (i) change in spoken object naming; and (ii) structural adaptation in the two peak clusters, than was change in another task—auditory word repetition—which requires articulation but not word retrieval. This suggests that the changes in spoken object naming reflected variation at the level of word-retrieval processes. Surprisingly, given their qualitatively similar activation profiles, hypertrophy in the anterior temporal region was associated with improving behaviour, while hypertrophy in the precentral gyrus was associated with declining behaviour. We predict that either or both of these regions might be fruitful targets for neural stimulation studies (suppressing the precentral region and/or enhancing the anterior temporal region), aiming to encourage recovery or arrest decline even years after stroke occurs.
      PubDate: 2017-04-24
      DOI: 10.1093/brain/awx086
       
  • Using transcranial magnetic stimulation of the undamaged brain to identify
           lesion sites that predict language outcome after stroke
    • Authors: Lorca-Puls DL; Gajardo-Vidal A, Seghier ML, et al.
      First page: 1729
      Abstract: Transcranial magnetic stimulation focused on either the left anterior supramarginal gyrus or opercular part of the left inferior frontal gyrus has been reported to transiently impair the ability to perform phonological more than semantic tasks. Here we tested whether phonological processing abilities were also impaired following lesions to these regions in right-handed, English speaking adults, who were investigated at least 1 year after a left-hemisphere stroke. When our regions of interest were limited to 0.5 cm3 of grey matter centred around sites that had been identified with transcranial magnetic stimulation-based functional localization, phonological impairments were observed in 74% (40/54) of patients with damage to the regions and 21% (21/100) of patients sparing these regions. This classification accuracy was better than that observed when using regions of interest centred on activation sites in previous functional magnetic resonance imaging studies of phonological processing, or transcranial magnetic stimulation sites that did not use functional localization. New regions of interest were generated by redefining the borders of each of the transcranial magnetic stimulation sites to include areas that were consistently damaged in the patients with phonological impairments. This increased the incidence of phonological impairments in the presence of damage to 85% (46/54) and also reduced the incidence of phonological impairments in the absence of damage to 15% (15/100). The difference in phonological processing abilities between those with and without damage to these ‘transcranial magnetic stimulation-guided’ regions remained highly significant even after controlling for the effect of lesion size. The classification accuracy of the transcranial magnetic stimulation-guided regions was validated in a second sample of 108 patients and found to be better than that for (i) functional magnetic resonance imaging-guided regions; (ii) a region identified from an unguided lesion overlap map; and (iii) a region identified from voxel-based lesion-symptom mapping. Finally, consistent with prior findings from functional imaging and transcranial magnetic stimulation in healthy participants, we show how damage to our transcranial magnetic stimulation-guided regions affected performance on phonologically more than semantically demanding tasks. The observation that phonological processing abilities were impaired years after the stroke, suggests that other brain regions were not able to fully compensate for the contribution that the transcranial magnetic stimulation-guided regions make to language tasks. More generally, our novel transcranial magnetic stimulation-guided lesion-deficit mapping approach shows how non-invasive stimulation of the healthy brain can be used to guide the identification of regions where brain damage is likely to cause persistent behavioural effects.
      PubDate: 2017-04-18
      DOI: 10.1093/brain/awx087
       
  • Selective impairment of goal-directed decision-making following lesions to
           the human ventromedial prefrontal cortex
    • Authors: Reber J; Feinstein JS, O’Doherty JP, et al.
      First page: 1743
      Abstract: See Manohar and Akam (doi:10.1093/brain/awx119) for a scientific commentary on this article.Neuroimaging studies suggest that the human ventromedial prefrontal cortex is a key region for goal-directed behaviour. However, it remains unclear whether the ventromedial prefrontal cortex is necessary for such behaviour. Here we used a canonical test from the animal literature designed to distinguish goal-directed from habit-based choice: namely, outcome devaluation. Patients with focal damage to the ventromedial prefrontal cortex showed deficits in goal-directed choice by persistently selecting actions for a food outcome that had been devalued through selective satiation. By contrast, the same patients had entirely intact acquisition of instrumental contingencies, demonstrating preserved habitual control, and also gave normal ratings of the hedonic value of the devalued food. These findings for the first time demonstrate a necessary and selective role for the human ventromedial prefrontal cortex in goal-directed choice, reconciling prior neuroimaging results in humans with lesion studies in animals, and providing a mechanistic explanation of the real-life deficits in decision-making that have been documented in patients with damage to this structure.
      PubDate: 2017-05-24
      DOI: 10.1093/brain/awx105
       
  • Real-time imaging of single neuronal cell apoptosis in patients with
           glaucoma
    • Authors: Cordeiro MF; Normando EM, Cardoso M, et al.
      First page: 1757
      Abstract: See Herms and Schön (doi:10.1093/brain/awx100) for a scientific commentary on this article.Retinal cell apoptosis occurs in many ocular neurodegenerative conditions including glaucoma—the major cause of irreversible blindness worldwide. Using a new imaging technique that we have called DARC (detection of apoptosing retinal cells), which until now has only been demonstrated in animal models, we assessed if annexin 5 labelled with fluorescent dye DY-776 (ANX776) could be used safely in humans to identify retinal cell apoptosis. Eight patients with glaucomatous neurodegeneration and evidence of progressive disease, and eight healthy subjects were randomly assigned to intravenous ANX776 doses of 0.1, 0.2, 0.4 and 0.5 mg in an open-label, phase 1 clinical trial. In addition to assessing the safety, tolerability and pharmacokinetics of ANX776, the study aimed to explore whether DARC could successfully visualize individual retinal cell apoptosis in vivo in humans, with the DARC count defined as the total number of unique ANX776-labelled spots. DARC enabled retinal cell apoptosis to be identified in the human retina using ANX776. Single ANX776-labelled cells were visualized in a dose-dependent pattern (P < 0.001) up to 6 h after injection. The DARC count was significantly higher (2.37-fold, 95% confidence interval: 1.4–4.03, P = 0.003) in glaucoma patients compared to healthy controls, and was significantly (P = 0.045) greater in patients who later showed increasing rates of disease progression, based on either optic disc, retinal nerve fibre layer or visual field parameters. Additionally, the DARC count significantly correlated with decreased central corneal thickness (Spearman’s R = −0.68, P = 0.006) and increased cup-disc ratios (Spearman’s R = 0.47, P = 0.038) in glaucoma patients and with increased age (Spearman’s R = 0.77, P = 0.001) in healthy controls. Finally, ANX776 was found to be safe and well-tolerated with no serious adverse events, and a short half-life (10–36 min). This proof-of-concept study demonstrates that retinal cell apoptosis can be identified in the human retina with increased levels of activity in glaucomatous neurodegenerative disease. To our knowledge, this is the first time individual neuronal apoptosis has been visualized in vivo in humans and is the first demonstration of detection of individual apoptotic cells in a neurodegenerative disease. Furthermore, our results suggest the level of apoptosis (‘DARC count’) is predictive of disease activity, indicating the potential of DARC as a surrogate marker. Although further trials are clearly needed, this study validates experimental findings supporting the use of DARC as a method of detection and monitoring of patients with glaucomatous neurodegeneration, where retinal ganglion cell apoptosis is an established process and where there is a real need for tools to non-invasively assess treatment efficacy.
      PubDate: 2017-04-26
      DOI: 10.1093/brain/awx088
       
  • Repurposed drugs targeting eIF2&alpha;-P-mediated translational
           repression prevent neurodegeneration in mice
    • Authors: Halliday M; Radford H, Zents KM, et al.
      First page: 1768
      Abstract: See Mercado and Hetz (doi:10.1093/brain/awx107) for a scientific commentary on this article.Signalling through the PERK/eIF2&alpha;-P branch of the unfolded protein response plays a critical role in controlling protein synthesis rates in cells. This pathway is overactivated in brains of patients with Alzheimer&rsquo;s disease and related disorders and has recently emerged as a promising therapeutic target for these currently untreatable conditions. Thus, in mouse models of neurodegenerative disease, prolonged overactivation of PERK/eIF2&alpha;-P signalling causes sustained attenuation of protein synthesis, leading to memory impairment and neuronal loss. Re-establishing translation rates by inhibition of eIF2&alpha;-P activity, genetically or pharmacologically, restores memory and prevents neurodegeneration and extends survival. However, the experimental compounds used preclinically are unsuitable for use in humans, due to associated toxicity or poor pharmacokinetic properties. To discover compounds that have anti-eIF2&alpha;-P activity suitable for clinical use, we performed phenotypic screens on a NINDS small molecule library of 1040 drugs. We identified two compounds, trazodone hydrochloride and dibenzoylmethane, which reversed eIF2&alpha;-P-mediated translational attenuation in&nbsp;vitro and in&nbsp;vivo. Both drugs were markedly neuroprotective in two mouse models of neurodegeneration, using clinically relevant doses over a prolonged period of time, without systemic toxicity. Thus, in prion-diseased mice, both trazodone and dibenzoylmethane treatment restored memory deficits, abrogated development of neurological signs, prevented neurodegeneration and significantly prolonged survival. In tauopathy-frontotemporal dementia mice, both drugs were neuroprotective, rescued memory deficits and reduced hippocampal atrophy. Further, trazodone reduced p-tau burden. These compounds therefore represent potential new disease-modifying treatments for dementia. Trazodone in particular, a licensed drug, should now be tested in clinical trials in patients.
      PubDate: 2017-04-19
      DOI: 10.1093/brain/awx074
       
  • Cognitive reserve and TMEM106B genotype modulate brain damage in
           presymptomatic frontotemporal dementia: a GENFI study
    • Authors: Premi E; Grassi M, van Swieten J, et al.
      First page: 1784
      Abstract: Frontotemporal dementia is a heterogeneous neurodegenerative disorder with around a third of cases having autosomal dominant inheritance. There is wide variability in phenotype even within affected families, raising questions about the determinants of the progression of disease and age at onset. It has been recently demonstrated that cognitive reserve, as measured by years of formal schooling, can counteract the ongoing pathological process. The TMEM106B genotype has also been found to be a modifier of the age at disease onset in frontotemporal dementia patients with TDP-43 pathology. This study therefore aimed to elucidate the modulating effect of environment (i.e. cognitive reserve as measured by educational attainment) and genetic background (i.e. TMEM106B polymorphism, rs1990622 T/C) on grey matter volume in a large cohort of presymptomatic subjects bearing frontotemporal dementia-related pathogenic mutations. Two hundred and thirty-one participants from the GENFI study were included: 108 presymptomatic MAPT, GRN, and C9orf72 mutation carriers and 123 non-carriers. For each subject, cortical and subcortical grey matter volumes were generated using a parcellation of the volumetric T1-weighted magnetic resonance imaging brain scan. TMEM106B genotyping was carried out, and years of education recorded. First, we obtained a composite measure of grey matter volume by graph-Laplacian principal component analysis, and then fitted a linear mixed-effect interaction model, considering the role of (i) genetic status; (ii) educational attainment; and (iii) TMEM106B genotype on grey matter volume. The presence of a mutation was associated with a lower grey matter volume (P = 0.002), even in presymptomatic subjects. Education directly affected grey matter volume in all the samples (P = 0.02) with lower education attainment being associated with lower volumes. TMEM106B genotype did not influence grey matter volume directly on its own but in mutation carriers it modulated the slope of the correlation between education and grey matter volume (P = 0.007). Together, these results indicate that brain atrophy in presymptomatic carriers of common frontotemporal dementia mutations is affected by both genetic and environmental factors such that TMEM106B enhances the benefit of cognitive reserve on brain structure. These findings should be considered in evaluating outcomes in future disease-modifying trials, and support the search for protective mechanisms in people at risk of dementia that might facilitate new therapeutic strategies.
      PubDate: 2017-04-27
      DOI: 10.1093/brain/awx103
       
  • Apathy and impulsivity in frontotemporal lobar degeneration syndromes
    • Authors: Lansdall CJ; Coyle-Gilchrist IS, Jones P, et al.
      First page: 1792
      Abstract: Apathy and impulsivity are common and disabling consequences of frontotemporal lobar degeneration. They cause substantial carer distress, but their aetiology remains elusive. There are critical limitations to previous studies in this area including (i) the assessment of either apathy or impulsivity alone, despite their frequent co-existence; (ii) the assessment of behavioural changes within single diagnostic groups; and (iii) the use of limited sets of tasks or questions that relate to just one aspect of these multifactorial constructs. We proposed an alternative, dimensional approach that spans behavioural and language variants of frontotemporal dementia, progressive supranuclear palsy and corticobasal syndrome. This accommodates the commonalities of apathy and impulsivity across disorders and reveals their cognitive and anatomical bases. The ability to measure the components of apathy and impulsivity and their associated neural correlates across diagnostic groups would provide better novel targets for pharmacological manipulations, and facilitate new treatment strategies and strengthen translational models. We therefore sought to determine the neurocognitive components of apathy and impulsivity in frontotemporal lobar degeneration syndromes. The frequency and characteristics of apathy and impulsivity were determined by neuropsychological and behavioural assessments in 149 patients and 50 controls from the PIck’s disease and Progressive supranuclear palsy Prevalence and INcidence study (PiPPIN). We derived dimensions of apathy and impulsivity using principal component analysis and employed these in volumetric analyses of grey and white matter in a subset of 70 patients (progressive supranuclear palsy, n = 22; corticobasal syndrome, n = 13; behavioural variant, n = 14; primary progressive aphasias, n = 21) and 27 control subjects. Apathy and impulsivity were present across diagnostic groups, despite being criteria for behavioural variant frontotemporal dementia alone. Measures of apathy and impulsivity frequently loaded onto the same components reflecting their overlapping relationship. However, measures from objective tasks, patient-rated questionnaires and carer-rated questionnaires loaded onto separate components and revealed distinct neurobiology. Corticospinal tracts correlated with patients’ self-ratings. In contrast, carer ratings correlated with atrophy in established networks for goal-directed behaviour, social cognition, motor control and vegetative functions, including frontostriatal circuits, orbital and temporal polar cortex, and the brainstem. Components reflecting response inhibition deficits correlated with focal frontal cortical atrophy. The dimensional approach to complex behavioural changes arising from frontotemporal lobar degeneration provides new insights into apathy and impulsivity, and the need for a joint therapeutic strategy against them. The separation of objective tests from subjective questionnaires, and patient from carer ratings, has important implications for clinical trial design.awx101media15448041163001
      PubDate: 2017-05-09
      DOI: 10.1093/brain/awx101
       
  • Progressive atrophy of the globus pallidus (primary atrophy of the
           pallidal system). A system disease of the paralysis agitans type,
           characterized by atrophy of the motor cells of the corpus striatum. A
           contribution to the function of the corpus striatum. By J. Ramsay Hunt MD,
           New York. Brain 1917; 40: 58–148
    • Authors: Compston A.
      First page: 1808
      PubDate: 2017-04-20
      DOI: 10.1093/brain/awx092
       
  • Dramatic science or scientific drama?
    • Authors: Goetz CG.
      First page: 1814
      PubDate: 2017-04-27
      DOI: 10.1093/brain/awx097
       
 
 
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