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Publisher: Oxford University Press   (Total: 396 journals)

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Showing 1 - 200 of 396 Journals sorted alphabetically
ACS Symposium Series     Full-text available via subscription   (SJR: 0.189, CiteScore: 0)
Acta Biochimica et Biophysica Sinica     Hybrid Journal   (Followers: 5, SJR: 0.79, CiteScore: 2)
Adaptation     Hybrid Journal   (Followers: 9, SJR: 0.143, CiteScore: 0)
Advances in Nutrition     Hybrid Journal   (Followers: 48, SJR: 2.196, CiteScore: 5)
Aesthetic Surgery J.     Hybrid Journal   (Followers: 6, SJR: 1.434, CiteScore: 1)
African Affairs     Hybrid Journal   (Followers: 64, SJR: 1.869, CiteScore: 2)
Age and Ageing     Hybrid Journal   (Followers: 91, SJR: 1.989, CiteScore: 4)
Alcohol and Alcoholism     Hybrid Journal   (Followers: 18, SJR: 1.376, CiteScore: 3)
American Entomologist     Full-text available via subscription   (Followers: 7)
American Historical Review     Hybrid Journal   (Followers: 155, SJR: 0.467, CiteScore: 1)
American J. of Agricultural Economics     Hybrid Journal   (Followers: 41, SJR: 2.113, CiteScore: 3)
American J. of Clinical Nutrition     Hybrid Journal   (Followers: 153, SJR: 3.438, CiteScore: 6)
American J. of Epidemiology     Hybrid Journal   (Followers: 180, SJR: 2.713, CiteScore: 3)
American J. of Hypertension     Hybrid Journal   (Followers: 25, SJR: 1.322, CiteScore: 3)
American J. of Jurisprudence     Hybrid Journal   (Followers: 18, SJR: 0.281, CiteScore: 1)
American J. of Legal History     Full-text available via subscription   (Followers: 8, SJR: 0.116, CiteScore: 0)
American Law and Economics Review     Hybrid Journal   (Followers: 27, SJR: 1.053, CiteScore: 1)
American Literary History     Hybrid Journal   (Followers: 15, SJR: 0.391, CiteScore: 0)
Analysis     Hybrid Journal   (Followers: 21, SJR: 1.038, CiteScore: 1)
Animal Frontiers     Hybrid Journal  
Annals of Behavioral Medicine     Hybrid Journal   (Followers: 15, SJR: 1.423, CiteScore: 3)
Annals of Botany     Hybrid Journal   (Followers: 36, SJR: 1.721, CiteScore: 4)
Annals of Oncology     Hybrid Journal   (Followers: 45, SJR: 5.599, CiteScore: 9)
Annals of the Entomological Society of America     Full-text available via subscription   (Followers: 10, SJR: 0.722, CiteScore: 1)
Annals of Work Exposures and Health     Hybrid Journal   (Followers: 32, SJR: 0.728, CiteScore: 2)
AoB Plants     Open Access   (Followers: 4, SJR: 1.28, CiteScore: 3)
Applied Economic Perspectives and Policy     Hybrid Journal   (Followers: 18, SJR: 0.858, CiteScore: 2)
Applied Linguistics     Hybrid Journal   (Followers: 56, SJR: 2.987, CiteScore: 3)
Applied Mathematics Research eXpress     Hybrid Journal   (Followers: 1, SJR: 1.241, CiteScore: 1)
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: 0.731, CiteScore: 2)
Aristotelian Society Supplementary Volume     Hybrid Journal   (Followers: 3)
Arthropod Management Tests     Hybrid Journal   (Followers: 2)
Astronomy & Geophysics     Hybrid Journal   (Followers: 43, SJR: 0.146, CiteScore: 0)
Behavioral Ecology     Hybrid Journal   (Followers: 52, SJR: 1.871, CiteScore: 3)
Bioinformatics     Hybrid Journal   (Followers: 307, SJR: 6.14, CiteScore: 8)
Biology Methods and Protocols     Hybrid Journal  
Biology of Reproduction     Full-text available via subscription   (Followers: 10, SJR: 1.446, CiteScore: 3)
Biometrika     Hybrid Journal   (Followers: 20, SJR: 3.485, CiteScore: 2)
BioScience     Hybrid Journal   (Followers: 29, SJR: 2.754, CiteScore: 4)
Bioscience Horizons : The National Undergraduate Research J.     Open Access   (Followers: 1, SJR: 0.146, CiteScore: 0)
Biostatistics     Hybrid Journal   (Followers: 17, SJR: 1.553, CiteScore: 2)
BJA : British J. of Anaesthesia     Hybrid Journal   (Followers: 167, SJR: 2.115, CiteScore: 3)
BJA Education     Hybrid Journal   (Followers: 64)
Brain     Hybrid Journal   (Followers: 68, SJR: 5.858, CiteScore: 7)
Briefings in Bioinformatics     Hybrid Journal   (Followers: 49, SJR: 2.505, CiteScore: 5)
Briefings in Functional Genomics     Hybrid Journal   (Followers: 3, SJR: 2.15, CiteScore: 3)
British J. for the Philosophy of Science     Hybrid Journal   (Followers: 35, SJR: 2.161, CiteScore: 2)
British J. of Aesthetics     Hybrid Journal   (Followers: 26, SJR: 0.508, CiteScore: 1)
British J. of Criminology     Hybrid Journal   (Followers: 588, SJR: 1.828, CiteScore: 3)
British J. of Social Work     Hybrid Journal   (Followers: 88, SJR: 1.019, CiteScore: 2)
British Medical Bulletin     Hybrid Journal   (Followers: 7, SJR: 1.355, CiteScore: 3)
British Yearbook of Intl. Law     Hybrid Journal   (Followers: 32)
Bulletin of the London Mathematical Society     Hybrid Journal   (Followers: 4, SJR: 1.376, CiteScore: 1)
Cambridge J. of Economics     Hybrid Journal   (Followers: 63, SJR: 0.764, CiteScore: 2)
Cambridge J. of Regions, Economy and Society     Hybrid Journal   (Followers: 11, SJR: 2.438, CiteScore: 4)
Cambridge Quarterly     Hybrid Journal   (Followers: 9, SJR: 0.104, CiteScore: 0)
Capital Markets Law J.     Hybrid Journal   (Followers: 2, SJR: 0.222, CiteScore: 0)
Carcinogenesis     Hybrid Journal   (Followers: 2, SJR: 2.135, CiteScore: 5)
Cardiovascular Research     Hybrid Journal   (Followers: 14, SJR: 3.002, CiteScore: 5)
Cerebral Cortex     Hybrid Journal   (Followers: 45, SJR: 3.892, CiteScore: 6)
CESifo Economic Studies     Hybrid Journal   (Followers: 17, SJR: 0.483, CiteScore: 1)
Chemical Senses     Hybrid Journal   (Followers: 1, SJR: 1.42, CiteScore: 3)
Children and Schools     Hybrid Journal   (Followers: 5, SJR: 0.246, CiteScore: 0)
Chinese J. of Comparative Law     Hybrid Journal   (Followers: 4, SJR: 0.412, CiteScore: 0)
Chinese J. of Intl. Law     Hybrid Journal   (Followers: 23, SJR: 0.329, CiteScore: 0)
Chinese J. of Intl. Politics     Hybrid Journal   (Followers: 10, SJR: 1.392, CiteScore: 2)
Christian Bioethics: Non-Ecumenical Studies in Medical Morality     Hybrid Journal   (Followers: 10, SJR: 0.183, CiteScore: 0)
Classical Receptions J.     Hybrid Journal   (Followers: 27, SJR: 0.123, CiteScore: 0)
Clean Energy     Open Access   (Followers: 1)
Clinical Infectious Diseases     Hybrid Journal   (Followers: 65, SJR: 5.051, CiteScore: 5)
Clinical Kidney J.     Open Access   (Followers: 3, SJR: 1.163, CiteScore: 2)
Communication Theory     Hybrid Journal   (Followers: 23, SJR: 2.424, CiteScore: 3)
Communication, Culture & Critique     Hybrid Journal   (Followers: 27, SJR: 0.222, CiteScore: 1)
Community Development J.     Hybrid Journal   (Followers: 27, SJR: 0.268, CiteScore: 1)
Computer J.     Hybrid Journal   (Followers: 9, SJR: 0.319, CiteScore: 1)
Conservation Physiology     Open Access   (Followers: 2, SJR: 1.818, CiteScore: 3)
Contemporary Women's Writing     Hybrid Journal   (Followers: 9, SJR: 0.121, CiteScore: 0)
Contributions to Political Economy     Hybrid Journal   (Followers: 5, SJR: 0.906, CiteScore: 1)
Critical Values     Full-text available via subscription  
Current Developments in Nutrition     Open Access   (Followers: 1)
Current Legal Problems     Hybrid Journal   (Followers: 29)
Current Zoology     Full-text available via subscription   (Followers: 2, SJR: 1.164, CiteScore: 2)
Database : The J. of Biological Databases and Curation     Open Access   (Followers: 8, SJR: 1.791, CiteScore: 3)
Digital Scholarship in the Humanities     Hybrid Journal   (Followers: 14, SJR: 0.259, CiteScore: 1)
Diplomatic History     Hybrid Journal   (Followers: 20, SJR: 0.45, CiteScore: 1)
DNA Research     Open Access   (Followers: 5, SJR: 2.866, CiteScore: 6)
Dynamics and Statistics of the Climate System     Open Access   (Followers: 4)
Early Music     Hybrid Journal   (Followers: 15, SJR: 0.139, CiteScore: 0)
Economic Policy     Hybrid Journal   (Followers: 40, SJR: 3.584, CiteScore: 3)
ELT J.     Hybrid Journal   (Followers: 24, SJR: 0.942, CiteScore: 1)
English Historical Review     Hybrid Journal   (Followers: 54, SJR: 0.612, CiteScore: 1)
English: J. of the English Association     Hybrid Journal   (Followers: 14, SJR: 0.1, CiteScore: 0)
Environmental Entomology     Full-text available via subscription   (Followers: 11, SJR: 0.818, CiteScore: 2)
Environmental Epigenetics     Open Access   (Followers: 3)
Environmental History     Hybrid Journal   (Followers: 27, SJR: 0.408, CiteScore: 1)
EP-Europace     Hybrid Journal   (Followers: 2, SJR: 2.748, CiteScore: 4)
Epidemiologic Reviews     Hybrid Journal   (Followers: 9, SJR: 4.505, CiteScore: 8)
ESHRE Monographs     Hybrid Journal  
Essays in Criticism     Hybrid Journal   (Followers: 17, SJR: 0.113, CiteScore: 0)
European Heart J.     Hybrid Journal   (Followers: 57, SJR: 9.315, CiteScore: 9)
European Heart J. - Cardiovascular Imaging     Hybrid Journal   (Followers: 9, SJR: 3.625, CiteScore: 3)
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. : Case Reports     Open Access  
European Heart J. Supplements     Hybrid Journal   (Followers: 8, SJR: 0.223, CiteScore: 0)
European J. of Cardio-Thoracic Surgery     Hybrid Journal   (Followers: 9, SJR: 1.681, CiteScore: 2)
European J. of Intl. Law     Hybrid Journal   (Followers: 188, SJR: 0.694, CiteScore: 1)
European J. of Orthodontics     Hybrid Journal   (Followers: 4, SJR: 1.279, CiteScore: 2)
European J. of Public Health     Hybrid Journal   (Followers: 20, SJR: 1.36, CiteScore: 2)
European Review of Agricultural Economics     Hybrid Journal   (Followers: 10, SJR: 1.172, CiteScore: 2)
European Review of Economic History     Hybrid Journal   (Followers: 29, SJR: 0.702, CiteScore: 1)
European Sociological Review     Hybrid Journal   (Followers: 41, SJR: 2.728, CiteScore: 3)
Evolution, Medicine, and Public Health     Open Access   (Followers: 11)
Family Practice     Hybrid Journal   (Followers: 16, SJR: 1.018, CiteScore: 2)
Fems Microbiology Ecology     Hybrid Journal   (Followers: 12, SJR: 1.492, CiteScore: 4)
Fems Microbiology Letters     Hybrid Journal   (Followers: 25, SJR: 0.79, CiteScore: 2)
Fems Microbiology Reviews     Hybrid Journal   (Followers: 30, SJR: 7.063, CiteScore: 13)
Fems Yeast Research     Hybrid Journal   (Followers: 14, SJR: 1.308, CiteScore: 3)
Food Quality and Safety     Open Access   (Followers: 1)
Foreign Policy Analysis     Hybrid Journal   (Followers: 24, SJR: 1.425, CiteScore: 1)
Forest Science     Hybrid Journal   (Followers: 7, SJR: 0.89, CiteScore: 2)
Forestry: An Intl. J. of Forest Research     Hybrid Journal   (Followers: 16, SJR: 1.133, CiteScore: 3)
Forum for Modern Language Studies     Hybrid Journal   (Followers: 6, SJR: 0.104, CiteScore: 0)
French History     Hybrid Journal   (Followers: 33, SJR: 0.118, CiteScore: 0)
French Studies     Hybrid Journal   (Followers: 20, SJR: 0.148, CiteScore: 0)
French Studies Bulletin     Hybrid Journal   (Followers: 10, SJR: 0.152, CiteScore: 0)
Gastroenterology Report     Open Access   (Followers: 2)
Genome Biology and Evolution     Open Access   (Followers: 13, SJR: 2.578, CiteScore: 4)
Geophysical J. Intl.     Hybrid Journal   (Followers: 35, SJR: 1.506, CiteScore: 3)
German History     Hybrid Journal   (Followers: 23, SJR: 0.161, CiteScore: 0)
GigaScience     Open Access   (Followers: 4, SJR: 5.022, CiteScore: 7)
Global Summitry     Hybrid Journal   (Followers: 1)
Glycobiology     Hybrid Journal   (Followers: 14, SJR: 1.493, CiteScore: 3)
Health and Social Work     Hybrid Journal   (Followers: 56, SJR: 0.388, CiteScore: 1)
Health Education Research     Hybrid Journal   (Followers: 15, SJR: 0.854, CiteScore: 2)
Health Policy and Planning     Hybrid Journal   (Followers: 24, SJR: 1.512, CiteScore: 2)
Health Promotion Intl.     Hybrid Journal   (Followers: 22, SJR: 0.812, CiteScore: 2)
History Workshop J.     Hybrid Journal   (Followers: 31, SJR: 1.278, CiteScore: 1)
Holocaust and Genocide Studies     Hybrid Journal   (Followers: 28, SJR: 0.105, CiteScore: 0)
Human Communication Research     Hybrid Journal   (Followers: 14, SJR: 2.146, CiteScore: 3)
Human Molecular Genetics     Hybrid Journal   (Followers: 8, SJR: 3.555, CiteScore: 5)
Human Reproduction     Hybrid Journal   (Followers: 71, SJR: 2.643, CiteScore: 5)
Human Reproduction Open     Open Access  
Human Reproduction Update     Hybrid Journal   (Followers: 19, SJR: 5.317, CiteScore: 10)
Human Rights Law Review     Hybrid Journal   (Followers: 57, SJR: 0.756, CiteScore: 1)
ICES J. of Marine Science: J. du Conseil     Hybrid Journal   (Followers: 52, SJR: 1.591, CiteScore: 3)
ICSID Review     Hybrid Journal   (Followers: 10)
ILAR J.     Hybrid Journal   (Followers: 2, SJR: 1.732, CiteScore: 4)
IMA J. of Applied Mathematics     Hybrid Journal   (SJR: 0.679, CiteScore: 1)
IMA J. of Management Mathematics     Hybrid Journal   (SJR: 0.538, CiteScore: 1)
IMA J. of Mathematical Control and Information     Hybrid Journal   (Followers: 2, SJR: 0.496, CiteScore: 1)
IMA J. of Numerical Analysis - advance access     Hybrid Journal   (SJR: 1.987, CiteScore: 2)
Industrial and Corporate Change     Hybrid Journal   (Followers: 10, SJR: 1.792, CiteScore: 2)
Industrial Law J.     Hybrid Journal   (Followers: 36, SJR: 0.249, CiteScore: 1)
Inflammatory Bowel Diseases     Hybrid Journal   (Followers: 44, SJR: 2.511, CiteScore: 4)
Information and Inference     Free  
Integrative and Comparative Biology     Hybrid Journal   (Followers: 8, SJR: 1.319, CiteScore: 2)
Interacting with Computers     Hybrid Journal   (Followers: 11, SJR: 0.292, CiteScore: 1)
Interactive CardioVascular and Thoracic Surgery     Hybrid Journal   (Followers: 7, SJR: 0.762, CiteScore: 1)
Intl. Affairs     Hybrid Journal   (Followers: 61, SJR: 1.505, CiteScore: 3)
Intl. Data Privacy Law     Hybrid Journal   (Followers: 25)
Intl. Health     Hybrid Journal   (Followers: 6, SJR: 0.851, CiteScore: 2)
Intl. Immunology     Hybrid Journal   (Followers: 3, SJR: 2.167, CiteScore: 4)
Intl. J. for Quality in Health Care     Hybrid Journal   (Followers: 37, SJR: 1.348, CiteScore: 2)
Intl. J. of Constitutional Law     Hybrid Journal   (Followers: 63, SJR: 0.601, CiteScore: 1)
Intl. J. of Epidemiology     Hybrid Journal   (Followers: 234, SJR: 3.969, CiteScore: 5)
Intl. J. of Law and Information Technology     Hybrid Journal   (Followers: 5, SJR: 0.202, CiteScore: 1)
Intl. J. of Law, Policy and the Family     Hybrid Journal   (Followers: 25, SJR: 0.223, CiteScore: 1)
Intl. J. of Lexicography     Hybrid Journal   (Followers: 9, SJR: 0.285, CiteScore: 1)
Intl. J. of Low-Carbon Technologies     Open Access   (Followers: 1, SJR: 0.403, CiteScore: 1)
Intl. J. of Neuropsychopharmacology     Open Access   (Followers: 3, SJR: 1.808, CiteScore: 4)
Intl. J. of Public Opinion Research     Hybrid Journal   (Followers: 11, SJR: 1.545, CiteScore: 1)
Intl. J. of Refugee Law     Hybrid Journal   (Followers: 35, SJR: 0.389, CiteScore: 1)
Intl. J. of Transitional Justice     Hybrid Journal   (Followers: 11, SJR: 0.724, CiteScore: 2)
Intl. Mathematics Research Notices     Hybrid Journal   (Followers: 1, SJR: 2.168, CiteScore: 1)
Intl. Political Sociology     Hybrid Journal   (Followers: 39, SJR: 1.465, CiteScore: 3)
Intl. Relations of the Asia-Pacific     Hybrid Journal   (Followers: 23, SJR: 0.401, CiteScore: 1)
Intl. Studies Perspectives     Hybrid Journal   (Followers: 9, SJR: 0.983, CiteScore: 1)
Intl. Studies Quarterly     Hybrid Journal   (Followers: 46, SJR: 2.581, CiteScore: 2)
Intl. Studies Review     Hybrid Journal   (Followers: 24, SJR: 1.201, CiteScore: 1)
ISLE: Interdisciplinary Studies in Literature and Environment     Hybrid Journal   (Followers: 2, SJR: 0.15, CiteScore: 0)
ITNOW     Hybrid Journal   (Followers: 1, SJR: 0.103, CiteScore: 0)
J. of African Economies     Hybrid Journal   (Followers: 15, SJR: 0.533, CiteScore: 1)
J. of American History     Hybrid Journal   (Followers: 46, SJR: 0.297, CiteScore: 1)
J. of Analytical Toxicology     Hybrid Journal   (Followers: 14, SJR: 1.065, CiteScore: 2)
J. of Antimicrobial Chemotherapy     Hybrid Journal   (Followers: 15, SJR: 2.419, CiteScore: 4)
J. of Antitrust Enforcement     Hybrid Journal   (Followers: 1)
J. of Applied Poultry Research     Hybrid Journal   (Followers: 4, SJR: 0.585, CiteScore: 1)
J. of Biochemistry     Hybrid Journal   (Followers: 40, SJR: 1.226, CiteScore: 2)
J. of Burn Care & Research     Hybrid Journal   (Followers: 9, SJR: 0.768, CiteScore: 2)
J. of Chromatographic Science     Hybrid Journal   (Followers: 18, SJR: 0.36, CiteScore: 1)
J. of Church and State     Hybrid Journal   (Followers: 11, SJR: 0.139, CiteScore: 0)
J. of Communication     Hybrid Journal   (Followers: 54, SJR: 4.411, CiteScore: 5)
J. of Competition Law and Economics     Hybrid Journal   (Followers: 35, SJR: 0.33, CiteScore: 0)
J. of Complex Networks     Hybrid Journal   (Followers: 2, SJR: 1.05, CiteScore: 4)
J. of Computer-Mediated Communication     Open Access   (Followers: 28, SJR: 2.961, CiteScore: 6)
J. of Conflict and Security Law     Hybrid Journal   (Followers: 12, SJR: 0.402, CiteScore: 0)
J. of Consumer Research     Full-text available via subscription   (Followers: 46, SJR: 5.856, CiteScore: 5)

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Journal Cover
Journal Prestige (SJR): 5.858
Citation Impact (citeScore): 7
Number of Followers: 68  
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0006-8950 - ISSN (Online) 1460-2156
Published by Oxford University Press Homepage  [396 journals]
  • Brain oscillations, inhibition and social inappropriateness in
           frontotemporal degeneration
    • Authors: Ibáñez A.
      Abstract: Sir,
      PubDate: Wed, 12 Sep 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy233
      Issue No: Vol. 141, No. 10 (2018)
  • Reply: Brain oscillations, inhibition and social inappropriateness in
           frontotemporal degeneration
    • Authors: Hughes L; Rittman T, Robbins T, et al.
      Abstract: Sir,
      PubDate: Wed, 12 Sep 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy235
      Issue No: Vol. 141, No. 10 (2018)
  • Two cases of CLIPPERS with increased number of perivascular CD20-positive
           B lymphocytes
    • Authors: Yi F; Tian Y, Chen X, et al.
      Abstract: Sir,
      PubDate: Thu, 06 Sep 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy234
      Issue No: Vol. 141, No. 10 (2018)
  • Reply: Two cases of CLIPPERS with increased number of perivascular
           CD20-positive B lymphocytes
    • Authors: Tobin W; Guo Y, Keegan B.
      Abstract: Sir,
      PubDate: Thu, 06 Sep 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy236
      Issue No: Vol. 141, No. 10 (2018)
  • Stem cell therapies in neurology: the good, the bad and the unknown
    • Authors: Lyon L.
      Abstract: Figure 1
      PubDate: Thu, 06 Sep 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy221
      Issue No: Vol. 141, No. 10 (2018)
  • Editorial
    • Authors: Kullmann D.
      Pages: 2823 - 2823
      Abstract: In this issue of Brain, Alex Doets, Christine Verboon, Bianca van den Berg and colleagues report the results of an international study of Guillain-Barré syndrome, which shows a higher frequency of pure motor presentation in Bangladesh, and of axonal subtype on electrophysiology, than in Europe/Americas and the rest of Asia. They also report regional differences in the incidence of the Miller Fisher variant and in outcome. It is unclear to what extent these differences relate to different rates of exposure to Campylobacter jejuni, which has been blamed for seasonal fluctuations in axonal Guillain-Barré syndrome in China. The epidemiology of neuro-immunological disease will no doubt continue to evolve, as witnessed by outbreaks of Guillain-Barré syndrome in South America shortly after the arrival of Zika virus on the continent a few years ago.
      PubDate: Tue, 25 Sep 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy249
      Issue No: Vol. 141, No. 10 (2018)
  • Quantitative postural models as biomarkers of balance in Parkinson’s
    • Authors: Xiang M; Glasauer S, Seemungal B.
      Pages: 2824 - 2827
      Abstract: This scientific commentary refers to ‘Balance control systems in Parkinson’s disease and the impact of pedunculopontine area stimulation’, by Perera et al.. (doi:10.1093/brain/awy216).
      PubDate: Tue, 25 Sep 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy250
      Issue No: Vol. 141, No. 10 (2018)
  • Stimulating cingulate: distinct behaviours arise from discrete zones
    • Authors: Apps M.
      Pages: 2827 - 2830
      Abstract: This scientific commentary refers to ‘Motor and emotional behaviours elicited by electrical stimulation of the human cingulate cortex’, by Caruana et al.. (doi:10.1093/brain/awy219).
      PubDate: Tue, 25 Sep 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy224
      Issue No: Vol. 141, No. 10 (2018)
  • Where do white matter alterations dovetail with the cascade model of
           Alzheimer’s disease'
    • Authors: Jacobs H; Buckley R.
      Pages: 2830 - 2833
      Abstract: This scientific commentary refers to ‘White matter diffusion alterations precede symptom onset in autosomal dominant Alzheimer’s disease’, by Araque Caballero et al.. (doi:10.1093/brain/awy229).
      PubDate: Tue, 25 Sep 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy243
      Issue No: Vol. 141, No. 10 (2018)
  • Learning from other autoimmunities to understand targeting of B cells to
           control multiple sclerosis
    • Authors: Baker D; Pryce G, Amor S, et al.
      Pages: 2834 - 2847
      Abstract: Although many suspected autoimmune diseases are thought to be T cell-mediated, the response to therapy indicates that depletion of B cells consistently inhibits disease activity. In multiple sclerosis, it appears that disease suppression is associated with the long-term reduction of memory B cells, which serves as a biomarker for disease activity in many other CD20+ B cell depletion-sensitive, autoimmune diseases. Following B cell depletion, the rapid repopulation by transitional (immature) and naïve (mature) B cells from the bone marrow masks the marked depletion and slow repopulation of lymphoid tissue-derived, memory B cells. This can provide long-term protection from a short treatment cycle. It seems that memory B cells, possibly via T cell stimulation, drive relapsing disease. However, their sequestration in ectopic follicles and the chronic activity of B cells and plasma cells in the central nervous system may drive progressive neurodegeneration directly via antigen-specific mechanisms or indirectly via glial-dependent mechanisms. While unproven, Epstein-Barr virus may be an aetiological trigger of multiple sclerosis. This infects mature B cells, drives the production of memory B cells and possibly provides co-stimulatory signals promoting T cell-independent activation that breaks immune tolerance to generate autoreactivity. Thus, a memory B cell centric mechanism can integrate: potential aetiology, genetics, pathology and response to therapy in multiple sclerosis and other autoimmune conditions with ectopic B cell activation that are responsive to memory B cell-depleting strategies.
      PubDate: Wed, 12 Sep 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy239
      Issue No: Vol. 141, No. 10 (2018)
  • Apathy in rapid eye movement sleep behaviour disorder is associated with
           serotonin depletion in the dorsal raphe nucleus
    • Authors: Barber T; Griffanti L, Muhammed K, et al.
      Pages: 2848 - 2854
      Abstract: Apathy is a common and under-recognized disorder that often emerges in the prodromal phase of Parkinsonian diseases. The mechanism by which this occurs is not known, but recent evidence from patients with established Parkinson’s disease suggests that serotonergic dysfunction may play a role. The integrity of the raphe serotonergic system can be assessed alongside dopaminergic basal ganglia imaging using the radioligand 123I-ioflupane, which binds both serotonin and dopamine transporters. To investigate the relative roles of these neurotransmitters in prodromal parkinsonism, we imaged patients with idiopathic rapid eye movement sleep behaviour disorder, the majority of whom will develop a parkinsonian disorder in future. Forty-three patients underwent brain imaging with 123I-ioflupane single photon emission computed tomography and structural MRI. Apathy was quantified using the Lille Apathy Rating Scale. Other clinical parkinsonian features were assessed using standard measures. A negative correlation was observed between apathy severity and serotonergic 123I-ioflupane signal in the dorsal raphe nucleus (r = −0.55, P < 0.001). There was no significant correlation between apathy severity and basal ganglia dopaminergic signal, nor between dorsal raphe signal and other neuropsychiatric scores. This specific association between apathy and raphe 123I-ioflupane signal suggests that the serotonergic system might represent a target for the treatment of apathy.
      PubDate: Wed, 12 Sep 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy240
      Issue No: Vol. 141, No. 10 (2018)
  • Improved mobility with metformin in patients with myotonic dystrophy type
           1: a randomized controlled trial
    • Authors: Bassez G; Audureau E, Hogrel J, et al.
      Pages: 2855 - 2865
      Abstract: Metformin, the well-known anti-diabetic drug, has been shown recently to improve the grip test performance of the DMSXL mouse model of myotonic dystrophy type 1. The drug may have positively affected muscle function via several molecular mechanisms, on RNA splicing, autophagia, insulin sensitivity or glycogen synthesis. Myotonic dystrophy remains essentially an unmet medical need. Since metformin benefits from a good toxicity profile, we investigated its potential for improving mobility in patients. Forty ambulatory adult patients were recruited consecutively at the neuromuscular reference centre of Henri-Mondor Hospital. Participants and investigators were all blinded to treatment until the end of the trial. Oral metformin or placebo was provided three times daily, with a dose-escalation period over 4 weeks up to 3 g/day, followed by 48 weeks at maximum dose. The primary outcome was the change in the distance walked during the 6-minute walk test, from baseline to the end of the study. Concomitant changes in muscle strength and effect on myotonia, gait variables, biological parameters and quality of life were explored. Patients randomized into two arms eventually revealed similar results in all physical measures and in the mean 6-minute walk test at baseline. For the 23/40 patients who fully completed the 1-year study, differences between the groups were statistically significant, with the treated group (n = 9) gaining a distance of 32.9 ± 32.7 m, while the placebo group (n = 14) gained 3.7 ± 32.4 m (P < 0.05). This improvement in mobility was associated with an increase in total mechanical power (P = 0.01), due to a concomitant increase in the cranial and antero-posterior directions suggesting an effect of the treatment on gait. Subanalysis revealed positive effects of metformin treatment on the 6-minute walk test at the first intermediate evaluation (after 16 weeks of treatment), quantitatively similar to those recorded at 1 year. In contrast, except for the expected limited weight loss associated to metformin treatment, there was no change in any of the other secondary endpoints, including myotonia and muscle strength. Patients in the treated group had a higher incidence of mild-to-moderate adverse effects, mostly gastrointestinal dysfunctions that required symptomatic treatment. Although results were statistically significant only for the per protocol population of patients and not in the intent-to-treat analysis, metformin at the maximal tolerated dose provided a promising effect on the mobility and gait abilities of myotonic patients. These encouraging results obtained in a small-scale monocentric phase II study call for replication in a well-powered multicentre phase III trial.
      PubDate: Wed, 29 Aug 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy231
      Issue No: Vol. 141, No. 10 (2018)
  • Regional variation of Guillain-Barré syndrome
    • Authors: Doets A; Verboon C, van den Berg B, et al.
      Pages: 2866 - 2877
      Abstract: Guillain-Barré syndrome is a heterogeneous disorder regarding the clinical presentation, electrophysiological subtype and outcome. Previous single country reports indicate that Guillain-Barré syndrome may differ among regions, but no systematic comparative studies have been conducted. Comparative studies are required to identify factors determining disease susceptibility, variation and prognosis, and to improve diagnostic criteria. The International Guillain-Barré Syndrome Outcome Study is a prospective, observational cohort study including all patients within the diagnostic spectrum, aiming to describe the heterogeneity of Guillain-Barré syndrome worldwide. The current study was based on the first 1000 inclusions with a follow-up of at least 1 year and confirmed the variation in clinical presentation, course and outcome between patients. The full clinical spectrum of Guillain-Barré syndrome was observed in patients from all countries participating in the International Guillain-Barré Syndrome Outcome Study, but the frequency of variants differed between regions. We compared three regions based on geography, income and previous reports of Guillain-Barré syndrome subtypes: ‘Europe/Americas’, ‘Asia’ (without Bangladesh), and ‘Bangladesh’. We excluded 75 (8%) patients because of alternative diagnoses, protocol violations, or missing data. The predominant clinical variant was sensorimotor in Europe/Americas (n = 387/562, 69%) and Asia (n = 27/63, 43%), and pure motor in Bangladesh (n = 74/107, 69%). Miller Fisher syndrome and Miller Fisher-Guillain-Barré overlap syndrome were more common in Asia (n = 14/63, 22%) than in the other two regions (Europe/Americas: n = 64/562, 11%; Bangladesh: n = 1/107, 1%) (P < 0.001). The predominant electrophysiological subtype was demyelinating in all regions (Europe/Americas: n = 312/573, 55%; Asia: n = 29/65, 45%; Bangladesh: n = 38/94, 40%). The axonal subtype occurred more often in Bangladesh (n = 34/94, 36%) than in Europe/Americas (n = 33/573, 6%) and other Asian countries (n = 4/65, 6%) (P < 0.001). In all regions, patients with the axonal subtype were younger, had fewer sensory deficits, and showed a trend towards poorer recovery compared to patients with the demyelinating subtype. The proportion of patients able to walk unaided after 1 year varied between Asia (n = 31/34, 91%), Europe/Americas (n = 334/404, 83%) and Bangladesh (n = 67/97, 69%) (P = 0.003). A similar variation was seen for mortality, being higher in Bangladesh (n = 19/114, 17%) than in Europe/Americas (n = 23/486, 5%) and Asia (n = 1/45, 2%) (P < 0.001). This study showed that factors related to geography have a major influence on clinical phenotype, disease severity, electrophysiological subtype, and outcome of Guillain-Barré syndrome.
      PubDate: Tue, 25 Sep 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy232
      Issue No: Vol. 141, No. 10 (2018)
  • UBA1/GARS-dependent pathways drive sensory-motor connectivity defects in
           spinal muscular atrophy
    • Authors: Shorrock H; van der Hoorn D, Boyd P, et al.
      Pages: 2878 - 2894
      Abstract: Deafferentation of motor neurons as a result of defective sensory-motor connectivity is a critical early event in the pathogenesis of spinal muscular atrophy, but the underlying molecular pathways remain unknown. We show that restoration of ubiquitin-like modifier-activating enzyme 1 (UBA1) was sufficient to correct sensory-motor connectivity in the spinal cord of mice with spinal muscular atrophy. Aminoacyl-tRNA synthetases, including GARS, were identified as downstream targets of UBA1. Regulation of GARS by UBA1 occurred via a non-canonical pathway independent of ubiquitylation. Dysregulation of UBA1/GARS pathways in spinal muscular atrophy mice disrupted sensory neuron fate, phenocopying GARS-dependent defects associated with Charcot-Marie-Tooth disease. Sensory neuron fate was corrected following restoration of UBA1 expression and UBA1/GARS pathways in spinal muscular atrophy mice. We conclude that defective sensory motor connectivity in spinal muscular atrophy results from perturbations in a UBA1/GARS pathway that modulates sensory neuron fate, thereby highlighting significant molecular and phenotypic overlap between spinal muscular atrophy and Charcot-Marie-Tooth disease.
      PubDate: Tue, 25 Sep 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy237
      Issue No: Vol. 141, No. 10 (2018)
  • A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72
    • Authors: Zhang M; Ferrari R, Tartaglia M, et al.
      Pages: 2895 - 2907
      Abstract: The G4C2-repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. The high phenotypic heterogeneity of C9orf72 patients includes a wide range in age of onset, modifiers of which are largely unknown. Age of onset could be influenced by environmental and genetic factors both of which may trigger DNA methylation changes at CpG sites. We tested the hypothesis that age of onset in C9orf72 patients is associated with some common single nucleotide polymorphisms causing a gain or loss of CpG sites and thus resulting in DNA methylation alterations. Combined analyses of epigenetic and genetic data have the advantage of detecting functional variants with reduced likelihood of false negative results due to excessive correction for multiple testing in genome-wide association studies. First, we estimated the association between age of onset in C9orf72 patients (n = 46) and the DNA methylation levels at all 7603 CpG sites available on the 450 k BeadChip that are mapped to common single nucleotide polymorphisms. This was followed by a genetic association study of the discovery (n = 144) and replication (n = 187) C9orf72 cohorts. We found that age of onset was reproducibly associated with polymorphisms within a 124.7 kb linkage disequilibrium block tagged by top-significant variation, rs9357140, and containing two overlapping genes (LOC101929163 and C6orf10). A meta-analysis of all 331 C9orf72 carriers revealed that every A-allele of rs9357140 reduced hazard by 30% (P = 0.0002); and the median age of onset in AA-carriers was 6 years later than GG-carriers. In addition, we investigated a cohort of C9orf72 negative patients (n = 2634) affected by frontotemporal dementia and/or amyotrophic lateral sclerosis; and also found that the AA-genotype of rs9357140 was associated with a later age of onset (adjusted P = 0.007 for recessive model). Phenotype analyses detected significant association only in the largest subgroup of patients with frontotemporal dementia (n = 2142, adjusted P = 0.01 for recessive model). Gene expression studies of frontal cortex tissues from 25 autopsy cases affected by amyotrophic lateral sclerosis revealed that the G-allele of rs9357140 is associated with increased brain expression of LOC101929163 (a non-coding RNA) and HLA-DRB1 (involved in initiating immune responses), while the A-allele is associated with their reduced expression. Our findings suggest that carriers of the rs9357140 GG-genotype (linked to an earlier age of onset) might be more prone to be in a pro-inflammatory state (e.g. by microglia) than AA-carriers. Further, investigating the functional links within the C6orf10/LOC101929163/HLA-DRB1 pathway will be critical to better define age-dependent pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis.
      PubDate: Tue, 25 Sep 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy238
      Issue No: Vol. 141, No. 10 (2018)
  • A feedback loop between dipeptide-repeat protein, TDP-43 and
           karyopherin-α mediates C9orf72-related neurodegeneration
    • Authors: Solomon D; Stepto A, Au W, et al.
      Pages: 2908 - 2924
      Abstract: Accumulation and aggregation of TDP-43 is a major pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia. TDP-43 inclusions also characterize patients with GGGGCC (G4C2) hexanucleotide repeat expansion in C9orf72 that causes the most common genetic form of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). Functional studies in cell and animal models have identified pathogenic mechanisms including repeat-induced RNA toxicity and accumulation of G4C2-derived dipeptide-repeat proteins. The role of TDP-43 dysfunction in C9ALS/FTD, however, remains elusive. We found G4C2-derived dipeptide-repeat protein but not G4C2-RNA accumulation caused TDP-43 proteinopathy that triggered onset and progression of disease in Drosophila models of C9ALS/FTD. Timing and extent of TDP-43 dysfunction was dependent on levels and identity of dipeptide-repeat proteins produced, with poly-GR causing early and poly-GA/poly-GP causing late onset of disease. Accumulating cytosolic, but not insoluble aggregated TDP-43 caused karyopherin-α2/4 (KPNA2/4) pathology, increased levels of dipeptide-repeat proteins and enhanced G4C2-related toxicity. Comparable KPNA4 pathology was observed in both sporadic frontotemporal dementia and C9ALS/FTD patient brains characterized by its nuclear depletion and cytosolic accumulation, irrespective of TDP-43 or dipeptide-repeat protein aggregates. These findings identify a vicious feedback cycle for dipeptide-repeat protein-mediated TDP-43 and subsequent KPNA pathology, which becomes self-sufficient of the initiating trigger and causes C9-related neurodegeneration.
      PubDate: Tue, 25 Sep 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy241
      Issue No: Vol. 141, No. 10 (2018)
  • Neuroprotective exendin-4 enhances hypothermia therapy in a model of
           hypoxic-ischaemic encephalopathy
    • Authors: Rocha-Ferreira E; Poupon L, Zelco A, et al.
      Pages: 2925 - 2942
      Abstract: Hypoxic-ischaemic encephalopathy remains a global health burden. Despite medical advances and treatment with therapeutic hypothermia, over 50% of cooled infants are not protected and still develop lifelong neurodisabilities, including cerebral palsy. Furthermore, hypothermia is not used in preterm cases or low resource settings. Alternatives or adjunct therapies are urgently needed. Exendin-4 is a drug used to treat type 2 diabetes mellitus that has also demonstrated neuroprotective properties, and is currently being tested in clinical trials for Alzheimer’s and Parkinson’s diseases. Therefore, we hypothesized a neuroprotective effect for exendin-4 in neonatal neurodisorders, particularly in the treatment of neonatal hypoxic-ischaemic encephalopathy. Initially, we confirmed that the glucagon like peptide 1 receptor (GLP1R) was expressed in the human neonatal brain and in murine neurons at postnatal Day 7 (human equivalent late preterm) and postnatal Day 10 (term). Using a well characterized mouse model of neonatal hypoxic-ischaemic brain injury, we investigated the potential neuroprotective effect of exendin-4 in both postnatal Day 7 and 10 mice. An optimal exendin-4 treatment dosing regimen was identified, where four high doses (0.5 µg/g) starting at 0 h, then at 12 h, 24 h and 36 h after postnatal Day 7 hypoxic-ischaemic insult resulted in significant brain neuroprotection. Furthermore, neuroprotection was sustained even when treatment using exendin-4 was delayed by 2 h post hypoxic-ischaemic brain injury. This protective effect was observed in various histopathological markers: tissue infarction, cell death, astrogliosis, microglial and endothelial activation. Blood glucose levels were not altered by high dose exendin-4 administration when compared to controls. Exendin-4 administration did not result in adverse organ histopathology (haematoxylin and eosin) or inflammation (CD68). Despite initial reduced weight gain, animals restored weight gain following end of treatment. Overall high dose exendin-4 administration was well tolerated. To mimic the clinical scenario, postnatal Day 10 mice underwent exendin-4 and therapeutic hypothermia treatment, either alone or in combination, and brain tissue loss was assessed after 1 week. Exendin-4 treatment resulted in significant neuroprotection alone, and enhanced the cerebroprotective effect of therapeutic hypothermia. In summary, the safety and tolerance of high dose exendin-4 administrations, combined with its neuroprotective effect alone or in conjunction with clinically relevant hypothermia make the repurposing of exendin-4 for the treatment of neonatal hypoxic-ischaemic encephalopathy particularly promising.
      PubDate: Fri, 24 Aug 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy220
      Issue No: Vol. 141, No. 10 (2018)
  • Induction of migraine-like headache, but not aura, by cilostazol in
           patients with migraine with aura
    • Authors: Butt J; Rostrup E, Hansen A, et al.
      Pages: 2943 - 2951
      Abstract: Whether migraine headache and migraine aura share common pathophysiological mechanisms remains to be understood. Cilostazol causes cAMP accumulation and provokes migraine-like headache in migraine patients without aura. We investigated if cilostazol induces aura and migraine-like headache in patients with migraine with aura and alters peripheral endothelial function and levels of endothelial markers. In a randomized, double-blinded, placebo-controlled crossover study, 16 patients with migraine with aura (of whom 12 patients exclusively had attacks of migraine with aura) received 200 mg cilostazol (Pletal®) or placebo on two separate days. The development, duration, and characteristics of aura and headache were recorded using a questionnaire. Peripheral endothelial function was assessed by digital pulse amplitude tonometry using EndoPAT2000, and endothelial markers (VCAM1, E-selectin, and VEGFA) were measured. After administration of cilostazol, 14 patients (88%) experienced headache compared with six patients (38%) after placebo (P = 0.009). The headache in 12 patients (75%) after cilostazol and one patient (6%) after placebo fulfilled the criteria for migraine-like attacks (P = 0.0002). Patients reported that the attack mimicked the headache phase during their usual migraine attacks. However, aura symptoms were elicited in one patient after cilostazol and one patient after placebo. Further, endothelial function, as assessed by peripheral arterial tonometry, and endothelial markers were not significantly altered by cilostazol. Accumulation of cAMP by cilostazol induces migraine-like headache, but not aura, in patients with migraine with aura, even in those who exclusively reported attacks of migraine with aura in their spontaneous attacks. These findings further support dissociation between the aura and the headache phase with a yet unknown trigger for the aura and link between aura and headache. In addition, cilostazol administration did not significantly alter endothelial function, as assessed by peripheral arterial tonometry, or the endothelial markers, VCAM1, E-selectin, and VEGFA. However, post hoc analyses showed that our study was statistically underpowered for these outcomes.
      PubDate: Wed, 22 Aug 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy228
      Issue No: Vol. 141, No. 10 (2018)
  • Evidence for peri-ictal blood–brain barrier dysfunction in patients
           with epilepsy
    • Authors: Rüber T; David B, Lüchters G, et al.
      Pages: 2952 - 2965
      Abstract: Epilepsy has been associated with a dysfunction of the blood–brain barrier. While there is ample evidence that a dysfunction of the blood–brain barrier contributes to epileptogenesis, blood–brain barrier dysfunction as a consequence of single epileptic seizures has not been systematically investigated. We hypothesized that blood–brain barrier dysfunction is temporally and anatomically associated with epileptic seizures in patients and used a newly-established quantitative MRI protocol to test our hypothesis. Twenty-three patients with epilepsy undergoing inpatient monitoring as part of their presurgical evaluation were included in this study (10 females, mean age ± standard deviation: 28.78 ± 8.45). For each patient, we acquired quantitative T1 relaxation time maps (qT1) after both ictal and interictal injection of gadolinium-based contrast agent. The postictal enhancement of contrast agent was quantified by subtracting postictal qT1 from interictal qT1 and the resulting ΔqT1 was used as a surrogate imaging marker of peri-ictal blood–brain barrier dysfunction. Additionally, the serum concentrations of MMP9 and S100, both considered biomarkers of blood–brain barrier dysfunction, were assessed in serum samples obtained prior to and after the index seizure. Fifteen patients exhibited secondarily generalized tonic-clonic seizures and eight patients exhibited focal seizures at ictal injection of contrast agent. By comparing ΔqT1 of the generalized tonic-clonic seizures and focal seizures groups, the anatomical association between ictal epileptic activity and postictal enhancement of contrast agent could be probed. The generalized tonic-clonic seizures group showed significantly higher ΔqT1 in the whole brain as compared to the focal seizures group. Specific analysis of scans acquired later than 3 h after the onset of the seizure revealed higher ΔqT1 in the generalized tonic-clonic seizures group as compared to the focal seizures group, which was strictly lateralized to the hemisphere of seizure onset. Both MMP9 and S100 showed a significantly increased postictal concentration. The current study provides evidence for the occurrence of a blood–brain barrier dysfunction, which is temporally and anatomically associated with epileptic seizures. qT1 after ictal contrast agent injection is rendered as valuable imaging marker of seizure-associated blood–brain barrier dysfunction and may be measured hours after the seizure. The observation of the strong anatomical association of peri-ictal blood–brain barrier dysfunction may spark the development of new functional imaging modalities for the post hoc visualization of brain areas affected by the seizure.
      PubDate: Tue, 25 Sep 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy242
      Issue No: Vol. 141, No. 10 (2018)
  • Interictal stereotactic-EEG functional connectivity in refractory focal
    • Authors: Lagarde S; Roehri N, Lambert I, et al.
      Pages: 2966 - 2980
      Abstract: Drug-refractory focal epilepsies are network diseases associated with functional connectivity alterations both during ictal and interictal periods. A large majority of studies on the interictal/resting state have focused on functional MRI-based functional connectivity. Few studies have used electrophysiology, despite its high temporal capacities. In particular, stereotactic-EEG is highly suitable to study functional connectivity because it permits direct intracranial electrophysiological recordings with relative large-scale sampling. Most previous studies in stereotactic-EEG have been directed towards temporal lobe epilepsy, which does not represent the whole spectrum of drug-refractory epilepsies. The present study aims at filling this gap, investigating interictal functional connectivity alterations behind cortical epileptic organization and its association with post-surgical prognosis. To this purpose, we studied a large cohort of 59 patients with malformation of cortical development explored by stereotactic-EEG with a wide spatial sampling (76 distinct brain areas were recorded, median of 13.2 per patient). We computed functional connectivity using non-linear correlation. We focused on three zones defined by stereotactic-EEG ictal activity: the epileptogenic zone, the propagation zone and the non-involved zone. First, we compared within-zone and between-zones functional connectivity. Second, we analysed the directionality of functional connectivity between these zones. Third, we measured the associations between functional connectivity measures and clinical variables, especially post-surgical prognosis. Our study confirms that functional connectivity differs according to the zone under investigation. We found: (i) a gradual decrease of the within-zone functional connectivity with higher values for epileptogenic zone and propagation zone, and lower for non-involved zones; (ii) preferential coupling between structures of the epileptogenic zone; (iii) preferential coupling between epileptogenic zone and propagation zone; and (iv) poorer post-surgical outcome in patients with higher functional connectivity of non-involved zone (within- non-involved zone, between non-involved zone and propagation zone functional connectivity). Our work suggests that, even during the interictal state, functional connectivity is reinforced within epileptic cortices (epileptogenic zone and propagation zone) with a gradual organization. Moreover, larger functional connectivity alterations, suggesting more diffuse disease, are associated with poorer post-surgical prognosis. This is consistent with computational studies suggesting that connectivity is crucial in order to model the spatiotemporal dynamics of seizures.10.1093/brain/awy214_video1awy214media15833456182001
      PubDate: Thu, 09 Aug 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy214
      Issue No: Vol. 141, No. 10 (2018)
  • Dynamic brain network states in human generalized spike-wave discharges
    • Authors: Tangwiriyasakul C; Perani S, Centeno M, et al.
      Pages: 2981 - 2994
      Abstract: Generalized spike-wave discharges in idiopathic generalized epilepsy are conventionally assumed to have abrupt onset and offset. However, in rodent models, discharges emerge during a dynamic evolution of brain network states, extending several seconds before and after the discharge. In human idiopathic generalized epilepsy, simultaneous EEG and functional MRI shows cortical regions may be active before discharges, and network connectivity around discharges may not be normal. Here, in human idiopathic generalized epilepsy, we investigated whether generalized spike-wave discharges emerge during a dynamic evolution of brain network states. Using EEG-functional MRI, we studied 43 patients and 34 healthy control subjects. We obtained 95 discharges from 20 patients. We compared data from patients with discharges with data from patients without discharges and healthy controls. Changes in MRI (blood oxygenation level-dependent) signal amplitude in discharge epochs were observed only at and after EEG onset, involving a sequence of parietal and frontal cortical regions then thalamus (P < 0.01, across all regions and measurement time points). Examining MRI signal phase synchrony as a measure of functional connectivity between each pair of 90 brain regions, we found significant connections (P < 0.01, across all connections and measurement time points) involving frontal, parietal and occipital cortex during discharges, and for 20 s after EEG offset. This network prominent during discharges showed significantly low synchrony (below 99% confidence interval for synchrony in this network in non-discharge epochs in patients) from 16 s to 10 s before discharges, then ramped up steeply to a significantly high level of synchrony 2 s before discharge onset. Significant connections were seen in a sensorimotor network in the minute before discharge onset. This network also showed elevated synchrony in patients without discharges compared to healthy controls (P = 0.004). During 6 s prior to discharges, additional significant connections to this sensorimotor network were observed, involving prefrontal and precuneus regions. In healthy subjects, significant connections involved a posterior cortical network. In patients with discharges, this posterior network showed significantly low synchrony during the minute prior to discharge onset. In patients without discharges, this network showed the same level of synchrony as in healthy controls. Our findings suggest persistently high sensorimotor network synchrony, coupled with transiently (at least 1 min) low posterior network synchrony, may be a state predisposing to generalized spike-wave discharge onset. Our findings also show that EEG onset and associated MRI signal amplitude change is embedded in a considerably longer period of evolving brain network states before and after discharge events.
      PubDate: Tue, 28 Aug 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy223
      Issue No: Vol. 141, No. 10 (2018)
  • Basal ganglia and cerebellar pathology in X-linked dystonia-parkinsonism
    • Authors: Hanssen H; Heldmann M, Prasuhn J, et al.
      Pages: 2995 - 3008
      Abstract: X-linked dystonia-parkinsonism is a neurodegenerative movement disorder characterized by adult-onset dystonia combined with parkinsonism over the disease course. Previous imaging and pathological findings indicate exclusive striatal atrophy with predominant pathology of the striosomal compartment in the dystonic phase of X-linked dystonia-parkinsonism. The striosome occupies 10–15% of the entire striatal volume and the density of striosomes follows a rostrocaudal gradient with the rostral striatum being considered striosome-rich. Recent quantitative MRI analyses provided evidence for an additional involvement of the white matter and the pallidum. In this study, we aimed to (i) disentangle the degree of atrophy in the different subdivisions of the striatum; (ii) investigate changes of cortical morphology; and (iii) elucidate the role of the cerebellum in X-linked dystonia-parkinsonism. T1-weighted MRI scans were acquired in 17 male X-linked dystonia-parkinsonism patients with predominant dystonia (40.1 ± 7.5 years) and 17 ethnicity-matched male healthy controls (35.2 ± 7.4 years). Voxel-based morphometry used a region of interest-based approach for the basal ganglia and primary motor cortex, whole brain analysis, and a separate analysis of the cerebellum. Cortical thickness and subcortical volume were measured. Volume loss in X-linked dystonia-parkinsonism affected all parts of the striatum (−29% voxel intensity) but was most pronounced in the associative subdivision (−41%; P < 0.001). The volume loss also involved the external and internal pallidum, albeit to a lesser extent than the striatum (−19% and −12%, P<0.001). Cortical thickness was reduced in the frontal (−4.3%) and temporal cortex (−6.1%). In addition, we found grey matter pathology in the associative part of the cerebellum and increased voxel intensities in the anterior sensorimotor part of the cerebellum and the dorsal ponto-mesencephalic brainstem. Taken together, our analysis of subcortical and cortical grey matter in the dystonic phase of X-linked dystonia-parkinsonism showed that (i) the striosome-enriched rostral striatum was most severely affected; and (ii) cortical thickness was only reduced in those regions that predominantly have anatomical connections to striosomes. Moreover, the cerebellum may be implicated in both disease-related and compensatory changes, highlighting the significance of the cerebellum in the pathophysiology of dystonia.
      PubDate: Tue, 28 Aug 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy222
      Issue No: Vol. 141, No. 10 (2018)
  • Balance control systems in Parkinson’s disease and the impact of
           pedunculopontine area stimulation
    • Authors: Perera T; Tan J, Cole M, et al.
      Pages: 3009 - 3022
      Abstract: Impaired balance is a major contributor to falls and diminished quality of life in Parkinson’s disease, yet the pathophysiology is poorly understood. Here, we assessed if patients with Parkinson’s disease and severe clinical balance impairment have deficits in the intermittent and continuous control systems proposed to maintain upright stance, and furthermore, whether such deficits are potentially reversible, with the experimental therapy of pedunculopontine nucleus deep brain stimulation. Two subject groups were assessed: (i) 13 patients with Parkinson’s disease and severe clinical balance impairment, implanted with pedunculopontine nucleus deep brain stimulators; and (ii) 13 healthy control subjects. Patients were assessed in the OFF medication state and blinded to two conditions; off and on pedunculopontine nucleus stimulation. Postural sway data (deviations in centre of pressure) were collected during quiet stance using posturography. Intermittent control of sway was assessed by calculating the frequency of intermittent switching behaviour (discontinuities), derived using a wavelet-based transformation of the sway time series. Continuous control of sway was assessed with a proportional–integral–derivative (PID) controller model using ballistic reaction time as a measure of feedback delay. Clinical balance impairment was assessed using the ‘pull test’ to rate postural reflexes and by rating attempts to arise from sitting to standing. Patients with Parkinson’s disease demonstrated reduced intermittent switching of postural sway compared with healthy controls. Patients also had abnormal feedback gains in postural sway according to the PID model. Pedunculopontine nucleus stimulation improved intermittent switching of postural sway, feedback gains in the PID model and clinical balance impairment. Clinical balance impairment correlated with intermittent switching of postural sway (rho = − 0.705, P < 0.001) and feedback gains in the PID model (rho = 0.619, P = 0.011). These results suggest that dysfunctional intermittent and continuous control systems may contribute to the pathophysiology of clinical balance impairment in Parkinson’s disease. Clinical balance impairment and their related control system deficits are potentially reversible, as demonstrated by their improvement with pedunculopontine nucleus deep brain stimulation.
      PubDate: Fri, 24 Aug 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy216
      Issue No: Vol. 141, No. 10 (2018)
  • Parkinsonian signs in patients with cervical dystonia treated with
           pallidal deep brain stimulation
    • Authors: Mahlknecht P; Georgiev D, Akram H, et al.
      Pages: 3023 - 3034
      Abstract: Pallidal deep brain stimulation is an established treatment in patients with dystonia. However, evidence from case series or uncontrolled studies suggests that it may lead in some patients to specific parkinsonian symptoms such as freezing of gait, micrographia, and bradykinesia. We investigated parkinsonian signs using the Movement Disorder Society Unified Parkinson’s Disease Rating Scale motor score by means of observer-blinded video ratings in a group of 29 patients treated with pallidal stimulation and a non-surgical control group of 22 patients, both with predominant cervical dystonia. Additional assessments included MRI-based models of volume of neural tissue activated to investigate areas of stimulation related to dystonic symptom control and those likely to induce parkinsonian signs as well as an EMG analysis to investigate functional vicinity of stimulation fields to the pyramidal tract. Compared with controls, stimulated patients had significantly higher motor scores (median, 25th–75th percentile: 14.0, 8.0–19.5 versus 3.0, 2.0–8.0; P < 0.0001), as well as bradykinesia (8.0, 6.0–14.0 versus 2.0, 0.0–3.0; P < 0.0001) and axial motor subscores (2.0, 1.0–4.0 versus 0.0, 0.0–1.0; P = 0.0002), while rigidity and tremor subscores were not different between groups. Parkinsonian signs were partially reversible upon switching stimulation off for a median of 90 min in a subset of 19 patients tolerating this condition. Furthermore, the stimulation group reported more features of freezing of gait on a questionnaire basis. Quality of life was better in stimulated patients compared with control patients, but parkinsonian signs were negatively associated with quality of life. In the descriptive imaging analysis maximum efficacy for dystonia improvement projected to the posteroventrolateral internal pallidum with overlapping clusters driving severity of bradykinesia and axial motor symptoms. The severities of parkinsonian signs were not correlated with functional vicinity to the pyramidal tract as assessed by EMG. In conclusion, parkinsonian signs, particularly bradykinesia and axial motor signs, due to pallidal stimulation in dystonic patients are frequent and negatively impact on motor functioning and quality of life. Therefore, patients with pallidal stimulation should be monitored closely for such signs both in clinical routine and future clinical trials. Spread of current outside the internal pallidum is an unlikely explanation for this phenomenon, which seems to be caused by stimulation of neural elements within the stimulation target volume.
      PubDate: Fri, 24 Aug 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy217
      Issue No: Vol. 141, No. 10 (2018)
  • Motor and emotional behaviours elicited by electrical stimulation of the
           human cingulate cortex
    • Authors: Caruana F; Gerbella M, Avanzini P, et al.
      Pages: 3035 - 3051
      Abstract: The cingulate cortex is a mosaic of different anatomical fields, whose functional characterization is still a matter of debate. In humans, one method that may provide useful insights on the role of the different cingulate regions, and to tackle the issue of the functional differences between its anterior, middle and posterior subsectors, is intracortical electrical stimulation. While previous reports showed that a variety of integrated behaviours could be elicited by stimulating the midcingulate cortex, little is known about the effects of the electrical stimulation of anterior and posterior cingulate regions. Moreover, the internal arrangement of different behaviours within the midcingulate cortex is still unknown. In the present study, we extended previous stimulation studies by retrospectively analysing all the clinical manifestations induced by intracerebral high frequency electrical stimulation (50 Hz, pulse width: 1 ms, 5 s, current intensity: average intensity of 2.7 ± 0.7 mA, biphasic) of the entire cingulate cortex in a cohort of 329 drug-resistant epileptic patients (1789 stimulation sites) undergoing stereo-electroencephalography for a presurgical evaluation. The large number of patients, on one hand, and the accurate multimodal image-based localization of stereo-electroencephalography electrodes, on the other hand, allowed us to assign specific functional properties to modern anatomical subdivisions of the cingulate cortex. Behavioural or subjective responses were elicited from the 32.3% of all cingulate sites, mainly located in the pregenual and midcingulate regions. We found clear functional differences between the pregenual part of the cingulate cortex, hosting the majority of emotional, interoceptive and autonomic responses, and the anterior midcingulate sector, controlling the majority of all complex motor behaviours. Particularly interesting was the ‘actotopic’ organization of the anterior midcingulate sector, arranged along the ventro-dorsal axis: (i) whole-body behaviours directed to the extra-personal space, such as getting-up impulses, were elicited ventrally, close to the corpus callosum; (ii) hand actions in the peripersonal space were evoked by the stimulation of the intermediate position; and (iii) body-directed actions were induced by the stimulation of the dorsal branch of the cingulate sulcus. The caudal part of the midcingulate cortex and the posterior cingulate cortex were, in contrast, poorly excitable, and mainly devoted to sensory modalities. In particular, the caudal part of the midcingulate cortex hosted the majority of vestibular responses, while posterior cingulate cortex was the principal recipient of visual effects. We will discuss our data in the light of current controversies on the role of the cingulate cortex in cognition and emotion.
      PubDate: Mon, 13 Aug 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy219
      Issue No: Vol. 141, No. 10 (2018)
  • Iron overload is accompanied by mitochondrial and lysosomal dysfunction in
           WDR45 mutant cells
    • Authors: Seibler P; Burbulla L, Dulovic M, et al.
      Pages: 3052 - 3064
      Abstract: Beta-propeller protein-associated neurodegeneration is a subtype of monogenic neurodegeneration with brain iron accumulation caused by de novo mutations in WDR45. The WDR45 protein functions as a beta-propeller scaffold and plays a putative role in autophagy through its interaction with phospholipids and autophagy-related proteins. Loss of WDR45 function due to disease-causing mutations has been linked to defects in autophagic flux in patient and animal cells. However, the role of WDR45 in iron homeostasis remains elusive. Here we studied patient-specific WDR45 mutant fibroblasts and induced pluripotent stem cell-derived midbrain neurons. Our data demonstrated that loss of WDR45 increased cellular iron levels and oxidative stress, accompanied by mitochondrial abnormalities, autophagic defects, and diminished lysosomal function. Restoring WDR45 levels partially rescued oxidative stress and the susceptibility to iron treatment, and activation of autophagy reduced the observed iron overload in WDR45 mutant cells. Our data suggest that iron-containing macromolecules and organelles cannot effectively be degraded through the lysosomal pathway due to loss of WDR45 function.
      PubDate: Thu, 30 Aug 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy230
      Issue No: Vol. 141, No. 10 (2018)
  • White matter diffusion alterations precede symptom onset in autosomal
           dominant Alzheimer’s disease
    • Authors: Araque Caballero M; Suárez-Calvet M, Duering M, et al.
      Pages: 3065 - 3080
      Abstract: White matter alterations are present in the majority of patients with Alzheimer’s disease type dementia. However, the spatiotemporal pattern of white matter changes preceding dementia symptoms in Alzheimer’s disease remains unclear, largely due to the inherent diagnostic uncertainty in the preclinical phase and increased risk of confounding age-related vascular disease and stroke in late-onset Alzheimer’s disease. In early-onset autosomal-dominantly inherited Alzheimer’s disease, participants are destined to develop dementia, which provides the opportunity to assess brain changes years before the onset of symptoms, and in the absence of ageing-related vascular disease. Here, we assessed mean diffusivity alterations in the white matter in 64 mutation carriers compared to 45 non-carrier family non-carriers. Using tract-based spatial statistics, we mapped the interaction of mutation status by estimated years from symptom onset on mean diffusivity. For major atlas-derived fibre tracts, we determined the earliest time point at which abnormal mean diffusivity changes in the mutation carriers were detectable. Lastly, we assessed the association between mean diffusivity and cerebrospinal fluid biomarkers of amyloid, tau, phosphorylated-tau, and soluble TREM2, i.e. a marker of microglia activity. Results showed a significant interaction of mutations status by estimated years from symptom onset, i.e. a stronger increase of mean diffusivity, within the posterior parietal and medial frontal white matter in mutation carriers compared with non-carriers. The earliest increase of mean diffusivity was observed in the forceps major, forceps minor and long projecting fibres—many connecting default mode network regions—between 5 to 10 years before estimated symptom onset. Higher mean diffusivity in fibre tracts was associated with lower grey matter volume in the tracts’ projection zones. Global mean diffusivity was correlated with lower cerebrospinal fluid levels of amyloid-β1-42 but higher levels of tau, phosphorylated-tau and soluble TREM2. Together, these results suggest that regionally selective white matter degeneration occurs years before the estimated symptom onset. Such white matter alterations are associated with primary Alzheimer’s disease pathology and microglia activity in the brain.
      PubDate: Tue, 25 Sep 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy229
      Issue No: Vol. 141, No. 10 (2018)
  • A road map for transforming stroke recovery
    • Authors: Ward N.
      Pages: 3081 - 3082
      Abstract: Figure 1
      PubDate: Tue, 25 Sep 2018 00:00:00 GMT
      DOI: 10.1093/brain/awy248
      Issue No: Vol. 141, No. 10 (2018)
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