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Publisher: Oxford University Press   (Total: 393 journals)

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Showing 1 - 200 of 393 Journals sorted alphabetically
Acta Biochimica et Biophysica Sinica     Hybrid Journal   (Followers: 5, SJR: 0.881, h-index: 38)
Adaptation     Hybrid Journal   (Followers: 8, SJR: 0.111, h-index: 4)
Advances in Nutrition     Hybrid Journal   (Followers: 42, SJR: 2.075, h-index: 36)
Aesthetic Surgery J.     Hybrid Journal   (Followers: 6, SJR: 1.538, h-index: 35)
African Affairs     Hybrid Journal   (Followers: 65, SJR: 1.512, h-index: 46)
Age and Ageing     Hybrid Journal   (Followers: 86, SJR: 1.611, h-index: 107)
Alcohol and Alcoholism     Hybrid Journal   (Followers: 18, SJR: 0.935, h-index: 80)
American Entomologist     Full-text available via subscription   (Followers: 6)
American Historical Review     Hybrid Journal   (Followers: 150, SJR: 0.652, h-index: 43)
American J. of Agricultural Economics     Hybrid Journal   (Followers: 40, SJR: 1.441, h-index: 77)
American J. of Clinical Nutrition     Hybrid Journal   (Followers: 146, SJR: 3.771, h-index: 262)
American J. of Epidemiology     Hybrid Journal   (Followers: 171, SJR: 3.047, h-index: 201)
American J. of Hypertension     Hybrid Journal   (Followers: 25, SJR: 1.397, h-index: 111)
American J. of Jurisprudence     Hybrid Journal   (Followers: 18)
American J. of Legal History     Full-text available via subscription   (Followers: 9, SJR: 0.151, h-index: 7)
American Law and Economics Review     Hybrid Journal   (Followers: 27, SJR: 0.824, h-index: 23)
American Literary History     Hybrid Journal   (Followers: 15, SJR: 0.185, h-index: 22)
Analysis     Hybrid Journal   (Followers: 21)
Animal Frontiers     Hybrid Journal  
Annals of Behavioral Medicine     Hybrid Journal   (Followers: 14, SJR: 2.112, h-index: 98)
Annals of Botany     Hybrid Journal   (Followers: 35, SJR: 1.912, h-index: 124)
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   (Followers: 29, SJR: 0.837, h-index: 57)
AoB Plants     Open Access   (Followers: 4, SJR: 0.78, h-index: 10)
Applied Economic Perspectives and Policy     Hybrid Journal   (Followers: 16, SJR: 0.884, h-index: 31)
Applied Linguistics     Hybrid Journal   (Followers: 55, 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: 20)
Arbitration Law Reports and Review     Hybrid Journal   (Followers: 14)
Archives of Clinical Neuropsychology     Hybrid Journal   (Followers: 30, SJR: 0.96, h-index: 71)
Aristotelian Society Supplementary Volume     Hybrid Journal   (Followers: 3, SJR: 0.102, h-index: 20)
Arthropod Management Tests     Hybrid Journal   (Followers: 2)
Astronomy & Geophysics     Hybrid Journal   (Followers: 42, SJR: 0.144, h-index: 15)
Behavioral Ecology     Hybrid Journal   (Followers: 51, SJR: 1.698, h-index: 92)
Bioinformatics     Hybrid Journal   (Followers: 291, SJR: 4.643, h-index: 271)
Biology Methods and Protocols     Hybrid Journal  
Biology of Reproduction     Full-text available via subscription   (Followers: 10, SJR: 1.646, h-index: 149)
Biometrika     Hybrid Journal   (Followers: 20, SJR: 2.801, h-index: 90)
BioScience     Hybrid Journal   (Followers: 30, 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: 17, SJR: 1.955, h-index: 55)
BJA : British J. of Anaesthesia     Hybrid Journal   (Followers: 165, SJR: 2.314, h-index: 133)
BJA Education     Hybrid Journal   (Followers: 64, SJR: 0.272, h-index: 20)
Brain     Hybrid Journal   (Followers: 68, 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: 3, 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: 26, SJR: 0.217, h-index: 18)
British J. of Criminology     Hybrid Journal   (Followers: 585, SJR: 1.373, h-index: 62)
British J. of Social Work     Hybrid Journal   (Followers: 86, 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: 31)
Bulletin of the London Mathematical Society     Hybrid Journal   (Followers: 4, SJR: 1.474, h-index: 31)
Cambridge J. of Economics     Hybrid Journal   (Followers: 61, SJR: 0.957, h-index: 59)
Cambridge J. of Regions, Economy and Society     Hybrid Journal   (Followers: 10, SJR: 1.067, h-index: 22)
Cambridge Quarterly     Hybrid Journal   (Followers: 9, SJR: 0.1, h-index: 7)
Capital Markets Law J.     Hybrid Journal   (Followers: 2)
Carcinogenesis     Hybrid Journal   (Followers: 2, SJR: 2.439, h-index: 167)
Cardiovascular Research     Hybrid Journal   (Followers: 13, SJR: 2.897, h-index: 175)
Cerebral Cortex     Hybrid Journal   (Followers: 45, SJR: 4.827, h-index: 192)
CESifo Economic Studies     Hybrid Journal   (Followers: 17, SJR: 0.501, h-index: 19)
Chemical Senses     Hybrid Journal   (Followers: 1, SJR: 1.436, h-index: 76)
Children and Schools     Hybrid Journal   (Followers: 5, SJR: 0.211, h-index: 18)
Chinese J. of Comparative Law     Hybrid Journal   (Followers: 4)
Chinese J. of Intl. Law     Hybrid Journal   (Followers: 22, 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: 10, SJR: 0.191, h-index: 8)
Classical Receptions J.     Hybrid Journal   (Followers: 25, SJR: 0.1, h-index: 3)
Clean Energy     Open Access  
Clinical Infectious Diseases     Hybrid Journal   (Followers: 62, SJR: 4.742, h-index: 261)
Clinical Kidney J.     Open Access   (Followers: 3, SJR: 0.338, h-index: 19)
Communication Theory     Hybrid Journal   (Followers: 21, SJR: 2.62, h-index: 53)
Communication, Culture & Critique     Hybrid Journal   (Followers: 25)
Community Development J.     Hybrid Journal   (Followers: 27, SJR: 0.47, h-index: 28)
Computer J.     Hybrid Journal   (Followers: 9, SJR: 0.371, h-index: 47)
Conservation Physiology     Open Access   (Followers: 2)
Contemporary Women's Writing     Hybrid Journal   (Followers: 9, SJR: 0.111, h-index: 3)
Contributions to Political Economy     Hybrid Journal   (Followers: 5, SJR: 0.313, h-index: 10)
Critical Values     Full-text available via subscription  
Current Developments in Nutrition     Open Access  
Current Legal Problems     Hybrid Journal   (Followers: 27)
Current Zoology     Full-text available via subscription   (Followers: 1, SJR: 0.999, h-index: 20)
Database : The J. of Biological Databases and Curation     Open Access   (Followers: 8, SJR: 1.068, h-index: 24)
Digital Scholarship in the Humanities     Hybrid Journal   (Followers: 14)
Diplomatic History     Hybrid Journal   (Followers: 20, SJR: 0.296, h-index: 22)
DNA Research     Open Access   (Followers: 5, SJR: 2.42, h-index: 77)
Dynamics and Statistics of the Climate System     Open Access   (Followers: 3)
Early Music     Hybrid Journal   (Followers: 15, SJR: 0.124, h-index: 11)
Economic Policy     Hybrid Journal   (Followers: 39, SJR: 2.052, h-index: 52)
ELT J.     Hybrid Journal   (Followers: 24, SJR: 1.26, h-index: 23)
English Historical Review     Hybrid Journal   (Followers: 51, SJR: 0.311, h-index: 10)
English: J. of the English Association     Hybrid Journal   (Followers: 14, 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: 3)
Environmental History     Hybrid Journal   (Followers: 26, SJR: 0.197, h-index: 25)
EP-Europace     Hybrid Journal   (Followers: 2, SJR: 2.201, h-index: 71)
Epidemiologic Reviews     Hybrid Journal   (Followers: 9, SJR: 3.917, h-index: 81)
ESHRE Monographs     Hybrid Journal  
Essays in Criticism     Hybrid Journal   (Followers: 16, SJR: 0.1, h-index: 6)
European Heart J.     Hybrid Journal   (Followers: 54, SJR: 6.997, h-index: 227)
European Heart J. - Cardiovascular Imaging     Hybrid Journal   (Followers: 8, 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: 7, SJR: 0.152, h-index: 31)
European J. of Cardio-Thoracic Surgery     Hybrid Journal   (Followers: 9, SJR: 1.568, h-index: 104)
European J. of Intl. Law     Hybrid Journal   (Followers: 173, 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: 20, SJR: 1.284, h-index: 64)
European Review of Agricultural Economics     Hybrid Journal   (Followers: 10, SJR: 1.549, h-index: 42)
European Review of Economic History     Hybrid Journal   (Followers: 28, SJR: 0.628, h-index: 24)
European Sociological Review     Hybrid Journal   (Followers: 40, SJR: 2.061, h-index: 53)
Evolution, Medicine, and Public Health     Open Access   (Followers: 10)
Family Practice     Hybrid Journal   (Followers: 14, SJR: 1.048, h-index: 77)
Fems Microbiology Ecology     Hybrid Journal   (Followers: 10, SJR: 1.687, h-index: 115)
Fems Microbiology Letters     Hybrid Journal   (Followers: 22, SJR: 1.126, h-index: 118)
Fems Microbiology Reviews     Hybrid Journal   (Followers: 27, SJR: 7.587, h-index: 150)
Fems Yeast Research     Hybrid Journal   (Followers: 14, SJR: 1.213, h-index: 66)
Food Quality and Safety     Open Access  
Foreign Policy Analysis     Hybrid Journal   (Followers: 23, SJR: 0.859, h-index: 10)
Forest Science     Hybrid Journal   (Followers: 4, SJR: 0.872, h-index: 59)
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: 32, SJR: 0.123, h-index: 10)
French Studies     Hybrid Journal   (Followers: 20, 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: 12, SJR: 3.22, h-index: 39)
Geophysical J. Intl.     Hybrid Journal   (Followers: 35, SJR: 1.839, h-index: 119)
German History     Hybrid Journal   (Followers: 22, SJR: 0.437, h-index: 13)
GigaScience     Open Access   (Followers: 3)
Global Summitry     Hybrid Journal   (Followers: 1)
Glycobiology     Hybrid Journal   (Followers: 14, SJR: 1.692, h-index: 101)
Health and Social Work     Hybrid Journal   (Followers: 55, SJR: 0.505, h-index: 40)
Health Education Research     Hybrid Journal   (Followers: 13, SJR: 0.814, h-index: 80)
Health Policy and Planning     Hybrid Journal   (Followers: 24, SJR: 1.628, h-index: 66)
Health Promotion Intl.     Hybrid Journal   (Followers: 21, SJR: 0.664, h-index: 60)
History Workshop J.     Hybrid Journal   (Followers: 29, SJR: 0.313, h-index: 20)
Holocaust and Genocide Studies     Hybrid Journal   (Followers: 26, SJR: 0.115, h-index: 13)
Human Communication Research     Hybrid Journal   (Followers: 13, SJR: 2.199, h-index: 61)
Human Molecular Genetics     Hybrid Journal   (Followers: 8, SJR: 4.288, h-index: 233)
Human Reproduction     Hybrid Journal   (Followers: 72, SJR: 2.271, h-index: 179)
Human Reproduction Update     Hybrid Journal   (Followers: 17, SJR: 4.678, h-index: 128)
Human Rights Law Review     Hybrid Journal   (Followers: 60, SJR: 0.7, h-index: 21)
ICES J. of Marine Science: J. du Conseil     Hybrid Journal   (Followers: 51, SJR: 1.233, h-index: 88)
ICSID Review     Hybrid Journal   (Followers: 12)
ILAR J.     Hybrid Journal   (Followers: 2, 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   (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: 10, SJR: 1.37, h-index: 81)
Industrial Law J.     Hybrid Journal   (Followers: 34, SJR: 0.184, h-index: 15)
Inflammatory Bowel Diseases     Hybrid Journal   (Followers: 42, SJR: 1.994, h-index: 107)
Information and Inference     Free  
Integrative and Comparative Biology     Hybrid Journal   (Followers: 7, 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: 6, SJR: 0.743, h-index: 35)
Intl. Affairs     Hybrid Journal   (Followers: 56, SJR: 1.264, h-index: 53)
Intl. Data Privacy Law     Hybrid Journal   (Followers: 31)
Intl. Health     Hybrid Journal   (Followers: 5, 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: 34, SJR: 1.593, h-index: 69)
Intl. J. of Constitutional Law     Hybrid Journal   (Followers: 64, SJR: 0.613, h-index: 19)
Intl. J. of Epidemiology     Hybrid Journal   (Followers: 198, SJR: 4.381, h-index: 145)
Intl. J. of Law and Information Technology     Hybrid Journal   (Followers: 5, SJR: 0.247, h-index: 8)
Intl. J. of Law, Policy and the Family     Hybrid Journal   (Followers: 30, SJR: 0.307, h-index: 15)
Intl. J. of Lexicography     Hybrid Journal   (Followers: 10, 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: 9, SJR: 0.906, h-index: 33)
Intl. J. of Refugee Law     Hybrid Journal   (Followers: 35, SJR: 0.231, h-index: 21)
Intl. J. of Transitional Justice     Hybrid Journal   (Followers: 12, 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: 36, SJR: 1.339, h-index: 19)
Intl. Relations of the Asia-Pacific     Hybrid Journal   (Followers: 22, SJR: 0.539, h-index: 17)
Intl. Studies Perspectives     Hybrid Journal   (Followers: 9, SJR: 0.998, h-index: 28)
Intl. Studies Quarterly     Hybrid Journal   (Followers: 44, SJR: 2.184, h-index: 68)
Intl. Studies Review     Hybrid Journal   (Followers: 20, 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: 1, SJR: 0.102, h-index: 4)
J. of African Economies     Hybrid Journal   (Followers: 14, SJR: 0.647, h-index: 30)
J. of American History     Hybrid Journal   (Followers: 45, SJR: 0.286, h-index: 34)
J. of Analytical Toxicology     Hybrid Journal   (Followers: 14, SJR: 1.038, h-index: 60)
J. of Antimicrobial Chemotherapy     Hybrid Journal   (Followers: 14, SJR: 2.157, h-index: 149)
J. of Antitrust Enforcement     Hybrid Journal   (Followers: 1)
J. of Applied Poultry Research     Hybrid Journal   (Followers: 4, SJR: 0.563, h-index: 43)
J. of Biochemistry     Hybrid Journal   (Followers: 41, SJR: 1.341, h-index: 96)
J. of Burn Care & Research     Hybrid Journal   (Followers: 9, SJR: 0.713, h-index: 57)
J. of Chromatographic Science     Hybrid Journal   (Followers: 18, SJR: 0.448, h-index: 42)
J. of Church and State     Hybrid Journal   (Followers: 11, SJR: 0.167, h-index: 11)
J. of Communication     Hybrid Journal   (Followers: 50, SJR: 3.327, h-index: 82)
J. of Competition Law and Economics     Hybrid Journal   (Followers: 35, SJR: 0.442, h-index: 16)
J. of Complex Networks     Hybrid Journal   (Followers: 2, SJR: 1.165, h-index: 5)
J. of Computer-Mediated Communication     Open Access   (Followers: 26, SJR: 2.878, h-index: 80)
J. of Conflict and Security Law     Hybrid Journal   (Followers: 13, 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)

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Journal Cover Brain
  [SJR: 6.097]   [H-I: 264]   [68 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  [393 journals]
  • Corrigendum
    • Abstract: Patricia Rodriguez-Rodriguez, Anna Sandebring-Matton, Paula Merino-Serrais, Cristina Parrado-Fernandez, Alberto Rabano, Bengt Winblad, Jesús Ávila, Isidre Ferrer, Angel Cedazo-Minguez. Tau hyperphosphorylation induces oligomeric insulin accumulation and insulin resistance in neurons. Brain 2017; 140: 3269–3285; 10.1093/brain/awx256.
      PubDate: Thu, 15 Mar 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy068
      Issue No: Vol. 141, No. 5 (2018)
  • Noisy but not placebo: defining metrics for effects of neurofeedback
    • Authors: Witte M; Kober S, Wood G.
      Abstract: Sir,
      PubDate: Tue, 13 Mar 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy060
      Issue No: Vol. 141, No. 5 (2018)
  • Reply: Noisy but not placebo: defining metrics for effects of
    • Authors: Schabus M.
      Abstract: Sir,
      PubDate: Tue, 13 Mar 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy061
      Issue No: Vol. 141, No. 5 (2018)
  • Towards personalized therapy for multiple sclerosis: limitations of
           observational data
    • Authors: Steyerberg E; Claggett B.
      Abstract: Sir,
      PubDate: Sat, 03 Mar 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy055
      Issue No: Vol. 141, No. 5 (2018)
  • Reply: Towards personalized therapy for multiple sclerosis: limitations of
           observational data
    • Authors: Kalincik T.
      Abstract: Sir,
      PubDate: Sat, 03 Mar 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy056
      Issue No: Vol. 141, No. 5 (2018)
  • The recurrent mutation in TMEM106B also causes hypomyelinating
           leukodystrophy in China and is a CpG hotspot
    • Authors: Yan H; Kubisiak T, Ji H, et al.
      Abstract: Sir,
      PubDate: Mon, 12 Feb 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy029
      Issue No: Vol. 141, No. 5 (2018)
  • Reply: The recurrent mutation in TMEM106B also causes hypomyelinating
           leukodystrophy in China and is a CpG hotspot
    • Authors: Simons C; Dyment D, van der Knaap M, et al.
      Abstract: Sir,
      PubDate: Mon, 12 Feb 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy030
      Issue No: Vol. 141, No. 5 (2018)
  • Editorial
    • Authors: Kullmann D.
      Pages: 1235 - 1235
      Abstract: In this issue of Brain Simon Shorvon looks back 70 years at the foundation of the National Health Service and how this changed the practice of neurology in the UK. Among the most vociferous opponents to the introduction of the NHS was Sir Francis Walshe, who edited this journal between 1937 and 1953 and never took up the offer of a salary from the state. Neurology was, however, a very small branch of medicine in the 1940s, and provision of the meagre diagnostic, and ever rarer therapeutic, services to the overwhelming majority of the British population became the responsibility of the NHS on 5 July 1948. Recent surveys in the USA have shown neurologists to be less likely to describe themselves as fiscally conservative or to be registered as Republicans than the average for medical practitioners. Psychiatrists are further to the political left than neurologists and, together with infectious disease specialists, are the sans-culottes of the medical profession. Whether this pattern applied to 1940s Britain is impossible to know, but at face value it would suggest that psychiatrists might have been more welcoming of the nationalization of their trade than neurologists. Psychiatry was, however, almost left out of the NHS, and its absorption at the last minute came with a peculiarity dating back to the Local Government Act 1937, whereby Mental Health Officer status was conferred on ‘mental hospital employees’, allowing them to retire on a full NHS pension at 55. This incentive, irksome to other medical practitioners, was only very recently phased out, and is only one of many factors that played a part in the last-minute inclusion of psychiatry in the NHS. It is, for instance, important to remember that almost 150 000 people diagnosed with serious mental health disorders lived in approximately 100 asylums in the countryside and on the outskirts of major cities. Most were certified or detained under the Mental Health Act, and if treatment was attempted, according to a Ministry of Health Report in 1950, it was often with electroconvulsive therapy, insulin shock treatment or prefrontal leucotomy.
      PubDate: Mon, 23 Apr 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy106
      Issue No: Vol. 141, No. 5 (2018)
  • The snowball effect of RNA binding protein dysfunction in amyotrophic
           lateral sclerosis
    • Authors: Fratta P; Isaacs A.
      Pages: 1236 - 1238
      Abstract: This scientific commentary refers to ‘TDP-43 regulates the alternative splicing of hnRNP A1 to yield an aggregation-prone variant in amyotrophic lateral sclerosis’, by Deshaies et al. (doi:10.1093/brain/awy062).
      PubDate: Mon, 23 Apr 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy091
      Issue No: Vol. 141, No. 5 (2018)
  • Functional ‘unlocking’: bedside detection of covert awareness
           after severe brain damage
    • Authors: Boly M; Laureys S.
      Pages: 1239 - 1241
      Abstract: This scientific commentary refers to ‘Characterization of EEG signals revealing covert cognition in the injured brain’, by Curley et al. (doi:10.1093/brain/awy070).
      PubDate: Mon, 23 Apr 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy080
      Issue No: Vol. 141, No. 5 (2018)
  • Is longitudinal tau PET ready for use in Alzheimer’s disease
           clinical trials'
    • Authors: Hansson O; Mormino E.
      Pages: 1241 - 1244
      Abstract: This scientific commentary refers to ‘Longitudinal tau PET in ageing and Alzheimer’s disease’, by Jack, Jr et al. (doi:10.1093/brain/awy059).
      PubDate: Mon, 23 Apr 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy065
      Issue No: Vol. 141, No. 5 (2018)
  • Disease progression models for dominantly-inherited Alzheimer’s
    • Authors: Li D; Donohue M.
      Pages: 1244 - 1246
      Abstract: This scientific commentary refers to ‘Data-driven models of dominantly-inherited Alzheimer’s disease progression’, by Oxtoby et al. (doi:10.1093/brain/awy050).
      PubDate: Mon, 23 Apr 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy089
      Issue No: Vol. 141, No. 5 (2018)
  • Perturbed autophagy and DNA repair converge to promote neurodegeneration
           in amyotrophic lateral sclerosis and dementia
    • Authors: Walker C; El-Khamisy S.
      Pages: 1247 - 1262
      Abstract: Maintaining genomic stability constitutes a major challenge facing cells. DNA breaks can arise from direct oxidative damage to the DNA backbone, the inappropriate activities of endogenous enzymes such as DNA topoisomerases, or due to transcriptionally-derived RNA/DNA hybrids (R-loops). The progressive accumulation of DNA breaks has been linked to several neurological disorders. Recently, however, several independent studies have implicated nuclear and mitochondrial genomic instability, perturbed co-transcriptional processing, and impaired cellular clearance pathways as causal and intertwined mechanisms underpinning neurodegeneration. Here, we discuss this emerging paradigm in the context of amyotrophic lateral sclerosis and frontotemporal dementia, and outline how this knowledge paves the way to novel therapeutic interventions.
      PubDate: Fri, 23 Mar 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy076
      Issue No: Vol. 141, No. 5 (2018)
  • Neurotransmitter deficits from frontotemporal lobar degeneration
    • Authors: Murley A; Rowe J.
      Pages: 1263 - 1285
      Abstract: Frontotemporal lobar degeneration causes a spectrum of complex degenerative disorders including frontotemporal dementia, progressive supranuclear palsy and corticobasal syndrome, each of which is associated with changes in the principal neurotransmitter systems. We review the evidence for these neurochemical changes and propose that they contribute to symptomatology of frontotemporal lobar degeneration, over and above neuronal loss and atrophy. Despite the development of disease-modifying therapies, aiming to slow neuropathological progression, it remains important to advance symptomatic treatments to reduce the disease burden and improve patients’ and carers’ quality of life. We propose that targeting the selective deficiencies in neurotransmitter systems, including dopamine, noradrenaline, serotonin, acetylcholine, glutamate and gamma-aminobutyric acid is an important strategy towards this goal. We summarize the current evidence-base for pharmacological treatments and suggest strategies to improve the development of new, effective pharmacological treatments.
      PubDate: Wed, 24 Jan 2018 00:00:00 GMT
      DOI: 10.1093/brain/awx327
      Issue No: Vol. 141, No. 5 (2018)
  • Mechanistic basis of an epistatic interaction reducing age at onset in
           hereditary spastic paraplegia
    • Authors: Newton T; Allison R, Edgar J, et al.
      Pages: 1286 - 1299
      Abstract: Many genetic neurological disorders exhibit variable expression within affected families, often exemplified by variations in disease age at onset. Epistatic effects (i.e. effects of modifier genes on the disease gene) may underlie this variation, but the mechanistic basis for such epistatic interactions is rarely understood. Here we report a novel epistatic interaction between SPAST and the contiguous gene DPY30, which modifies age at onset in hereditary spastic paraplegia, a genetic axonopathy. We found that patients with hereditary spastic paraplegia caused by genomic deletions of SPAST that extended into DPY30 had a significantly younger age at onset. We show that, like spastin, the protein encoded by SPAST, the DPY30 protein controls endosomal tubule fission, traffic of mannose 6-phosphate receptors from endosomes to the Golgi, and lysosomal ultrastructural morphology. We propose that additive effects on this pathway explain the reduced age at onset of hereditary spastic paraplegia in patients who are haploinsufficient for both genes.
      PubDate: Thu, 22 Feb 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy034
      Issue No: Vol. 141, No. 5 (2018)
  • Metastatic group 3 medulloblastoma is driven by PRUNE1 targeting
           NME1–TGF-β–OTX2–SNAIL via PTEN inhibition
    • Authors: Ferrucci V; de Antonellis P, Pennino F, et al.
      Pages: 1300 - 1319
      Abstract: Genetic modifications during development of paediatric groups 3 and 4 medulloblastoma are responsible for their highly metastatic properties and poor patient survival rates. PRUNE1 is highly expressed in metastatic medulloblastoma group 3, which is characterized by TGF-β signalling activation, c-MYC amplification, and OTX2 expression. We describe the process of activation of the PRUNE1 signalling pathway that includes its binding to NME1, TGF-β activation, OTX2 upregulation, SNAIL (SNAI1) upregulation, and PTEN inhibition. The newly identified small molecule pyrimido-pyrimidine derivative AA7.1 enhances PRUNE1 degradation, inhibits this activation network, and augments PTEN expression. Both AA7.1 and a competitive permeable peptide that impairs PRUNE1/NME1 complex formation, impair tumour growth and metastatic dissemination in orthotopic xenograft models with a metastatic medulloblastoma group 3 cell line (D425-Med cells). Using whole exome sequencing technology in metastatic medulloblastoma primary tumour cells, we also define 23 common ‘non-synonymous homozygous’ deleterious gene variants as part of the protein molecular network of relevance for metastatic processes. This PRUNE1/TGF-β/OTX2/PTEN axis, together with the medulloblastoma-driver mutations, is of relevance for future rational and targeted therapies for metastatic medulloblastoma group 3.10.1093/brain/awy039_video1awy039media15742053534001
      PubDate: Tue, 27 Feb 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy039
      Issue No: Vol. 141, No. 5 (2018)
  • TDP-43 regulates the alternative splicing of hnRNP A1 to yield an
           aggregation-prone variant in amyotrophic lateral sclerosis
    • Authors: Deshaies J; Shkreta L, Moszczynski A, et al.
      Pages: 1320 - 1333
      Abstract: See Fratta and Isaacs (doi:10.1093/brain/awy091) for a scientific commentary on this article.The RNA binding proteins TDP-43 (encoded by TARDBP) and hnRNP A1 (HNRNPA1) are each mutated in certain amyotrophic lateral sclerosis cases and are often mislocalized in cytoplasmic aggregates within motor neurons of affected patients. Cytoplasmic inclusions of TDP-43, which are accompanied by a depletion of nuclear TDP-43, are observed in most amyotrophic lateral sclerosis cases and nearly half of frontotemporal dementia cases. Here, we report that TDP-43 binds HNRNPA1 pre-mRNA and modulates its splicing, and that depletion of nuclear TDP-43 results in increased inclusion of a cassette exon in the HNRNPA1 transcript, and consequently elevated protein levels of an isoform containing an elongated prion-like domain, referred to as hnRNP A1B. Combined in vivo and in vitro approaches demonstrated greater fibrillization propensity for hnRNP A1B, which drives protein aggregation and is toxic to cells. Moreover, amyotrophic lateral sclerosis patients with documented TDP-43 pathology showed neuronal hnRNP A1B cytoplasmic accumulation, indicating that TDP-43 mislocalization may contribute to neuronal vulnerability and loss via altered HNRNPA1 pre-mRNA splicing and function. Given that TDP-43 and hnRNP A1 each bind, and thus modulate, a third of the transcriptome, our data suggest a much broader disruption in RNA metabolism than previously considered.
      PubDate: Mon, 19 Mar 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy062
      Issue No: Vol. 141, No. 5 (2018)
  • T helper 17.1 cells associate with multiple sclerosis disease activity:
           perspectives for early intervention
    • Authors: van Langelaar J; van der Vuurst de Vries R, Janssen M, et al.
      Pages: 1334 - 1349
      Abstract: Interleukin-17-expressing CD4+ T helper 17 (Th17) cells are considered as critical regulators of multiple sclerosis disease activity. However, depending on the species and pro-inflammatory milieu, Th17 cells are functionally heterogeneous, consisting of subpopulations that differentially produce interleukin-17, interferon-gamma and granulocyte macrophage colony-stimulating factor. In the current study, we studied distinct effector phenotypes of human Th17 cells and their correlation with disease activity in multiple sclerosis patients. T helper memory populations single- and double-positive for C-C chemokine receptor 6 (CCR6) and CXC chemokine receptor 3 (CXCR3) were functionally assessed in blood and/or cerebrospinal fluid from a total of 59 patients with clinically isolated syndrome, 35 untreated patients and 24 natalizumab-treated patients with relapsing-remitting multiple sclerosis, and nine patients with end-stage multiple sclerosis. Within the clinically isolated syndrome group, 23 patients had a second attack within 1 year and 26 patients did not experience subsequent attacks during a follow-up of >5 years. Low frequencies of T helper 1 (Th1)-like Th17 (CCR6+CXCR3+), and not Th17 (CCR6+CXCR3−) effector memory populations in blood strongly associated with a rapid diagnosis of clinically definite multiple sclerosis. In cerebrospinal fluid of clinically isolated syndrome and relapsing-remitting multiple sclerosis patients, Th1-like Th17 effector memory cells were abundant and showed increased production of interferon-gamma and granulocyte macrophage colony-stimulating factor compared to paired CCR6+ and CCR6−CD8+ T cell populations and their blood equivalents after short-term culturing. Their local enrichment was confirmed ex vivo using cerebrospinal fluid and brain single-cell suspensions. Across all pro-inflammatory T helper cells analysed in relapsing-remitting multiple sclerosis blood, Th1-like Th17 subpopulation T helper 17.1 (Th17.1; CCR6+CXCR3+CCR4−) expressed the highest very late antigen-4 levels and selectively accumulated in natalizumab-treated patients who remained free of clinical relapses. This was not found in patients who experienced relapses during natalizumab treatment. The enhanced potential of Th17.1 cells to infiltrate the central nervous system was supported by their predominance in cerebrospinal fluid of early multiple sclerosis patients and their preferential transmigration across human brain endothelial layers. These findings reveal a dominant contribution of Th1-like Th17 subpopulations, in particular Th17.1 cells, to clinical disease activity and provide a strong rationale for more specific and earlier use of T cell-targeted therapy in multiple sclerosis.
      PubDate: Thu, 05 Apr 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy069
      Issue No: Vol. 141, No. 5 (2018)
  • Protein instability, haploinsufficiency, and cortical hyper-excitability
           underlie STXBP1 encephalopathy
    • Authors: Kovačević J; Maroteaux G, Schut D, et al.
      Pages: 1350 - 1374
      Abstract: De novo heterozygous mutations in STXBP1/Munc18-1 cause early infantile epileptic encephalopathies (EIEE4, OMIM #612164) characterized by infantile epilepsy, developmental delay, intellectual disability, and can include autistic features. We characterized the cellular deficits for an allelic series of seven STXBP1 mutations and developed four mouse models that recapitulate the abnormal EEG activity and cognitive aspects of human STXBP1-encephalopathy. Disease-causing STXBP1 variants supported synaptic transmission to a variable extent on a null background, but had no effect when overexpressed on a heterozygous background. All disease variants had severely decreased protein levels. Together, these cellular studies suggest that impaired protein stability and STXBP1 haploinsufficiency explain STXBP1-encephalopathy and that, therefore, Stxbp1+/− mice provide a valid mouse model. Simultaneous video and EEG recordings revealed that Stxbp1+/− mice with different genomic backgrounds recapitulate the seizure/spasm phenotype observed in humans, characterized by myoclonic jerks and spike-wave discharges that were suppressed by the antiepileptic drug levetiracetam. Mice heterozygous for Stxbp1 in GABAergic neurons only, showed impaired viability, 50% died within 2–3 weeks, and the rest showed stronger epileptic activity. c-Fos staining implicated neocortical areas, but not other brain regions, as the seizure foci. Stxbp1+/− mice showed impaired cognitive performance, hyperactivity and anxiety-like behaviour, without altered social behaviour. Taken together, these data demonstrate the construct, face and predictive validity of Stxbp1+/− mice and point to protein instability, haploinsufficiency and imbalanced excitation in neocortex, as the underlying mechanism of STXBP1-encephalopathy. The mouse models reported here are valid models for development of therapeutic interventions targeting STXBP1-encephalopathy.
      PubDate: Mon, 12 Mar 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy046
      Issue No: Vol. 141, No. 5 (2018)
  • Disrupted dynamic network reconfiguration of the language system in
           temporal lobe epilepsy
    • Authors: He X; Bassett D, Chaitanya G, et al.
      Pages: 1375 - 1389
      Abstract: Temporal lobe epilepsy tends to reshape the language system causing maladaptive reorganization that can be characterized by task-based functional MRI, and eventually can contribute to surgical decision making processes. However, the dynamic interacting nature of the brain as a complex system is often neglected, with many studies treating the language system as a static monolithic structure. Here, we demonstrate that as a specialized and integrated system, the language network is inherently dynamic, characterized by rich patterns of regional interactions, whose transient dynamics are disrupted in patients with temporal lobe epilepsy. Specifically, we applied tools from dynamic network neuroscience to functional MRI data collected from 50 temporal lobe epilepsy patients and 30 matched healthy controls during performance of a verbal fluency task, as well as during rest. By assigning 16 language-related regions into four subsystems (i.e. bilateral frontal and temporal), we observed regional specialization in both the probability of transient interactions and the frequency of such changes, in both healthy controls and patients during task performance but not rest. Furthermore, we found that both left and right temporal lobe epilepsy patients displayed reduced interactions within the left frontal ‘core’ subsystem compared to the healthy controls, while left temporal lobe epilepsy patients were unique in showing enhanced interactions between the left frontal ‘core’ and the right temporal subsystems. Also, both patient groups displayed reduced flexibility in the transient interactions of the left temporal and right frontal subsystems, which formed the ‘periphery’ of the language network. Importantly, such group differences were again evident only during task condition. Lastly, through random forest regression, we showed that dynamic reconfiguration of the language system tracks individual differences in verbal fluency with superior prediction accuracy compared to traditional activation-based static measures. Our results suggest dynamic network measures may be an effective biomarker for detecting the language dysfunction associated with neurological diseases such as temporal lobe epilepsy, specifying both the type of neuronal communications that are missing in these patients and those that are potentially added but maladaptive. Further advancements along these lines, transforming how we characterize and map language networks in the brain, have a high probability of altering clinical decision making in neurosurgical centres.10.1093/brain/awy042_video1awy042media15754656112001
      PubDate: Thu, 15 Mar 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy042
      Issue No: Vol. 141, No. 5 (2018)
  • KEAP1 inhibition is neuroprotective and suppresses the development of
    • Authors: Shekh-Ahmad T; Eckel R, Dayalan Naidu S, et al.
      Pages: 1390 - 1403
      Abstract: Hippocampal sclerosis is a common acquired disease that is a major cause of drug-resistant epilepsy. A mechanism that has been proposed to lead from brain insult to hippocampal sclerosis is the excessive generation of reactive oxygen species, and consequent mitochondrial failure. Here we use a novel strategy to increase endogenous antioxidant defences using RTA 408, which we show activates nuclear factor erythroid 2-related factor 2 (Nrf2, encoded by NFE2L2) through inhibition of kelch like ECH associated protein 1 (KEAP1) through its primary sensor C151. Activation of Nrf2 with RTA 408 inhibited reactive oxygen species production, mitochondrial depolarization and cell death in an in vitro model of seizure-like activity. RTA 408 given after status epilepticus in vivo increased ATP, prevented neuronal death, and dramatically reduced (by 94%) the frequency of late spontaneous seizures for at least 4 months following status epilepticus. Thus, acute KEAP1 inhibition following status epilepticus exerts a neuroprotective and disease-modifying effect, supporting the hypothesis that reactive oxygen species generation is a key event in the development of epilepsy.
      PubDate: Mon, 12 Mar 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy071
      Issue No: Vol. 141, No. 5 (2018)
  • Characterization of EEG signals revealing covert cognition in the injured
    • Authors: Curley W; Forgacs P, Voss H, et al.
      Pages: 1404 - 1421
      Abstract: See Boly and Laureys (doi:10.1093/brain/awy080) for a scientific commentary on this article.Patients with severe brain injury are difficult to assess and frequently subject to misdiagnosis. ‘Cognitive motor dissociation’ is a term used to describe a subset of such patients with preserved cognition as detected with neuroimaging methods but not evident in behavioural assessments. Unlike the locked-in state, cognitive motor dissociation after severe brain injury is prominently marked by concomitant injuries across the cerebrum in addition to limited or no motoric function. In the present study, we sought to characterize the EEG signals used as indicators of cognition in patients with disorders of consciousness and examine their reliability for potential future use to re-establish communication. We compared EEG-based assessments to the results of using similar methods with functional MRI. Using power spectral density analysis to detect EEG evidence of task performance (Two Group Test, P ≤ 0.05, with false discovery rate correction), we found evidence of the capacity to follow commands in 21 of 28 patients with severe brain injury and all 15 healthy individuals studied. We found substantial variability in the temporal and spatial characteristics of significant EEG signals among the patients in contrast to only modest variation in these domains across healthy controls; the majority of healthy controls showed suppression of either 8–12 Hz ‘alpha’ or 13–40 Hz ‘beta’ power during task performance, or both. Nine of the 21 patients with EEG evidence of command-following also demonstrated functional MRI evidence of command-following. Nine of the patients with command-following capacity demonstrated by EEG showed no behavioural evidence of a communication channel as detected by a standardized behavioural assessment, the Coma Recovery Scale – Revised. We further examined the potential contributions of fluctuations in arousal that appeared to co-vary with some patients’ ability to reliably generate EEG signals in response to command. Five of nine patients with statistically indeterminate responses to one task tested showed a positive response after accounting for variations in overall background state (as visualized in the qualitative shape of the power spectrum) and grouping of trial runs with similar background state characteristics. Our findings reveal signal variations of EEG responses in patients with severe brain injuries and provide insight into the underlying physiology of cognitive motor dissociation. These results can help guide future efforts aimed at re-establishment of communication in such patients who will need customization for brain–computer interfaces.
      PubDate: Mon, 19 Mar 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy070
      Issue No: Vol. 141, No. 5 (2018)
  • Artificial limb representation in amputees
    • Authors: van den Heiligenberg F; Orlov T, Macdonald S, et al.
      Pages: 1422 - 1433
      Abstract: The human brain contains multiple hand-selective areas, in both the sensorimotor and visual systems. Could our brain repurpose neural resources, originally developed for supporting hand function, to represent and control artificial limbs' We studied individuals with congenital or acquired hand-loss (hereafter one-handers) using functional MRI. We show that the more one-handers use an artificial limb (prosthesis) in their everyday life, the stronger visual hand-selective areas in the lateral occipitotemporal cortex respond to prosthesis images. This was found even when one-handers were presented with images of active prostheses that share the functionality of the hand but not necessarily its visual features (e.g. a ‘hook’ prosthesis). Further, we show that daily prosthesis usage determines large-scale inter-network communication across hand-selective areas. This was demonstrated by increased resting state functional connectivity between visual and sensorimotor hand-selective areas, proportional to the intensiveness of everyday prosthesis usage. Further analysis revealed a 3-fold coupling between prosthesis activity, visuomotor connectivity and usage, suggesting a possible role for the motor system in shaping use-dependent representation in visual hand-selective areas, and/or vice versa. Moreover, able-bodied control participants who routinely observe prosthesis usage (albeit less intensively than the prosthesis users) showed significantly weaker associations between degree of prosthesis observation and visual cortex activity or connectivity. Together, our findings suggest that altered daily motor behaviour facilitates prosthesis-related visual processing and shapes communication across hand-selective areas. This neurophysiological substrate for prosthesis embodiment may inspire rehabilitation approaches to improve usage of existing substitutionary devices and aid implementation of future assistive and augmentative technologies.
      PubDate: Fri, 09 Mar 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy054
      Issue No: Vol. 141, No. 5 (2018)
  • The striatal kinase DCLK3 produces neuroprotection against mutant
    • Authors: Galvan L; Francelle L, Gaillard M, et al.
      Pages: 1434 - 1454
      Abstract: The neurobiological functions of a number of kinases expressed in the brain are unknown. Here, we report new findings on DCLK3 (doublecortin like kinase 3), which is preferentially expressed in neurons in the striatum and dentate gyrus. Its function has never been investigated. DCLK3 expression is markedly reduced in Huntington’s disease. Recent data obtained in studies related to cancer suggest DCLK3 could have an anti-apoptotic effect. Thus, we hypothesized that early loss of DCLK3 in Huntington’s disease may render striatal neurons more susceptible to mutant huntingtin (mHtt). We discovered that DCLK3 silencing in the striatum of mice exacerbated the toxicity of an N-terminal fragment of mHtt. Conversely, overexpression of DCLK3 reduced neurodegeneration produced by mHtt. DCLK3 also produced beneficial effects on motor symptoms in a knock-in mouse model of Huntington’s disease. Using different mutants of DCLK3, we found that the kinase activity of the protein plays a key role in neuroprotection. To investigate the potential mechanisms underlying DCLK3 effects, we studied the transcriptional changes produced by the kinase domain in human striatal neurons in culture. Results show that DCLK3 regulates in a kinase-dependent manner the expression of many genes involved in transcription regulation and nucleosome/chromatin remodelling. Consistent with this, histological evaluation showed DCLK3 is present in the nucleus of striatal neurons and, protein-protein interaction experiments suggested that the kinase domain interacts with zinc finger proteins, including the transcriptional activator adaptor TADA3, a core component of the Spt-ada-Gcn5 acetyltransferase (SAGA) complex which links histone acetylation to the transcription machinery. Our novel findings suggest that the presence of DCLK3 in striatal neurons may play a key role in transcription regulation and chromatin remodelling in these brain cells, and show that reduced expression of the kinase in Huntington’s disease could render the striatum highly vulnerable to neurodegeneration.
      PubDate: Fri, 09 Mar 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy057
      Issue No: Vol. 141, No. 5 (2018)
  • Distinct effects of apathy and dopamine on effort-based decision-making in
           Parkinson’s disease
    • Authors: Le Heron C; Plant O, Manohar S, et al.
      Pages: 1455 - 1469
      Abstract: Effort-based decision-making is a cognitive process crucial to normal motivated behaviour. Apathy is a common and disabling complication of Parkinson’s disease, but its aetiology remains unclear. Intriguingly, the neural substrates associated with apathy also subserve effort-based decision-making in animal models and humans. Furthermore, the dopaminergic system plays a core role in motivating effortful behaviour for reward, and its dysfunction has been proposed to play a crucial role in the aetiology of apathy in Parkinson’s disease. We hypothesized that disrupted effort-based decision-making underlies the syndrome of apathy in Parkinson’s disease, and that this disruption may be modulated by the dopaminergic system. An effort-based decision-making task was administered to 39 patients with Parkinson’s disease, with and without clinical apathy, ON and OFF their normal dopaminergic medications across two separate sessions, as well as 32 healthy age- and gender-matched controls. On a trial-by-trial basis, participants decided whether to accept or reject offers of monetary reward in return for exerting different levels of physical effort via handheld, individually calibrated dynamometers. Effort and reward were manipulated independently, such that offers spanned the full range of effort/reward combinations. Apathy was assessed using the Lille apathy rating scale. Motor effects of the dopamine manipulation were assessed using the Unified Parkinson’s Disease Rating Scale part three motor score. The primary outcome variable was choice (accept/decline offer) analysed using a hierarchical generalized linear mixed effects model, and the vigour of squeeze (Newtons exerted above required force). Both apathy and dopamine depletion were associated with reduced acceptance of offers. However, these effects were driven by dissociable patterns of responding. While apathy was characterized by increased rejection of predominantly low reward offers, dopamine increased responding to high effort, high reward offers, irrespective of underlying motivational state. Dopamine also exerted a main effect on motor vigour, increasing force production independently of reward offered, while apathy did not affect this measure. The findings demonstrate that disrupted effort-based decision-making underlies Parkinson’s disease apathy, but in a manner distinct to that caused by dopamine depletion. Apathy is associated with reduced incentivization by the rewarding outcomes of actions. In contrast, dopamine has a general effect in motivating behaviour for high effort, high reward options without altering the response pattern that characterizes the apathetic state. Thus, the motivational deficit observed in Parkinson’s disease appears not to be simply secondary to dopaminergic depletion of mesocorticolimbic pathways, suggesting non-dopaminergic therapeutic strategies for apathy may be important future targets.
      PubDate: Mon, 23 Apr 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy110
      Issue No: Vol. 141, No. 5 (2018)
  • Electromagnetic signatures of the preclinical and prodromal stages of
           Alzheimer’s disease
    • Authors: Nakamura A; Cuesta P, Fernández A, et al.
      Pages: 1470 - 1485
      Abstract: Biomarkers useful for the predementia stages of Alzheimer’s disease are needed. Electroencephalography and magnetoencephalography (MEG) are expected to provide potential biomarker candidates for evaluating the predementia stages of Alzheimer’s disease. However, the physiological relevance of EEG/MEG signal changes and their role in pathophysiological processes such as amyloid-β deposition and neurodegeneration need to be elucidated. We evaluated 28 individuals with mild cognitive impairment and 38 cognitively normal individuals, all of whom were further classified into amyloid-β-positive mild cognitive impairment (n = 17, mean age 74.7 ± 5.4 years, nine males), amyloid-β-negative mild cognitive impairment (n = 11, mean age 73.8 ± 8.8 years, eight males), amyloid-β-positive cognitively normal (n = 13, mean age 71.8 ± 4.4 years, seven males), and amyloid-β-negative cognitively normal (n = 25, mean age 72.5 ± 3.4 years, 11 males) individuals using Pittsburgh compound B-PET. We measured resting state MEG for 5 min with the eyes closed, and investigated regional spectral patterns of MEG signals using atlas-based region of interest analysis. Then, the relevance of the regional spectral patterns and their associations with pathophysiological backgrounds were analysed by integrating information from Pittsburgh compound B-PET, fluorodeoxyglucose-PET, structural MRI, and cognitive tests. The results demonstrated that regional spectral patterns of resting state activity could be separated into several types of MEG signatures as follows: (i) the effects of amyloid-β deposition were expressed as the alpha band power augmentation in medial frontal areas; (ii) the delta band power increase in the same region was associated with disease progression within the Alzheimer’s disease continuum and was correlated with entorhinal atrophy and an Alzheimer’s disease-like regional decrease in glucose metabolism; and (iii) the global theta power augmentation, which was previously considered to be an Alzheimer’s disease-related EEG/MEG signature, was associated with general cognitive decline and hippocampal atrophy, but was not specific to Alzheimer’s disease because these changes could be observed in the absence of amyloid-β deposition. The results suggest that these MEG signatures may be useful as unique biomarkers for the predementia stages of Alzheimer’s disease.
      PubDate: Wed, 07 Mar 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy044
      Issue No: Vol. 141, No. 5 (2018)
  • Preferential degradation of cognitive networks differentiates
           Alzheimer’s disease from ageing
    • Authors: Chhatwal J; Schultz A, Johnson K, et al.
      Pages: 1486 - 1500
      Abstract: Converging evidence from structural, metabolic and functional connectivity MRI suggests that neurodegenerative diseases, such as Alzheimer’s disease, target specific neural networks. However, age-related network changes commonly co-occur with neuropathological cascades, limiting efforts to disentangle disease-specific alterations in network function from those associated with normal ageing. Here we elucidate the differential effects of ageing and Alzheimer’s disease pathology through simultaneous analyses of two functional connectivity MRI datasets: (i) young participants harbouring highly-penetrant mutations leading to autosomal-dominant Alzheimer’s disease from the Dominantly Inherited Alzheimer’s Network (DIAN), an Alzheimer’s disease cohort in which age-related comorbidities are minimal and likelihood of progression along an Alzheimer’s disease trajectory is extremely high; and (ii) young and elderly participants from the Harvard Aging Brain Study, a cohort in which imaging biomarkers of amyloid burden and neurodegeneration can be used to disambiguate ageing alone from preclinical Alzheimer’s disease. Consonant with prior reports, we observed the preferential degradation of cognitive (especially the default and dorsal attention networks) over motor and sensory networks in early autosomal-dominant Alzheimer’s disease, and found that this distinctive degradation pattern was magnified in more advanced stages of disease. Importantly, a nascent form of the pattern observed across the autosomal-dominant Alzheimer’s disease spectrum was also detectable in clinically normal elderly with clear biomarker evidence of Alzheimer’s disease pathology (preclinical Alzheimer’s disease). At the more granular level of individual connections between node pairs, we observed that connections within cognitive networks were preferentially targeted in Alzheimer’s disease (with between network connections relatively spared), and that connections between positively coupled nodes (correlations) were preferentially degraded as compared to connections between negatively coupled nodes (anti-correlations). In contrast, ageing in the absence of Alzheimer’s disease biomarkers was characterized by a far less network-specific degradation across cognitive and sensory networks, of between- and within-network connections, and of connections between positively and negatively coupled nodes. We go on to demonstrate that formalizing the differential patterns of network degradation in ageing and Alzheimer’s disease may have the practical benefit of yielding connectivity measurements that highlight early Alzheimer’s disease-related connectivity changes over those due to age-related processes. Together, the contrasting patterns of connectivity in Alzheimer’s disease and ageing add to prior work arguing against Alzheimer’s disease as a form of accelerated ageing, and suggest multi-network composite functional connectivity MRI metrics may be useful in the detection of early Alzheimer’s disease-specific alterations co-occurring with age-related connectivity changes. More broadly, our findings are consistent with a specific pattern of network degradation associated with the spreading of Alzheimer’s disease pathology within targeted neural networks.
      PubDate: Wed, 07 Mar 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy053
      Issue No: Vol. 141, No. 5 (2018)
  • Nucleus basalis of Meynert degeneration precedes and predicts cognitive
           impairment in Parkinson’s disease
    • Authors: Schulz J; Pagano G, Fernández Bonfante J, et al.
      Pages: 1501 - 1516
      Abstract: Currently, no reliable predictors of cognitive impairment in Parkinson’s disease exist. We hypothesized that microstructural changes at grey matter T1-weighted MRI and diffusion tensor imaging in the cholinergic system nuclei and associated limbic pathways underlie cognitive impairment in Parkinson’s disease. We performed a cross-sectional comparison between patients with Parkinson’s disease with and without cognitive impairment. We also performed a longitudinal 36-month follow-up study of cognitively intact Parkinson’s disease patients, comparing patients who remained cognitively intact to those who developed cognitive impairment. Patients with Parkinson’s disease with cognitive impairment showed lower grey matter volume and increased mean diffusivity in the nucleus basalis of Meynert, compared to patients with Parkinson’s disease without cognitive impairment. These results were confirmed both with region of interest and voxel-based analyses, and after partial volume correction. Lower grey matter volume and increased mean diffusivity in the nucleus basalis of Meynert was predictive for developing cognitive impairment in cognitively intact patients with Parkinson’s disease, independent of other clinical and non-clinical markers of the disease. Structural and microstructural alterations in entorhinal cortex, amygdala, hippocampus, insula, and thalamus were not predictive for developing cognitive impairment in Parkinson’s disease. Our findings provide evidence that degeneration of the nucleus basalis of Meynert precedes and predicts the onset of cognitive impairment, and might be used in a clinical setting as a reliable biomarker to stratify patients at higher risk of cognitive decline.
      PubDate: Wed, 21 Mar 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy072
      Issue No: Vol. 141, No. 5 (2018)
  • Longitudinal tau PET in ageing and Alzheimer’s disease
    • Authors: Jack C; Jr, Wiste H, Schwarz C, et al.
      Pages: 1517 - 1528
      Abstract: See Hansson and Mormino (doi:10.1093/brain/awy065) for a scientific commentary on this article.Our objective was to compare different whole-brain and region-specific measurements of within-person change on serial tau PET and evaluate its utility for clinical trials. We studied 126 individuals: 59 cognitively unimpaired with normal amyloid, 37 cognitively unimpaired with abnormal amyloid, and 30 cognitively impaired with an amnestic phenotype and abnormal amyloid. All had baseline amyloid PET and two tau PET, MRI, and clinical assessments. We compared the topography across all cortical regions of interest of tau PET accumulation rates and the rates of four different whole-brain or region-specific meta-regions of interest among the three clinical groups. We computed sample size estimates for change in tau PET, cortical volume, and memory/mental status indices for use as outcome measures in clinical trials. The cognitively unimpaired normal amyloid group had no observable tau accumulation throughout the brain. Tau accumulation rates in cognitively unimpaired abnormal amyloid were low [0.006 standardized uptake value ratio (SUVR), 0.5%, per year] but greater than rates in the cognitively unimpaired normal amyloid group in the basal and mid-temporal, retrosplenial, posterior cingulate, and entorhinal regions of interest. Thus, the earliest elevation in accumulation rates was widespread and not confined to the entorhinal cortex. Tau accumulation rates in the cognitively impaired abnormal amyloid group were 0.053 SUVR (3%) per year and greater than rates in cognitively unimpaired abnormal amyloid in all cortical areas except medial temporal. Rates of accumulation in the four meta-regions of interest differed but only slightly from one another. Among all tau PET meta-regions of interest, sample size estimates were smallest for a temporal lobe composite within cognitively unimpaired abnormal amyloid and for the late Alzheimer’s disease meta-region of interest within cognitively impaired abnormal amyloid. The ordering of the sample size estimates by outcome measure was MRI < tau PET < cognitive measures. At a group-wise level, observable rates of short-term serial tau accumulation were only seen in the presence of abnormal amyloid. As disease progressed to clinically symptomatic stages (cognitively impaired abnormal amyloid), observable rates of tau accumulation were seen uniformly throughout the brain providing evidence that tau does not accumulate in one area at a time or in start-stop, stepwise sequence. The information captured by rate measures in different meta-regions of interest, even those with little topographic overlap, was similar. The implication is that rate measurements from simple meta-regions of interest, without the need for Braak-like staging, may be sufficient to capture progressive within-person accumulation of pathologic tau. Tau PET SUVR measures should be an efficient outcome measure in disease-modifying clinical trials.
      PubDate: Mon, 12 Mar 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy059
      Issue No: Vol. 141, No. 5 (2018)
  • Data-driven models of dominantly-inherited Alzheimer’s disease
    • Authors: Oxtoby N; Young A, Cash D, et al.
      Pages: 1529 - 1544
      Abstract: See Li and Donohue (doi:10.1093/brain/awy089) for a scientific commentary on this article.Dominantly-inherited Alzheimer’s disease is widely hoped to hold the key to developing interventions for sporadic late onset Alzheimer’s disease. We use emerging techniques in generative data-driven disease progression modelling to characterize dominantly-inherited Alzheimer’s disease progression with unprecedented resolution, and without relying upon familial estimates of years until symptom onset. We retrospectively analysed biomarker data from the sixth data freeze of the Dominantly Inherited Alzheimer Network observational study, including measures of amyloid proteins and neurofibrillary tangles in the brain, regional brain volumes and cortical thicknesses, brain glucose hypometabolism, and cognitive performance from the Mini-Mental State Examination (all adjusted for age, years of education, sex, and head size, as appropriate). Data included 338 participants with known mutation status (211 mutation carriers in three subtypes: 163 PSEN1, 17 PSEN2, and 31 APP) and a baseline visit (age 19–66; up to four visits each, 1.1 ± 1.9 years in duration; spanning 30 years before, to 21 years after, parental age of symptom onset). We used an event-based model to estimate sequences of biomarker changes from baseline data across disease subtypes (mutation groups), and a differential equation model to estimate biomarker trajectories from longitudinal data (up to 66 mutation carriers, all subtypes combined). The two models concur that biomarker abnormality proceeds as follows: amyloid deposition in cortical then subcortical regions (∼24 ± 11 years before onset); phosphorylated tau (17 ± 8 years), tau and amyloid-β changes in cerebrospinal fluid; neurodegeneration first in the putamen and nucleus accumbens (up to 6 ± 2 years); then cognitive decline (7 ± 6 years), cerebral hypometabolism (4 ± 4 years), and further regional neurodegeneration. Our models predicted symptom onset more accurately than predictions that used familial estimates: root mean squared error of 1.35 years versus 5.54 years. The models reveal hidden detail on dominantly-inherited Alzheimer’s disease progression, as well as providing data-driven systems for fine-grained patient staging and prediction of symptom onset with great potential utility in clinical trials.
      PubDate: Thu, 22 Mar 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy050
      Issue No: Vol. 141, No. 5 (2018)
  • A neurocomputational account of reward and novelty processing and effects
           of psychostimulants in attention deficit hyperactivity disorder
    • Authors: Sethi A; Voon V, Critchley H, et al.
      Pages: 1545 - 1557
      Abstract: Computational models of reinforcement learning have helped dissect discrete components of reward-related function and characterize neurocognitive deficits in psychiatric illnesses. Stimulus novelty biases decision-making, even when unrelated to choice outcome, acting as if possessing intrinsic reward value to guide decisions toward uncertain options. Heightened novelty seeking is characteristic of attention deficit hyperactivity disorder, yet how this influences reward-related decision-making is computationally encoded, or is altered by stimulant medication, is currently uncertain. Here we used an established reinforcement-learning task to model effects of novelty on reward-related behaviour during functional MRI in 30 adults with attention deficit hyperactivity disorder and 30 age-, sex- and IQ-matched control subjects. Each participant was tested on two separate occasions, once ON and once OFF stimulant medication. OFF medication, patients with attention deficit hyperactivity disorder showed significantly impaired task performance (P = 0.027), and greater selection of novel options (P = 0.004). Moreover, persistence in selecting novel options predicted impaired task performance (P = 0.025). These behavioural deficits were accompanied by a significantly lower learning rate (P = 0.011) and heightened novelty signalling within the substantia nigra/ventral tegmental area (family-wise error corrected P < 0.05). Compared to effects in controls, stimulant medication improved attention deficit hyperactivity disorder participants’ overall task performance (P = 0.011), increased reward-learning rates (P = 0.046) and enhanced their ability to differentiate optimal from non-optimal novel choices (P = 0.032). It also reduced substantia nigra/ventral tegmental area responses to novelty. Preliminary cross-sectional evidence additionally suggested an association between long-term stimulant treatment and a reduction in the rewarding value of novelty. These data suggest that aberrant substantia nigra/ventral tegmental area novelty processing plays an important role in the suboptimal reward-related decision-making characteristic of attention deficit hyperactivity disorder. Compared to effects in controls, abnormalities in novelty processing and reward-related learning were improved by stimulant medication, suggesting that they may be disorder-specific targets for the pharmacological management of attention deficit hyperactivity disorder symptoms.
      PubDate: Tue, 13 Mar 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy048
      Issue No: Vol. 141, No. 5 (2018)
  • Altruistic decisions following penetrating traumatic brain injury
    • Authors: Moll J; de Oliveira-Souza R, Basilio R, et al.
      Pages: 1558 - 1569
      Abstract: The cerebral correlates of altruistic decisions have increasingly attracted the interest of neuroscientists. To date, investigations on the neural underpinnings of altruistic decisions have primarily been conducted in healthy adults undergoing functional neuroimaging as they engaged in decisions to punish third parties. The chief purpose of the present study was to investigate altruistic decisions following focal brain damage with a novel altruistic decision task. In contrast to studies that have focused either on altruistic punishment or donation, the Altruistic Decision Task allows players to anonymously punish or donate to 30 charitable organizations involved with salient societal issues such as abortion, nuclear energy and civil rights. Ninety-four Vietnam War veterans with variable patterns of penetrating traumatic brain injury and 28 healthy veterans who also served in combat participated in the study as normal controls. Participants were asked to invest $1 to punish or reward real societal organizations, or keep the money for themselves. Associations between lesion distribution and performance on the task were analysed with multivariate support vector regression, which enables the assessment of the joint contribution of multiple regions in the determination of a given behaviour of interest. Our main findings were: (i) bilateral dorsomedial prefrontal lesions increased altruistic punishment, whereas lesions of the right perisylvian region and left temporo-insular cortex decreased punishment; (ii) altruistic donations were increased by bilateral lesions of the dorsomedial parietal cortex, whereas lesions of the right posterior superior temporal sulcus and middle temporal gyri decreased donations; (iii) altruistic punishment and donation were only weakly correlated, emphasizing their dissociable neuroanatomical associations; and (iv) altruistic decisions were not related to post-traumatic personality changes. These findings indicate that altruistic punishment and donation are determined by largely non-overlapping cerebral regions, which have previously been implicated in social cognition and moral experience such as evaluations of intentionality and intuitions of justice and morality.10.1093/brain/awy064_video1awy064media15758316955001
      PubDate: Sat, 24 Mar 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy064
      Issue No: Vol. 141, No. 5 (2018)
  • How the coming of the NHS changed British neurology
    • Authors: Shorvon S.
      Pages: 1570 - 1575
      Abstract: Figure 1The British National Health Service (NHS) celebrates its 70th anniversary on July 5th 2018. Simon Shorvon paints a picture of professional neurological practice in the early days of the NHS, describing the pressing issues of the time, and the far-reaching changes that occurred as the NHS gathered its stride.
      PubDate: Fri, 06 Apr 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy090
      Issue No: Vol. 141, No. 5 (2018)
  • Corrigendum
    • Abstract: Yoshitsugu Aoki, Raquel Manzano, Yi Lee, Ruxandra Dafinca, Misako Aoki, Andrew G. L. Douglas, Miguel A. Varela, Chaitra Sathyaprakash, Jakub Scaber, Paola Barbagallo, Pieter Vader, Imre Mäger, Kariem Ezzat, Martin R. Turner, Naoki Ito, Samanta Gasco, Norihiko Ohbayashi, Samir El Andaloussi, Shin’ichi Takeda, Mitsunori Fukuda, Kevin Talbot and Matthew J. A. Wood. C9orf72 and RAB7L1 regulate vesicle trafficking in amyotrophic lateral sclerosis and frontotemporal dementia. BRAIN 2017; 140: doi:10.1093/brain/awx024.
      PubDate: Sat, 18 Mar 2017 00:00:00 GMT
      DOI: 10.1093/brain/awx078
      Issue No: Vol. 141, No. 5 (2017)
School of Mathematical and Computer Sciences
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