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Publisher: Oxford University Press   (Total: 369 journals)

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Showing 1 - 200 of 369 Journals sorted alphabetically
Acta Biochimica et Biophysica Sinica     Hybrid Journal   (Followers: 6, SJR: 0.881, h-index: 38)
Adaptation     Hybrid Journal   (Followers: 8, SJR: 0.111, h-index: 4)
Aesthetic Surgery J.     Hybrid Journal   (Followers: 6, SJR: 1.538, h-index: 35)
African Affairs     Hybrid Journal   (Followers: 57, SJR: 1.512, h-index: 46)
Age and Ageing     Hybrid Journal   (Followers: 80, SJR: 1.611, h-index: 107)
Alcohol and Alcoholism     Hybrid Journal   (Followers: 14, SJR: 0.935, h-index: 80)
American Entomologist     Full-text available via subscription   (Followers: 5)
American Historical Review     Hybrid Journal   (Followers: 125, SJR: 0.652, h-index: 43)
American J. of Agricultural Economics     Hybrid Journal   (Followers: 41, SJR: 1.441, h-index: 77)
American J. of Epidemiology     Hybrid Journal   (Followers: 152, SJR: 3.047, h-index: 201)
American J. of Hypertension     Hybrid Journal   (Followers: 18, SJR: 1.397, h-index: 111)
American J. of Jurisprudence     Hybrid Journal   (Followers: 15)
American journal of legal history     Full-text available via subscription   (Followers: 4, SJR: 0.151, h-index: 7)
American Law and Economics Review     Hybrid Journal   (Followers: 26, SJR: 0.824, h-index: 23)
American Literary History     Hybrid Journal   (Followers: 12, SJR: 0.185, h-index: 22)
Analysis     Hybrid Journal   (Followers: 23)
Annals of Botany     Hybrid Journal   (Followers: 33, SJR: 1.912, h-index: 124)
Annals of Occupational Hygiene     Hybrid Journal   (Followers: 25, SJR: 0.837, h-index: 57)
Annals of Oncology     Hybrid Journal   (Followers: 48, SJR: 4.362, h-index: 173)
Annals of the Entomological Society of America     Full-text available via subscription   (Followers: 9, SJR: 0.642, h-index: 53)
Annals of Work Exposures and Health     Hybrid Journal  
AoB Plants     Open Access   (Followers: 4, SJR: 0.78, h-index: 10)
Applied Economic Perspectives and Policy     Hybrid Journal   (Followers: 18, SJR: 0.884, h-index: 31)
Applied Linguistics     Hybrid Journal   (Followers: 51, SJR: 1.749, h-index: 63)
Applied Mathematics Research eXpress     Hybrid Journal   (Followers: 1, SJR: 0.779, h-index: 11)
Arbitration Intl.     Full-text available via subscription   (Followers: 19)
Arbitration Law Reports and Review     Hybrid Journal   (Followers: 12)
Archives of Clinical Neuropsychology     Hybrid Journal   (Followers: 26, SJR: 0.96, h-index: 71)
Aristotelian Society Supplementary Volume     Hybrid Journal   (Followers: 2, SJR: 0.102, h-index: 20)
Arthropod Management Tests     Hybrid Journal   (Followers: 2)
Astronomy & Geophysics     Hybrid Journal   (Followers: 47, SJR: 0.144, h-index: 15)
Behavioral Ecology     Hybrid Journal   (Followers: 46, SJR: 1.698, h-index: 92)
Bioinformatics     Hybrid Journal   (Followers: 225, SJR: 4.643, h-index: 271)
Biology Methods and Protocols     Hybrid Journal  
Biology of Reproduction     Full-text available via subscription   (Followers: 9, SJR: 1.646, h-index: 149)
Biometrika     Hybrid Journal   (Followers: 18, SJR: 2.801, h-index: 90)
BioScience     Hybrid Journal   (Followers: 28, SJR: 2.374, h-index: 154)
Bioscience Horizons : The National Undergraduate Research J.     Open Access   (Followers: 1, SJR: 0.213, h-index: 9)
Biostatistics     Hybrid Journal   (Followers: 15, SJR: 1.955, h-index: 55)
BJA : British J. of Anaesthesia     Hybrid Journal   (Followers: 133, SJR: 2.314, h-index: 133)
BJA Education     Hybrid Journal   (Followers: 65, SJR: 0.272, h-index: 20)
Brain     Hybrid Journal   (Followers: 61, SJR: 6.097, h-index: 264)
Briefings in Bioinformatics     Hybrid Journal   (Followers: 44, SJR: 4.086, h-index: 73)
Briefings in Functional Genomics     Hybrid Journal   (Followers: 4, SJR: 1.771, h-index: 50)
British J. for the Philosophy of Science     Hybrid Journal   (Followers: 33, SJR: 1.267, h-index: 38)
British J. of Aesthetics     Hybrid Journal   (Followers: 24, SJR: 0.217, h-index: 18)
British J. of Criminology     Hybrid Journal   (Followers: 494, SJR: 1.373, h-index: 62)
British J. of Social Work     Hybrid Journal   (Followers: 78, 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: 26)
Bulletin of the London Mathematical Society     Hybrid Journal   (Followers: 3, SJR: 1.474, h-index: 31)
Cambridge J. of Economics     Hybrid Journal   (Followers: 55, SJR: 0.957, h-index: 59)
Cambridge J. of Regions, Economy and Society     Hybrid Journal   (Followers: 9, SJR: 1.067, h-index: 22)
Cambridge Quarterly     Hybrid Journal   (Followers: 10, SJR: 0.1, h-index: 7)
Capital Markets Law J.     Hybrid Journal  
Carcinogenesis     Hybrid Journal   (Followers: 2, SJR: 2.439, h-index: 167)
Cardiovascular Research     Hybrid Journal   (Followers: 11, SJR: 2.897, h-index: 175)
Cerebral Cortex     Hybrid Journal   (Followers: 38, SJR: 4.827, h-index: 192)
CESifo Economic Studies     Hybrid Journal   (Followers: 15, 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: 3)
Chinese J. of Intl. Law     Hybrid Journal   (Followers: 19, SJR: 0.737, h-index: 11)
Chinese J. of Intl. Politics     Hybrid Journal   (Followers: 8, SJR: 1.238, h-index: 15)
Christian Bioethics: Non-Ecumenical Studies in Medical Morality     Hybrid Journal   (Followers: 11, SJR: 0.191, h-index: 8)
Classical Receptions J.     Hybrid Journal   (Followers: 17, SJR: 0.1, h-index: 3)
Clinical Infectious Diseases     Hybrid Journal   (Followers: 59, SJR: 4.742, h-index: 261)
Clinical Kidney J.     Open Access   (Followers: 4, SJR: 0.338, h-index: 19)
Community Development J.     Hybrid Journal   (Followers: 23, SJR: 0.47, h-index: 28)
Computer J.     Hybrid Journal   (Followers: 8, SJR: 0.371, h-index: 47)
Conservation Physiology     Open Access   (Followers: 1)
Contemporary Women's Writing     Hybrid Journal   (Followers: 11, SJR: 0.111, h-index: 3)
Contributions to Political Economy     Hybrid Journal   (Followers: 6, SJR: 0.313, h-index: 10)
Critical Values     Full-text available via subscription  
Current Legal Problems     Hybrid Journal   (Followers: 25)
Current Zoology     Full-text available via subscription   (SJR: 0.999, h-index: 20)
Database : The J. of Biological Databases and Curation     Open Access   (Followers: 11, SJR: 1.068, h-index: 24)
Digital Scholarship in the Humanities     Hybrid Journal   (Followers: 12)
Diplomatic History     Hybrid Journal   (Followers: 18, SJR: 0.296, h-index: 22)
DNA Research     Open Access   (Followers: 4, SJR: 2.42, h-index: 77)
Dynamics and Statistics of the Climate System     Open Access   (Followers: 2)
Early Music     Hybrid Journal   (Followers: 13, SJR: 0.124, h-index: 11)
Economic Policy     Hybrid Journal   (Followers: 51, SJR: 2.052, h-index: 52)
ELT J.     Hybrid Journal   (Followers: 25, SJR: 1.26, h-index: 23)
English Historical Review     Hybrid Journal   (Followers: 45, SJR: 0.311, h-index: 10)
English: J. of the English Association     Hybrid Journal   (Followers: 12, SJR: 0.144, h-index: 3)
Environmental Entomology     Full-text available via subscription   (Followers: 11, SJR: 0.791, h-index: 66)
Environmental Epigenetics     Open Access   (Followers: 1)
Environmental History     Hybrid Journal   (Followers: 25, SJR: 0.197, h-index: 25)
EP-Europace     Hybrid Journal   (Followers: 2, SJR: 2.201, h-index: 71)
Epidemiologic Reviews     Hybrid Journal   (Followers: 9, SJR: 3.917, h-index: 81)
ESHRE Monographs     Hybrid Journal  
Essays in Criticism     Hybrid Journal   (Followers: 15, SJR: 0.1, h-index: 6)
European Heart J.     Hybrid Journal   (Followers: 48, SJR: 6.997, h-index: 227)
European Heart J. - Cardiovascular Imaging     Hybrid Journal   (Followers: 9, SJR: 2.044, h-index: 58)
European Heart J. - Cardiovascular Pharmacotherapy     Full-text available via subscription   (Followers: 1)
European Heart J. - Quality of Care and Clinical Outcomes     Hybrid Journal  
European Heart J. Supplements     Hybrid Journal   (Followers: 8, SJR: 0.152, h-index: 31)
European J. of Cardio-Thoracic Surgery     Hybrid Journal   (Followers: 7, SJR: 1.568, h-index: 104)
European J. of Intl. Law     Hybrid Journal   (Followers: 145, SJR: 0.722, h-index: 38)
European J. of Orthodontics     Hybrid Journal   (Followers: 4, SJR: 1.09, h-index: 60)
European J. of Public Health     Hybrid Journal   (Followers: 22, SJR: 1.284, h-index: 64)
European Review of Agricultural Economics     Hybrid Journal   (Followers: 12, SJR: 1.549, h-index: 42)
European Review of Economic History     Hybrid Journal   (Followers: 25, SJR: 0.628, h-index: 24)
European Sociological Review     Hybrid Journal   (Followers: 37, SJR: 2.061, h-index: 53)
Evolution, Medicine, and Public Health     Open Access   (Followers: 11)
Family Practice     Hybrid Journal   (Followers: 13, SJR: 1.048, h-index: 77)
Fems Microbiology Ecology     Hybrid Journal   (Followers: 9, SJR: 1.687, h-index: 115)
Fems Microbiology Letters     Hybrid Journal   (Followers: 20, SJR: 1.126, h-index: 118)
Fems Microbiology Reviews     Hybrid Journal   (Followers: 25, SJR: 7.587, h-index: 150)
Fems Yeast Research     Hybrid Journal   (Followers: 13, SJR: 1.213, h-index: 66)
Foreign Policy Analysis     Hybrid Journal   (Followers: 21, SJR: 0.859, h-index: 10)
Forestry: An Intl. J. of Forest Research     Hybrid Journal   (Followers: 17, 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: 29, SJR: 0.123, h-index: 10)
French Studies     Hybrid Journal   (Followers: 19, SJR: 0.119, h-index: 7)
French Studies Bulletin     Hybrid Journal   (Followers: 10, SJR: 0.102, h-index: 3)
Gastroenterology Report     Open Access   (Followers: 2)
Genome Biology and Evolution     Open Access   (Followers: 10, SJR: 3.22, h-index: 39)
Geophysical J. Intl.     Hybrid Journal   (Followers: 31, SJR: 1.839, h-index: 119)
German History     Hybrid Journal   (Followers: 25, SJR: 0.437, h-index: 13)
GigaScience     Open Access   (Followers: 3)
Global Summitry     Hybrid Journal  
Glycobiology     Hybrid Journal   (Followers: 14, SJR: 1.692, h-index: 101)
Health and Social Work     Hybrid Journal   (Followers: 46, SJR: 0.505, h-index: 40)
Health Education Research     Hybrid Journal   (Followers: 12, SJR: 0.814, h-index: 80)
Health Policy and Planning     Hybrid Journal   (Followers: 21, SJR: 1.628, h-index: 66)
Health Promotion Intl.     Hybrid Journal   (Followers: 20, SJR: 0.664, h-index: 60)
History Workshop J.     Hybrid Journal   (Followers: 27, SJR: 0.313, h-index: 20)
Holocaust and Genocide Studies     Hybrid Journal   (Followers: 23, SJR: 0.115, h-index: 13)
Human Molecular Genetics     Hybrid Journal   (Followers: 9, SJR: 4.288, h-index: 233)
Human Reproduction     Hybrid Journal   (Followers: 75, SJR: 2.271, h-index: 179)
Human Reproduction Update     Hybrid Journal   (Followers: 15, SJR: 4.678, h-index: 128)
Human Rights Law Review     Hybrid Journal   (Followers: 58, SJR: 0.7, h-index: 21)
ICES J. of Marine Science: J. du Conseil     Hybrid Journal   (Followers: 53, SJR: 1.233, h-index: 88)
ICSID Review     Hybrid Journal   (Followers: 9)
ILAR J.     Hybrid Journal   (Followers: 1, SJR: 1.099, h-index: 51)
IMA J. of Applied Mathematics     Hybrid Journal   (SJR: 0.329, h-index: 26)
IMA J. of Management Mathematics     Hybrid Journal   (Followers: 2, SJR: 0.351, h-index: 20)
IMA J. of Mathematical Control and Information     Hybrid Journal   (Followers: 2, SJR: 0.661, h-index: 28)
IMA J. of Numerical Analysis - advance access     Hybrid Journal   (SJR: 2.032, h-index: 44)
Industrial and Corporate Change     Hybrid Journal   (Followers: 8, SJR: 1.37, h-index: 81)
Industrial Law J.     Hybrid Journal   (Followers: 29, SJR: 0.184, h-index: 15)
Information and Inference     Free  
Integrative and Comparative Biology     Hybrid Journal   (Followers: 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: 4, SJR: 0.743, h-index: 35)
Intl. Data Privacy Law     Hybrid Journal   (Followers: 26)
Intl. Health     Hybrid Journal   (Followers: 4, SJR: 0.835, h-index: 15)
Intl. Immunology     Hybrid Journal   (Followers: 3, SJR: 1.613, h-index: 111)
Intl. J. for Quality in Health Care     Hybrid Journal   (Followers: 32, SJR: 1.593, h-index: 69)
Intl. J. of Constitutional Law     Hybrid Journal   (Followers: 59, SJR: 0.613, h-index: 19)
Intl. J. of Epidemiology     Hybrid Journal   (Followers: 115, SJR: 4.381, h-index: 145)
Intl. J. of Law and Information Technology     Hybrid Journal   (Followers: 3, SJR: 0.247, h-index: 8)
Intl. J. of Law, Policy and the Family     Hybrid Journal   (Followers: 28, SJR: 0.307, h-index: 15)
Intl. J. of Lexicography     Hybrid Journal   (Followers: 8, SJR: 0.404, h-index: 18)
Intl. J. of Low-Carbon Technologies     Open Access   (Followers: 1, SJR: 0.457, h-index: 12)
Intl. J. of Neuropsychopharmacology     Open Access   (Followers: 3, SJR: 1.69, h-index: 79)
Intl. J. of Public Opinion Research     Hybrid Journal   (Followers: 8, SJR: 0.906, h-index: 33)
Intl. J. of Refugee Law     Hybrid Journal   (Followers: 32, SJR: 0.231, h-index: 21)
Intl. J. of Transitional Justice     Hybrid Journal   (Followers: 13, SJR: 0.833, h-index: 12)
Intl. Mathematics Research Notices     Hybrid Journal   (Followers: 1, SJR: 2.052, h-index: 42)
Intl. Political Sociology     Hybrid Journal   (Followers: 25, SJR: 1.339, h-index: 19)
Intl. Relations of the Asia-Pacific     Hybrid Journal   (Followers: 17, SJR: 0.539, h-index: 17)
Intl. Studies Perspectives     Hybrid Journal   (Followers: 7, SJR: 0.998, h-index: 28)
Intl. Studies Quarterly     Hybrid Journal   (Followers: 34, SJR: 2.184, h-index: 68)
Intl. Studies Review     Hybrid Journal   (Followers: 17, SJR: 0.783, h-index: 38)
ISLE: Interdisciplinary Studies in Literature and Environment     Hybrid Journal   (Followers: 1, SJR: 0.155, h-index: 4)
ITNOW     Hybrid Journal   (Followers: 2, SJR: 0.102, h-index: 4)
J. of African Economies     Hybrid Journal   (Followers: 15, SJR: 0.647, h-index: 30)
J. of American History     Hybrid Journal   (Followers: 38, SJR: 0.286, h-index: 34)
J. of Analytical Toxicology     Hybrid Journal   (Followers: 13, SJR: 1.038, h-index: 60)
J. of Antimicrobial Chemotherapy     Hybrid Journal   (Followers: 18, SJR: 2.157, h-index: 149)
J. of Antitrust Enforcement     Hybrid Journal   (Followers: 1)
J. of Applied Poultry Research     Hybrid Journal   (Followers: 3, SJR: 0.563, h-index: 43)
J. of Biochemistry     Hybrid Journal   (Followers: 44, SJR: 1.341, h-index: 96)
J. of Chromatographic Science     Hybrid Journal   (Followers: 16, SJR: 0.448, h-index: 42)
J. of Church and State     Hybrid Journal   (Followers: 11, SJR: 0.167, h-index: 11)
J. of Competition Law and Economics     Hybrid Journal   (Followers: 34, SJR: 0.442, h-index: 16)
J. of Complex Networks     Hybrid Journal   (Followers: 1, SJR: 1.165, h-index: 5)
J. of Conflict and Security Law     Hybrid Journal   (Followers: 11, SJR: 0.196, h-index: 15)
J. of Consumer Research     Full-text available via subscription   (Followers: 39, SJR: 4.896, h-index: 121)
J. of Crohn's and Colitis     Hybrid Journal   (Followers: 9, SJR: 1.543, h-index: 37)
J. of Cybersecurity     Hybrid Journal   (Followers: 3)
J. of Deaf Studies and Deaf Education     Hybrid Journal   (Followers: 8, SJR: 0.69, h-index: 36)
J. of Design History     Hybrid Journal   (Followers: 15, SJR: 0.166, h-index: 14)
J. of Economic Entomology     Full-text available via subscription   (Followers: 6, SJR: 0.894, h-index: 76)
J. of Economic Geography     Hybrid Journal   (Followers: 33, SJR: 2.909, h-index: 69)
J. of Environmental Law     Hybrid Journal   (Followers: 23, SJR: 0.457, h-index: 20)
J. of European Competition Law & Practice     Hybrid Journal   (Followers: 19)
J. of Experimental Botany     Hybrid Journal   (Followers: 13, SJR: 2.798, h-index: 163)
J. of Financial Econometrics     Hybrid Journal   (Followers: 21, SJR: 1.314, h-index: 27)
J. of Global Security Studies     Hybrid Journal   (Followers: 2)
J. of Heredity     Hybrid Journal   (Followers: 3, SJR: 1.024, h-index: 76)
J. of Hindu Studies     Hybrid Journal   (Followers: 7, SJR: 0.186, h-index: 3)
J. of Hip Preservation Surgery     Open Access  
J. of Human Rights Practice     Hybrid Journal   (Followers: 20, SJR: 0.399, h-index: 10)
J. of Infectious Diseases     Hybrid Journal   (Followers: 40, SJR: 4, h-index: 209)
J. of Insect Science     Open Access   (Followers: 10, SJR: 0.388, h-index: 31)
J. of Integrated Pest Management     Open Access   (Followers: 1)

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Journal Cover Brain
  [SJR: 6.097]   [H-I: 264]   [61 followers]  Follow
    
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0006-8950 - ISSN (Online) 1460-2156
   Published by Oxford University Press Homepage  [369 journals]
  • A human cellular model to study peripheral myelination and demyelinating
           neuropathies
    • Authors: Saporta MA; Shy ME.
      Abstract: This scientific commentary refers to ‘Co-cultures with stem cell-derived human sensory neurons reveal regulators of peripheral myelination’, by Clark et al.. (doi:10.1093/brain/awx012).
      PubDate: 2017-03-25
       
  • Multi-modal imaging and photosensitive epilepsy: a link between resting
           brain rhythms and seizure genesis
    • Authors: Hamandi K.
      Abstract: This scientific commentary refers to ‘Photosensitive epilepsy is associated with reduced inhibition of alpha rhythm generating networks’, by Vaudano et al.. (doi:10.1093/brain/awx009).
      PubDate: 2017-03-25
       
  • Neurofeedback or neuroplacebo'
    • Authors: Thibault RT; Lifshitz M, Raz A.
      Abstract: This scientific commentary refers to ‘Better than sham' A double-blind placebo-controlled neurofeedback study in primary insomnia’, by Schabus et al.. (doi:10.1093/brain/awx011).
      PubDate: 2017-03-25
       
  • Is antipsychotic sensitivity in Alzheimer’s disease secondary to
           abnormal blood–brain barrier integrity'
    • Authors: Caravaggio F; Graff-Guerrero A.
      Abstract: This scientific commentary refers to ‘Therapeutic window of dopamine D2/3 receptor occupancy to treat psychosis in Alzheimer’s disease’, by Reeves et al.. (doi:10.1093/brain/aww359).
      PubDate: 2017-03-25
       
  • Corrigendum
    • Abstract: Ana Lopez, Suzee E. Lee, Kevin Wojta, Eliana Marisa Ramos, Eric Klein, Jason Chen, Adam L. Boxer, Maria Luisa Gorno-Tempini, Daniel H. Geschwind, Lars Schlotawa, Nikolay V. Ogryzko, Eileen H. Bigio, Emily Rogalski, Sandra Weintraub, Marsel M. Mesulam, Angeleen Fleming, Giovanni Coppola, Bruce L. Miller, David C. Rubinsztein. A152T tau allele causes neurodegeneration that can be ameliorated in a zebrafish model by autophagy induction. Brain 2017; 140: 1128–1146; 10.1093/brain/awx005.
      PubDate: 2017-03-25
       
  • Alzheimer’s disease: where next for anti-amyloid therapies'
    • Authors: Hardy J; De Strooper B.
      Abstract: The recent failures of the solanezumab Expedition 3 and the verubecestat phase II/III trials to significantly slow disease progression in mild or mild-to-moderate Alzheimer’s disease are considerable disappointments. They are causing soul searching in the field: are we on the right track and what do we need to do to get effective mechanistic therapies' While there have been previous trial failures of anti-amyloid therapies, most of these had clear problems during their preclinical development, which perhaps should have allowed their failure to be foreseen (Karran and Hardy, 2014). The solanezumab trial, in contrast, had been approached with cautious optimism in the light of the marginally positive data on clinical slowing in mild disease in secondary analyses of the earlier Expedition and Expedition 2 trials (Doody et al., 2014). Verubecestat appeared to be a safe and effective BACE-1 inhibitor (Kennedy et al., 2016) allowing effective amyloid-β lowering in the CNS. Thus both approaches appeared to have overcome most of the shortcomings encountered in previous trials although the fact that biomarker confirmation of Alzheimer pathology was not required in the verubecestat trial was a clear shortcoming. In addition, the two approaches are complementary as they hit the amyloid-β peptide from either the clearance side (solanezumab) or from the production side (verubecestat). Thus, these were two serious tests of the amyloid hypothesis, and, in practical clinical terms, both turned out negative.
      PubDate: 2017-03-25
       
  • Long-term outcomes of allogeneic haematopoietic stem cell transplantation
           for adult cerebral X-linked adrenoleukodystrophy
    • Authors: Kühl J; Suarez F, Gillett GT, et al.
      Abstract: The adult cerebral inflammatory form of X-linked adrenoleukodystrophy is a rapidly progressive neurodegenerative disease, as devastating as childhood cerebral adrenoleukodystrophy. Allogeneic haematopoietic stem cell transplantation has been demonstrated to provide long-term neurological benefits for boys with the childhood cerebral form, but results in adults are sparse and inconclusive. We analysed data from 14 adult males with adult cerebral adrenoleukodystrophy treated with allogeneic haematopoietic stem cell transplantation on a compassionate basis in four European centres. All presented with cerebral demyelinating lesions and gadolinium enhancement. Median age at diagnosis of adult cerebral adrenoleukodystrophy was 33 years (range 21–48 years). In addition to cerebral inflammation, five patients had established severe motor disability from adrenomyeloneuropathy affecting only the spinal cord and peripheral nerves (Expanded Disability Status Scale score ≥ 6). Eight patients survived (estimated survival 57 ± 13%) with a median follow-up of 65 months (minimum 38 months). Death was directly transplant-/infection-related (n = 3), due to primary disease progression in advanced adult cerebral adrenoleukodystrophy (n = 1), or secondary disease progression (n = 2) after transient multi-organ failure or non-engraftment. Specific complications during stem cell transplantation included deterioration of motor and bladder functions (n = 12) as well as behavioural changes (n = 8). Arrest of progressive cerebral demyelination and prevention of severe loss of neurocognition was achieved in all eight survivors, but deterioration of motor function occurred in the majority (n = 5). Limited motor dysfunction (Expanded Disability Status Scale score < 6) prior to transplantation was associated with significantly improved survival [78 ± 14% (n = 9) versus 20 ± 18%(n = 5); P < 0.05] and maintenance of ambulation (Expanded Disability Status Scale score < 7) post-transplant (78% versus 0%; P = 0.021). In contrast, bilateral involvement of the internal capsule on brain MRI was associated with poorer survival [20 ± 18% (n = 5) versus 78 ± 14% (n = 9); P < 0.05]. This study is the first to support the feasibility, complications and potential long-term neurological benefit of allogeneic haematopoietic stem cell transplantation in adult cerebral adrenoleukodystrophy. Further studies are warranted to attempt to improve outcomes through patient selection and optimization of transplantation protocols.
      PubDate: 2017-03-25
       
  • Altered sleep homeostasis correlates with cognitive impairment in patients
           with focal epilepsy
    • Authors: Boly M; Jones B, Findlay G, et al.
      Abstract: In animal studies, both seizures and interictal spikes induce synaptic potentiation. Recent evidence suggests that electroencephalogram slow wave activity during sleep reflects synaptic potentiation during wake, and that its homeostatic decrease during the night is associated with synaptic renormalization and its beneficial effects. Here we asked whether epileptic activity induces plastic changes that can be revealed by high-density electroencephalography recordings during sleep in 15 patients with focal epilepsy and 15 control subjects. Compared to controls, patients with epilepsy displayed increased slow wave activity power during non-rapid eye movement sleep over widespread, bilateral scalp regions. This global increase in slow wave activity power was positively correlated with the frequency of secondarily generalized seizures in the 3–5 days preceding the recordings. Individual patients also showed local increases in sleep slow wave activity power at scalp locations matching their seizure focus. This local increase in slow wave activity power was positively correlated with the frequency of interictal spikes during the last hour of wakefulness preceding sleep. By contrast, frequent interictal spikes during non-rapid eye movement sleep predicted a reduced homeostatic decrease in the slope of sleep slow waves during the night, which in turn predicted reduced daytime learning. Patients also showed an increase in sleep spindle power, which was negatively correlated with intelligence quotient. Altogether, these findings suggest that both seizures and interictal spikes may induce long-lasting changes in the human brain that can be sensitively detected by electroencephalographic markers of sleep homeostasis. Furthermore, abnormalities in sleep markers are correlated with cognitive impairment, suggesting that not only seizures, but also interictal spikes can have negative consequences.
      PubDate: 2017-03-14
       
  • The difference between compensation, and mechanism-specific spatial
           recovery
    • Authors: Barrett AM.
      Abstract: Sir,
      PubDate: 2017-03-05
       
  • Reply: The difference between compensation, and mechanism-specific spatial
           recovery
    • Authors: Takamura Y; Imanishi M, Osaka M, et al.
      Abstract: Sir,
      PubDate: 2017-03-05
       
  • Brain temporal complexity in explaining the therapeutic and cognitive
           effects of seizure therapy
    • Authors: Farzan F; Atluri S, Mei Y, et al.
      Abstract: Over 350 million people worldwide suffer from depression, a third of whom are medication-resistant. Seizure therapy remains the most effective treatment in depression, even when many treatments fail. The utility of seizure therapy is limited due to its cognitive side effects and stigma. The biological targets of seizure therapy remain unknown, hindering design of new treatments with comparable efficacy. Seizures impact the brains temporal dynamicity observed through electroencephalography. This dynamicity reflects richness of information processing across distributed brain networks subserving affective and cognitive processes. We investigated the hypothesis that seizure therapy impacts mood (depressive symptoms) and cognition by modulating brain temporal dynamicity. We obtained resting-state electroencephalography from 34 patients (age = 46.0 ± 14.0, 21 females) receiving two types of seizure treatments—electroconvulsive therapy or magnetic seizure therapy. We used multi-scale entropy to quantify the complexity of the brain’s temporal dynamics before and after seizure therapy. We discovered that reduction of complexity in fine timescales underlined successful therapeutic response to both seizure treatments. Greater reduction in complexity of fine timescales in parieto-occipital and central brain regions was significantly linked with greater improvement in depressive symptoms. Greater increase in complexity of coarse timescales was associated with greater decline in cognition including the autobiographical memory. These findings were region and timescale specific. That is, change in complexity in occipital regions (e.g. O2 electrode or right occipital pole) at fine timescales was only associated with change in depressive symptoms, and not change in cognition, and change in complexity in parieto-central regions (e.g. Pz electrode or intra and transparietal sulcus) at coarser timescale was only associated with change in cognition, and not depressive symptoms. Finally, region and timescale specific changes in complexity classified both antidepressant and cognitive response to seizure therapy with good (80%) and excellent (95%) accuracy, respectively. In this study, we discovered a novel biological target of seizure therapy: complexity of the brain resting state dynamics. Region and timescale dependent changes in complexity of the brain resting state dynamics is a novel mechanistic marker of response to seizure therapy that explains both the antidepressant response and cognitive changes associated with this treatment. This marker has tremendous potential to guide design of the new generation of antidepressant treatments.
      PubDate: 2017-03-03
       
  • Rewiring the primary somatosensory cortex in carpal tunnel syndrome with
           acupuncture
    • Authors: Maeda Y; Kim H, Kettner N, et al.
      Abstract: Carpal tunnel syndrome is the most common entrapment neuropathy, affecting the median nerve at the wrist. Acupuncture is a minimally-invasive and conservative therapeutic option, and while rooted in a complex practice ritual, acupuncture overlaps significantly with many conventional peripherally-focused neuromodulatory therapies. However, the neurophysiological mechanisms by which acupuncture impacts accepted subjective/psychological and objective/physiological outcomes are not well understood. Eligible patients (n = 80, 65 female, age: 49.3 ± 8.6 years) were enrolled and randomized into three intervention arms: (i) verum electro-acupuncture ‘local’ to the more affected hand; (ii) verum electro-acupuncture at ‘distal’ body sites, near the ankle contralesional to the more affected hand; and (iii) local sham electro-acupuncture using non-penetrating placebo needles. Acupuncture therapy was provided for 16 sessions over 8 weeks. Boston Carpal Tunnel Syndrome Questionnaire assessed pain and paraesthesia symptoms at baseline, following therapy and at 3-month follow-up. Nerve conduction studies assessing median nerve sensory latency and brain imaging data were acquired at baseline and following therapy. Functional magnetic resonance imaging assessed somatotopy in the primary somatosensory cortex using vibrotactile stimulation over three digits (2, 3 and 5). While all three acupuncture interventions reduced symptom severity, verum (local and distal) acupuncture was superior to sham in producing improvements in neurophysiological outcomes, both local to the wrist (i.e. median sensory nerve conduction latency) and in the brain (i.e. digit 2/3 cortical separation distance). Moreover, greater improvement in second/third interdigit cortical separation distance following verum acupuncture predicted sustained improvements in symptom severity at 3-month follow-up. We further explored potential differential mechanisms of local versus distal acupuncture using diffusion tensor imaging of white matter microstructure adjacent to the primary somatosensory cortex. Compared to healthy adults (n = 34, 28 female, 49.7 ± 9.9 years old), patients with carpal tunnel syndrome demonstrated increased fractional anisotropy in several regions and, for these regions we found that improvement in median nerve latency was associated with reduction of fractional anisotropy near (i) contralesional hand area following verum, but not sham, acupuncture; (ii) ipsilesional hand area following local, but not distal or sham, acupuncture; and (iii) ipsilesional leg area following distal, but not local or sham, acupuncture. As these primary somatosensory cortex subregions are distinctly targeted by local versus distal acupuncture electrostimulation, acupuncture at local versus distal sites may improve median nerve function at the wrist by somatotopically distinct neuroplasticity in the primary somatosensory cortex following therapy. Our study further suggests that improvements in primary somatosensory cortex somatotopy can predict long-term clinical outcomes for carpal tunnel syndrome.
      PubDate: 2017-03-02
       
  • PRUNE is crucial for normal brain development and mutated in microcephaly
           with neurodevelopmental impairment
    • Authors: Zollo M; Ahmed M, Ferrucci V, et al.
      Abstract: PRUNE is a member of the DHH (Asp-His-His) phosphoesterase protein superfamily of molecules important for cell motility, and implicated in cancer progression. Here we investigated multiple families from Oman, India, Iran and Italy with individuals affected by a new autosomal recessive neurodevelopmental and degenerative disorder in which the cardinal features include primary microcephaly and profound global developmental delay. Our genetic studies identified biallelic mutations of PRUNE1 as responsible. Our functional assays of disease-associated variant alleles revealed impaired microtubule polymerization, as well as cell migration and proliferation properties, of mutant PRUNE. Additionally, our studies also highlight a potential new role for PRUNE during microtubule polymerization, which is essential for the cytoskeletal rearrangements that occur during cellular division and proliferation. Together these studies define PRUNE as a molecule fundamental for normal human cortical development and define cellular and clinical consequences associated with PRUNE mutation.
      PubDate: 2017-02-28
       
  • High intra-familiar clinical variability in MORC2 mutated CMT2 patients
    • Authors: Semplicini C; Ollagnon-Roman E, Leonard-Louis S, et al.
      Abstract: Sir,
      PubDate: 2017-02-23
       
  • Better than sham' A double-blind placebo-controlled neurofeedback
           study in primary insomnia
    • Authors: Schabus M; Griessenberger H, Gnjezda M, et al.
      Abstract: See Thibault et al. (doi:10.1093/awx033) for a scientific commentary on this article.Neurofeedback training builds upon the simple concept of instrumental conditioning, i.e. behaviour that is rewarded is more likely to reoccur, an effect Thorndike referred to as the ‘law of effect’. In the case of neurofeedback, information about specific electroencephalographic activity is fed back to the participant who is rewarded whenever the desired electroencephalography pattern is generated. If some kind of hyperarousal needs to be addressed, the neurofeedback community considers sensorimotor rhythm neurofeedback as the gold standard. Earlier treatment approaches using sensorimotor-rhythm neurofeedback indicated that training to increase 12–15 Hz sensorimotor rhythm over the sensorimotor cortex during wakefulness could reduce attention-deficit/hyperactivity disorder and epilepsy symptoms and even improve sleep quality by enhancing sleep spindle activity (lying in the same frequency range). In the present study we sought to critically test whether earlier findings on the positive effect of sensorimotor rhythm neurofeedback on sleep quality and memory could also be replicated in a double-blind placebo-controlled study on 25 patients with insomnia. Patients spent nine polysomnography nights and 12 sessions of neurofeedback and 12 sessions of placebo-feedback training (sham) in our laboratory. Crucially, we found both neurofeedback and placebo feedback to be equally effective as reflected in subjective measures of sleep complaints suggesting that the observed improvements were due to unspecific factors such as experiencing trust and receiving care and empathy from experimenters. In addition, these improvements were not reflected in objective electroencephalographic-derived measures of sleep quality. Furthermore, objective electroencephalographic measures that potentially reflected mechanisms underlying the efficacy of neurofeedback such as spectral electroencephalographic measures and sleep spindle parameters remained unchanged following 12 training sessions. A stratification into ‘true’ insomnia patients and ‘insomnia misperceivers’ (subjective, but no objective sleep problems) did not alter the results. Based on this comprehensive and well-controlled study, we conclude that for the treatment of primary insomnia, neurofeedback does not have a specific efficacy beyond unspecific placebo effects. Importantly, we do not find an advantage of neurofeedback over placebo feedback, therefore it cannot be recommended as an alternative to cognitive behavioural therapy for insomnia, the current (non-pharmacological) standard-of-care treatment. In addition, our study may foster a critical discussion that generally questions the effectiveness of neurofeedback, and emphasizes the importance of demonstrating neurofeedback efficacy in other study samples and disorders using truly placebo and double-blind controlled trials.
      PubDate: 2017-02-23
       
  • Operationalizing compensation over time in neurodegenerative disease
    • Authors: Gregory S; Long JD, Klöppel S, et al.
      Abstract: In pre-clinical Huntington's disease, normal behaviour is maintained despite neurodegeneration, suggesting a mechanism of compensation. Gregory, Long et al. present two mathematical models of compensation over time and their operationalisation for neuroimaging.
      PubDate: 2017-02-23
       
  • C9orf72 and RAB7L1 regulate vesicle trafficking in amyotrophic lateral
           sclerosis and frontotemporal dementia
    • Authors: Aoki Y; Manzano R, Lee Y, et al.
      Abstract: A non-coding hexanucleotide repeat expansion in intron 1 of the C9orf72 gene is the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD), however, the precise molecular mechanism by which the C9orf72 hexanucleotide repeat expansion directs C9ALS/FTD pathogenesis remains unclear. Here, we report a novel disease mechanism arising due to the interaction of C9ORF72 with the RAB7L1 GTPase to regulate vesicle trafficking. Endogenous interaction between C9ORF72 and RAB7L1 was confirmed in human SH-SY5Y neuroblastoma cells. The C9orf72 hexanucleotide repeat expansion led to haploinsufficiency resulting in severely defective intracellular and extracellular vesicle trafficking and a dysfunctional trans-Golgi network phenotype in patient-derived fibroblasts and induced pluripotent stem cell-derived motor neurons. Genetic ablation of RAB7L1or C9orf72 in SH-SY5Y cells recapitulated the findings in C9ALS/FTD fibroblasts and induced pluripotent stem cell neurons. When C9ORF72 was overexpressed or antisense oligonucleotides were targeted to the C9orf72 hexanucleotide repeat expansion to upregulate normal variant 1 transcript levels, the defective vesicle trafficking and dysfunctional trans-Golgi network phenotypes were reversed, suggesting that both loss- and gain-of-function mechanisms play a role in disease pathogenesis. In conclusion, we have identified a novel mechanism for C9ALS/FTD pathogenesis highlighting the molecular regulation of intracellular and extracellular vesicle trafficking as an important pathway in C9ALS/FTD pathogenesis.
      PubDate: 2017-02-23
       
  • Effects of prefrontal cortex damage on emotion understanding: EEG and
           behavioural evidence
    • Authors: Perry A; Saunders SN, Stiso J, et al.
      Abstract: Humans are highly social beings that interact with each other on a daily basis. In these complex interactions, we get along by being able to identify others’ actions and infer their intentions, thoughts and feelings. One of the major theories accounting for this critical ability assumes that the understanding of social signals is based on a primordial tendency to simulate observed actions by activating a mirror neuron system. If mirror neuron regions are important for action and emotion recognition, damage to regions in this network should lead to deficits in these domains. In the current behavioural and EEG study, we focused on the lateral prefrontal cortex including dorsal and ventral prefrontal cortex and utilized a series of task paradigms, each measuring a different aspect of recognizing others’ actions or emotions from body cues. We examined 17 patients with lesions including (n = 8) or not including (n = 9) the inferior frontal gyrus, a core mirror neuron system region, and compared their performance to matched healthy control subjects (n = 18), in behavioural tasks and in an EEG observation—execution task measuring mu suppression. Our results provide support for the role of the lateral prefrontal cortex in understanding others’ emotions, by showing that even unilateral lesions result in deficits in both accuracy and reaction time in tasks involving the recognition of others’ emotions. In tasks involving the recognition of actions, patients showed a general increase in reaction time, but not a reduction in accuracy. Deficits in emotion recognition can be seen by either direct damage to the inferior frontal gyrus, or via damage to dorsal lateral prefrontal cortex regions, resulting in deteriorated performance and less EEG mu suppression over sensorimotor cortex.
      PubDate: 2017-02-22
       
  • Adaptive human immunity drives remyelination in a mouse model of
           demyelination
    • Authors: El Behi M; Sanson C, Bachelin C, et al.
      Abstract: One major challenge in multiple sclerosis is to understand the cellular and molecular mechanisms leading to disease severity progression. The recently demonstrated correlation between disease severity and remyelination emphasizes the importance of identifying factors leading to a favourable outcome. Why remyelination fails or succeeds in multiple sclerosis patients remains largely unknown, mainly because remyelination has never been studied within a humanized pathological context that would recapitulate major events in plaque formation such as infiltration of inflammatory cells. Therefore, we developed a new paradigm by grafting healthy donor or multiple sclerosis patient lymphocytes in the demyelinated lesion of nude mice spinal cord. We show that lymphocytes play a major role in remyelination whose efficacy is significantly decreased in mice grafted with multiple sclerosis lymphocytes compared to those grafted with healthy donors lymphocytes. Mechanistically, we demonstrated in vitro that lymphocyte-derived mediators influenced differentiation of oligodendrocyte precursor cells through a crosstalk with microglial cells. Among mice grafted with lymphocytes from different patients, we observed diverse remyelination patterns reproducing for the first time the heterogeneity observed in multiple sclerosis patients. Comparing lymphocyte secretory profile from patients exhibiting high and low remyelination ability, we identified novel molecules involved in oligodendrocyte precursor cell differentiation and validated CCL19 as a target to improve remyelination. Specifically, exogenous CCL19 abolished oligodendrocyte precursor cell differentiation observed in patients with high remyelination pattern. Multiple sclerosis lymphocytes exhibit intrinsic capacities to coordinate myelin repair and further investigation on patients with high remyelination capacities will provide new pro-regenerative strategies.
      PubDate: 2017-02-22
       
  • GWAS-linked PPARGC1A variant in Asian patients with essential tremor
    • Authors: Xiao B; Deng X, Ng E, et al.
      Abstract: Sir, Essential tremor (ET) is a common movement disorder with genetic factors contributing to its pathogenesis. Linkage analyses have identified four distinct chromosomal regions related to ET (Gulcher et al., 1997; Higgins et al., 1997; Shatunov et al., 2006; Hicks et al., 2016) while mutations in HS1BP3 and FUS have been ascribed to cause monogenic ET (Higgins et al., 2005; Merner et al., 2012). We read with interest the recent genome-wide association study (GWAS) by Muller et al. (2016) where they identified three loci to be associated with ET in the Caucasian population. Two gene variants, rs10937625 in STK32B and rs17590046 in PPARGC1A, identified in their discovery dataset were replicated in an independent multi-centre cohort. To take these findings further, we conducted a case control association study of these two variants in our Asian population. We included 939 subjects including 469 patients with ET (age 51.0 ± 20.0 years, 264 males) and 470 age- and gender-matched controls (age 53.1 ± 9.0 years, 256 males) who were recruited from movement disorder outpatient clinics in National Neuroscience Institute (Singapore General Hospital and Tan Tock Seng hospital). The patients were diagnosed by movement disorder specialists according to the Movement Disorder Society (MDS) consensus diagnostic criteria (Deuschl et al., 1998). Genotypes of rs10937625 and rs17590046 were determined by TaqMan®-based probe on a 7500 RT-PCR system (Life Technologies). Five per cent of results were randomly selected and validated by Sanger sequencing analysis. Allele frequencies were estimated using chi-square test. Our study was approved by Singhealth Centralized Institutional Review Board and written informed consent from all subjects was obtained. There was an association between rs17590046 and ET (Table 1). There were 63 heterozygous variants (TT to TC) and one homozygous variant (TT to CC) of 469 ET cases. Eighty-one heterozygous variants and six homozygous variants were found in 470 controls [P = 0.025, odds ratio (OR) 0.678, 95% confidence interval (CI) 0.481–0.956] (Table 1). However, no association with ET was observed for rs10937625. The heterozygous variant (TT to TC) was present in 110 cases and 114 controls, with homozygous variant (TT to CC) in eight cases and 11 controls (P = 0.549, OR 0.915, 95% CI 0.699–1.198) (Table 2). The minor allele frequency (MAF) for rs17590046 reported by Muller et al. (2016) was 0.1668 in cases and 0.2054 in controls, whereas in our study, the MAF was 0.0693 in cases and 0.0989 in controls. The differences in MAF may be due to genetic variation between races. Table 1Genotype of rs17590046 in ET cases and controlsGenotypeETControlsOR (95%CI)P-valueTT405383TC6381CC16TC + CC64870.678 (0.481–0.956)0.025Table 2Genotype of rs10937625 in ET cases and controlsGenotypeETControlsOR (95%CI)P-valueTT351345TC110114CC811TC + CC1181250.915 (0.699–1.198)0.549 Despite concerns about the clinical and genetic heterogeneity of ET, we provide the first replication of rs17590046 in ET outside the Caucasian population. The odds ratio of rs17590046 in our Asian subjects (OR 0.678) was similar to that in Caucasians (OR 0.80) reported by Muller et al. (2016), even though our sample size was smaller and expectedly the statistical significance in our study was less robust. Further studies in other populations will be of interest.
      PubDate: 2017-02-20
       
  • Decreased integration and information capacity in stroke measured by whole
           brain models of resting state activity
    • Authors: Adhikari MH; Hacker CD, Siegel JS, et al.
      Abstract: While several studies have shown that focal lesions affect the communication between structurally normal regions of the brain, and that these changes may correlate with behavioural deficits, their impact on brain’s information processing capacity is currently unknown. Here we test the hypothesis that focal lesions decrease the brain’s information processing capacity, of which changes in functional connectivity may be a measurable correlate. To measure processing capacity, we turned to whole brain computational modelling to estimate the integration and segregation of information in brain networks. First, we measured functional connectivity between different brain areas with resting state functional magnetic resonance imaging in healthy subjects (n = 26), and subjects who had suffered a cortical stroke (n = 36). We then used a whole-brain network model that coupled average excitatory activities of local regions via anatomical connectivity. Model parameters were optimized in each healthy or stroke participant to maximize correlation between model and empirical functional connectivity, so that the model’s effective connectivity was a veridical representation of healthy or lesioned brain networks. Subsequently, we calculated two model-based measures: ‘integration’, a graph theoretical measure obtained from functional connectivity, which measures the connectedness of brain networks, and ‘information capacity’, an information theoretical measure that cannot be obtained empirically, representative of the segregative ability of brain networks to encode distinct stimuli. We found that both measures were decreased in stroke patients, as compared to healthy controls, particularly at the level of resting-state networks. Furthermore, we found that these measures, especially information capacity, correlate with measures of behavioural impairment and the segregation of resting-state networks empirically measured. This study shows that focal lesions affect the brain’s ability to represent stimuli and task states, and that information capacity measured through whole brain models is a theory-driven measure of processing capacity that could be used as a biomarker of injury for outcome prediction or target for rehabilitation intervention.
      PubDate: 2017-02-20
       
  • Neural mechanisms of reinforcement learning in unmedicated patients with
           major depressive disorder
    • Authors: Rothkirch M; Tonn J, Köhler S, et al.
      Abstract: According to current concepts, major depressive disorder is strongly related to dysfunctional neural processing of motivational information, entailing impairments in reinforcement learning. While computational modelling can reveal the precise nature of neural learning signals, it has not been used to study learning-related neural dysfunctions in unmedicated patients with major depressive disorder so far. We thus aimed at comparing the neural coding of reward and punishment prediction errors, representing indicators of neural learning-related processes, between unmedicated patients with major depressive disorder and healthy participants. To this end, a group of unmedicated patients with major depressive disorder (n = 28) and a group of age- and sex-matched healthy control participants (n = 30) completed an instrumental learning task involving monetary gains and losses during functional magnetic resonance imaging. The two groups did not differ in their learning performance. Patients and control participants showed the same level of prediction error-related activity in the ventral striatum and the anterior insula. In contrast, neural coding of reward prediction errors in the medial orbitofrontal cortex was reduced in patients. Moreover, neural reward prediction error signals in the medial orbitofrontal cortex and ventral striatum showed negative correlations with anhedonia severity. Using a standard instrumental learning paradigm we found no evidence for an overall impairment of reinforcement learning in medication-free patients with major depressive disorder. Importantly, however, the attenuated neural coding of reward in the medial orbitofrontal cortex and the relation between anhedonia and reduced reward prediction error-signalling in the medial orbitofrontal cortex and ventral striatum likely reflect an impairment in experiencing pleasure from rewarding events as a key mechanism of anhedonia in major depressive disorder.
      PubDate: 2017-02-20
       
  • Photosensitive epilepsy is associated with reduced inhibition of alpha
           rhythm generating networks
    • Authors: Elisabetta Vaudano A; Ruggieri A, Avanzini P, et al.
      Abstract: See Hamandi (doi:10.1093/awx049) for a scientific commentary on this article.Photosensitivity is a condition in which lights induce epileptiform activities. This abnormal electroencephalographic response has been associated with hyperexcitability of the visuo-motor system. Here, we evaluate if intrinsic dysfunction of this network is present in brain activity at rest, independently of any stimulus and of any paroxysmal electroencephalographic activity. To address this issue, we investigated the haemodynamic correlates of the spontaneous alpha rhythm, which is considered the hallmark of the brain resting state, in photosensitive patients and in people without photosensitivity. Second, we evaluated the whole-brain functional connectivity of the visual thalamic nuclei in the various populations of subjects under investigation. Forty-four patients with epilepsy and 16 healthy control subjects underwent an electroencephalography-correlated functional magnetic resonance imaging study, during an eyes-closed condition. The following patient groups were included: (i) genetic generalized epilepsy with photosensitivity, 16 subjects (mean age 25 ± 10 years); (ii) genetic generalized epilepsy without photosensitivity, 13 patients (mean age 25 ± 11 years); (iii) focal epilepsy, 15 patients (mean age 25 ± 9 years). For each subject, the posterior alpha power variations were convolved with the standard haemodynamic response function and used as a regressor. Within- and between-groups second level analyses were performed. Whole brain functional connectivity was evaluated for two thalamic regions of interest, based on the haemodynamic findings, which included the posterior thalamus (pulvinar) and the medio-dorsal thalamic nuclei. Genetic generalized epilepsy with photosensitivity demonstrated significantly greater mean alpha-power with respect to controls and other epilepsy groups. In photosensitive epilepsy, alpha-related blood oxygen level-dependent signal changes demonstrated lower decreases relative to all other groups in the occipital, sensory-motor, anterior cingulate and supplementary motor cortices. Coherently, the same brain regions demonstrated abnormal connectivity with the visual thalamus only in epilepsy patients with photosensitivity. As predicted, our findings indicate that the cortical-subcortical network generating the alpha oscillation at rest is different in people with epilepsy and visual sensitivity. This difference consists of a decreased alpha-related inhibition of the visual cortex and sensory-motor networks at rest. These findings represent the substrate of the clinical manifestations (i.e. myoclonus) of the photoparoxysmal response. Moreover, our results provide the first evidence of the existence of a functional link between the circuits that trigger the visual sensitivity phenomenon and those that generate the posterior alpha rhythm.
      PubDate: 2017-02-20
       
  • Spatiotemporal mapping of epileptic spikes using simultaneous
           EEG-functional MRI
    • Authors: Walz JM; Pedersen M, Omidvarnia A, et al.
      Abstract: Epileptic spikes occur on the sub-second timescale and are known to involve not only epileptic foci but also large-scale distributed brain networks. There is likely to be a sequence of neural activity in multiple brain regions that occurs within the duration of a single spike, but standard electroencephalography-functional magnetic resonance imaging analyses, which use only the timing of the spikes to model the functional magnetic resonance imaging data, cannot determine the sequence of these activations. Our aim in this study is to temporally resolve these spatial activations to observe the spatiotemporal dynamics of the spike-related neural activity at a sub-second timescale. We studied eight focal epilepsy patients (age 11–42 years, six female) and used amplitude features of the electroencephalogram specific to different spike components (early and late peaks and troughs) to encode temporal information into our functional magnetic resonance imaging models. This enables us to associate each activation with a specific model of each of the spike components to infer the temporal order of these spike-related spatial activations. In seven of eight patients the distributed networks were associated with the late spike component. The focal activations were more variably coupled with time epochs, but tended to precede the distributed network effects. We also found that incorporating electroencephalogram features into the models increased sensitivity and in six patients revealed additional regions unseen in the standard analysis result. This included strong bilateral thalamus activation in two patients. We demonstrate the clinical utility of this approach in a patient who recently underwent a successful surgical resection of the region where we saw enhanced activation using electroencephalogram amplitude information specific to the early spike component. This focal cluster of activation was larger and more precisely tracked the anatomy compared to what was seen using the standard timing-based analysis. Our novel electroencephalography-functional magnetic resonance imaging data fusion approach, which utilizes information based on the single spike variability across all electroencephalogram channels, has the potential to help us better understand epileptic networks and aid in the interpretation of functional magnetic resonance imaging activation maps during treatment planning.
      PubDate: 2017-02-20
       
  • MRI-visible perivascular space location is associated with Alzheimer's
           disease independently of amyloid burden
    • Authors: Banerjee G; Kim H, Fox Z, et al.
      Abstract: Perivascular spaces that are visible on magnetic resonance imaging (MRI) are a neuroimaging marker of cerebral small vessel disease. Their location may relate to the type of underlying small vessel pathology: those in the white matter centrum semi-ovale have been associated with cerebral amyloid angiopathy, while those in the basal ganglia have been associated with deep perforating artery arteriolosclerosis. As cerebral amyloid angiopathy is an almost invariable pathological finding in Alzheimer’s disease, we hypothesized that MRI-visible perivascular spaces in the centrum semi-ovale would be associated with a clinical diagnosis of Alzheimer’s disease, whereas those in the basal ganglia would be associated with subcortical vascular cognitive impairment. We also hypothesized that MRI-visible perivascular spaces in the centrum semi-ovale would be associated with brain amyloid burden, as detected by amyloid positron emission tomography using 11C-Pittsburgh B compound (PiB-PET). Two hundred and twenty-six patients (Alzheimer’s disease n = 110; subcortical vascular cognitive impairment n = 116) with standardized MRI and PiB-PET imaging were included. MRI-visible perivascular spaces were rated using a validated 4-point visual rating scale, and then categorized by severity (‘none/mild’, ‘moderate’ or ‘frequent/severe’). Univariable and multivariable regression analyses were performed. Those with Alzheimer’s disease-related cognitive impairment were younger, more likely to have a positive PiB-PET scan and carry at least one apolipoprotein E ɛ4 allele; those with subcortical vascular cognitive impairment were more likely to have hypertension, diabetes mellitus, hyperlipidaemia, prior stroke, lacunes, deep microbleeds, and carry the apolipoprotein E ɛ3 allele. In adjusted analyses, the severity of MRI-visible perivascular spaces in the centrum semi-ovale was independently associated with clinically diagnosed Alzheimer’s disease (frequent/severe grade odds ratio 6.26, 95% confidence interval 1.66–23.58; P = 0.017, compared with none/mild grade), whereas the severity of MRI-visible perivascular spaces in the basal ganglia was associated with clinically diagnosed subcortical vascular cognitive impairment and negatively predicted Alzheimer’s disease (frequent/severe grade odds ratio 0.03, 95% confidence interval 0.00–0.44; P = 0.009, compared with none/mild grade). MRI-visible perivascular space severity in either location did not predict PiB-PET. These findings provide further evidence that the anatomical distribution of MRI-visible perivascular spaces may reflect the underlying cerebral small vessel disease. Using MRI-visible perivascular space location and severity together with other imaging markers may improve the diagnostic value of neuroimaging in memory clinic populations, in particular in differentiating between clinically diagnosed Alzheimer’s and subcortical vascular cognitive impairment.
      PubDate: 2017-02-17
       
  • The Hunting of the Snark: a search for the history of neuropsychiatry
    • Authors: Scull A.
      PubDate: 2017-02-17
       
  • Ubiquitin-related network underlain by (CAG) n loci modulate age at onset
           in Machado-Joseph disease
    • Authors: Chen Z; Wang C, Zheng C, et al.
      Abstract: Sir,
      PubDate: 2017-02-15
       
  • Co-cultures with stem cell-derived human sensory neurons reveal regulators
           of peripheral myelination
    • Authors: Clark AJ; Kaller MS, Galino J, et al.
      Abstract: See Saporta and Shy (doi:10.1093/awx048) for a scientific commentary on this article.Effective bidirectional signalling between axons and Schwann cells is essential for both the development and maintenance of peripheral nerve function. We have established conditions by which human induced pluripotent stem cell-derived sensory neurons can be cultured with rat Schwann cells, and have produced for the first time long-term and stable myelinating co-cultures with human neurons. These cultures contain the specialized domains formed by axonal interaction with myelinating Schwann cells, such as clustered voltage-gated sodium channels at the node of Ranvier and Shaker-type potassium channel (Kv1.2) at the juxtaparanode. Expression of type III neuregulin-1 (TIIINRG1) in induced pluripotent stem cell-derived sensory neurons strongly enhances myelination, while conversely pharmacological blockade of the NRG1-ErbB pathway prevents myelination, providing direct evidence for the ability of this pathway to promote the myelination of human sensory axons. The β-secretase, BACE1 is a protease needed to generate active NRG1 from the full-length form. Due to the fact that it also cleaves amyloid precursor protein, BACE1 is a therapeutic target in Alzheimer’s disease, however, consistent with its role in NRG1 processing we find that BACE1 inhibition significantly impairs myelination in our co-culture system. In order to exploit co-cultures to address other clinically relevant problems, they were exposed to anti-disialosyl ganglioside antibodies, including those derived from a patient with a sensory predominant, inflammatory neuropathy with mixed axonal and demyelinating electrophysiology. The co-cultures reveal that both mouse and human disialosyl antibodies target the nodal axolemma, induce acute axonal degeneration in the presence of complement, and impair myelination. The human, neuropathy-associated IgM antibody is also shown to induce complement-independent demyelination. Myelinating co-cultures using human induced pluripotent stem cell-derived sensory neurons thus provide insights into the cellular and molecular specialization of axoglial signalling, how pharmacological agents may promote or impede such signalling and the pathogenic effects of ganglioside antibodies.awx012media15372351982001
      PubDate: 2017-02-15
       
  • The modulatory effect of adaptive deep brain stimulation on beta bursts in
           Parkinson’s disease
    • Authors: Tinkhauser G; Pogosyan A, Little S, et al.
      Abstract: Adaptive deep brain stimulation uses feedback about the state of neural circuits to control stimulation rather than delivering fixed stimulation all the time, as currently performed. In patients with Parkinson’s disease, elevations in beta activity (13–35 Hz) in the subthalamic nucleus have been demonstrated to correlate with clinical impairment and have provided the basis for feedback control in trials of adaptive deep brain stimulation. These pilot studies have suggested that adaptive deep brain stimulation may potentially be more effective, efficient and selective than conventional deep brain stimulation, implying mechanistic differences between the two approaches. Here we test the hypothesis that such differences arise through differential effects on the temporal dynamics of beta activity. The latter is not constantly increased in Parkinson’s disease, but comes in bursts of different durations and amplitudes. We demonstrate that the amplitude of beta activity in the subthalamic nucleus increases in proportion to burst duration, consistent with progressively increasing synchronization. Effective adaptive deep brain stimulation truncated long beta bursts shifting the distribution of burst duration away from long duration with large amplitude towards short duration, lower amplitude bursts. Critically, bursts with shorter duration are negatively and bursts with longer duration positively correlated with the motor impairment off stimulation. Conventional deep brain stimulation did not change the distribution of burst durations. Although both adaptive and conventional deep brain stimulation suppressed mean beta activity amplitude compared to the unstimulated state, this was achieved by a selective effect on burst duration during adaptive deep brain stimulation, whereas conventional deep brain stimulation globally suppressed beta activity. We posit that the relatively selective effect of adaptive deep brain stimulation provides a rationale for why this approach could be more efficacious than conventional continuous deep brain stimulation in the treatment of Parkinson’s disease, and helps inform how adaptive deep brain stimulation might best be delivered.
      PubDate: 2017-02-13
       
  • A152T tau allele causes neurodegeneration that can be ameliorated in a
           zebrafish model by autophagy induction
    • Authors: Lopez A; Lee SE, Wojta K, et al.
      Abstract: Mutations in the gene encoding tau (MAPT) cause frontotemporal dementia spectrum disorders. A rare tau variant p.A152T was reported as a risk factor for frontotemporal dementia spectrum and Alzheimer’s disease in an initial case-control study. Such findings need replication in an independent cohort. We analysed an independent multinational cohort comprising 3100 patients with neurodegenerative disease and 4351 healthy control subjects and found p.A152T associated with significantly higher risk for clinically defined frontotemporal dementia and progressive supranuclear palsy syndrome. To assess the functional and biochemical consequences of this variant, we generated transgenic zebrafish models expressing wild-type or A152T-tau, where A152T caused neurodegeneration and proteasome compromise. Impaired proteasome activity may also enhance accumulation of other proteins associated with this variant. We increased A152T clearance kinetics by both pharmacological and genetic upregulation of autophagy and ameliorated the disease pathology observed in A152T-tau fish. Thus, autophagy-upregulating therapies may be a strategy for the treatment for tauopathies.
      PubDate: 2017-02-09
       
  • SLC30A9 mutation affecting intracellular zinc homeostasis causes a novel
           cerebro-renal syndrome
    • Authors: Perez Y; Shorer Z, Liani-Leibson K, et al.
      Abstract: A novel autosomal recessive cerebro-renal syndrome was identified in consanguineous Bedouin kindred: neurological deterioration was evident as of early age, progressing into severe intellectual disability, profound ataxia, camptocormia and oculomotor apraxia. Brain MRI was normal. Four of the six affected individuals also had early-onset nephropathy with features of tubulo-interstitial nephritis, hypertension and tendency for hyperkalemia, though none had rapid deterioration of renal function. Genome wide linkage analysis identified an ∼18 Mb disease-associated locus on chromosome 4 (maximal logarithm of odds score 4.4 at D4S2971; θ = 0). Whole exome sequencing identified a single mutation in SLC30A9 within this locus, segregating as expected within the kindred and not found in a homozygous state in 300 Bedouin controls. We showed that SLC30A9 (solute carrier family 30 member 9; also known as ZnT-9) is ubiquitously expressed with high levels in cerebellum, skeletal muscle, thymus and kidney. Confocal analysis of SH-SY5Y cells overexpressing SLC30A9 fused to enhanced green fluorescent protein demonstrated vesicular cytosolic localization associated with the endoplasmic reticulum, not co-localizing with endosomal or Golgi markers. SLC30A9 encodes a putative zinc transporter (by similarity) previously associated with Wnt signalling. However, using dual-luciferase reporter assay in SH-SY5Y cells we showed that Wnt signalling was not affected by the mutation. Based on protein modelling, the identified mutation is expected to affect SLC30A9’s highly conserved cation efflux domain, putatively disrupting its transmembrane helix structure. Cytosolic Zn2+ measurements in HEK293 cells overexpressing wild-type and mutant SLC30A9 showed lower zinc concentration within mutant rather than wild-type SLC30A9 cells. This suggests that SLC30A9 has zinc transport properties affecting intracellular zinc homeostasis, and that the molecular mechanism of the disease is through defective function of this novel activity of SLC30A9 rather than by a defect in its previously described role in transcriptional activation of Wnt signalling.
      PubDate: 2017-02-09
       
  • Improving working memory performance in brain-injured patients using
           hypnotic suggestion
    • Authors: Lindeløv JK; Overgaard R, Overgaard M.
      Abstract: Working memory impairment is prevalent in brain injured patients across lesion aetiologies and severities. Unfortunately, rehabilitation efforts for this impairment have hitherto yielded small or no effects. Here we show in a randomized actively controlled trial that working memory performance can be effectively restored by suggesting to hypnotized patients that they have regained their pre-injury level of working memory functioning. Following four 1-h sessions, 27 patients had a medium-sized improvement relative to 22 active controls (Bayes factors of 342 and 37.5 on the two aggregate outcome measures) and a very large improvement relative to 19 passive controls (Bayes factor = 1.7 × 1013). This was a long-term effect as revealed by no deterioration following a 6.7 week no-contact period (Bayes factors = 7.1 and 1.3 in favour of no change). To control for participant-specific effects, the active control group was crossed over to the working memory suggestion and showed superior improvement. By the end of the study, both groups reached a performance level at or above the healthy population mean with standardized mean differences between 1.55 and 2.03 relative to the passive control group. We conclude that, if framed correctly, hypnotic suggestion can effectively improve working memory following acquired brain injury. The speed and consistency with which this improvement occurred, indicate that there may be a residual capacity for normal information processing in the injured brain.
      PubDate: 2017-02-04
       
  • Therapeutic window of dopamine D2/3 receptor occupancy to treat psychosis
           in Alzheimer’s disease
    • Authors: Reeves S; McLachlan E, Bertrand J, et al.
      Abstract: See Caravaggio and Graff-Guerrero (doi:10.1093/awx023) for a scientific commentary on this article.Antipsychotic drugs, originally developed to treat schizophrenia, are used to treat psychosis, agitation and aggression in Alzheimer’s disease. In the absence of dopamine D2/3 receptor occupancy data to inform antipsychotic prescribing for psychosis in Alzheimer’s disease, the mechanisms underpinning antipsychotic efficacy and side effects are poorly understood. This study used a population approach to investigate the relationship between amisulpride blood concentration and central D2/3 occupancy in older people with Alzheimer’s disease by combining: (i) pharmacokinetic data (280 venous samples) from a phase I single (50 mg) dose study in healthy older people (n = 20, 65–79 years); (ii) pharmacokinetic, 18F-fallypride D2/3 receptor imaging and clinical outcome data on patients with Alzheimer’s disease who were prescribed amisulpride (25–75 mg daily) to treat psychosis as part of an open study (n = 28; 69–92 years; 41 blood samples, five pretreatment scans, 19 post-treatment scans); and (iii) 18F-fallypride imaging of an antipsychotic free Alzheimer’s disease control group (n = 10, 78–92 years), to provide additional pretreatment data. Non-linear mixed effects modelling was used to describe pharmacokinetic-occupancy curves in caudate, putamen and thalamus. Model outputs were used to estimate threshold steady state blood concentration and occupancy required to elicit a clinically relevant response (>25% reduction in scores on delusions, hallucinations and agitation domains of the Neuropsychiatric Inventory) and extrapyramidal side effects (Simpson Angus Scale scores > 3). Average steady state blood levels were low (71 ± 30 ng/ml), and associated with high D2/3 occupancies (65 ± 8%, caudate; 67 ± 11%, thalamus; 52 ± 11%, putamen). Antipsychotic clinical response occurred at a threshold concentration of 20 ng/ml and D2/3 occupancies of 43% (caudate), 25% (putamen), 43% (thalamus). Extrapyramidal side effects (n = 7) emerged at a threshold concentration of 60 ng/ml, and D2/3 occupancies of 61% (caudate), 49% (putamen) and 69% (thalamus). This study has established that, as in schizophrenia, there is a therapeutic window of D2/3 receptor occupancy for optimal treatment of psychosis in Alzheimer’s disease. We have also shown that occupancies within and beyond this window are achieved at very low amisulpride doses in Alzheimer’s disease due to higher than anticipated occupancies for a given blood drug concentration. Our findings support a central pharmacokinetic contribution to antipsychotic sensitivity in Alzheimer’s disease and implicate the blood-brain barrier, which controls central drug access. Whether high D2/3 receptor occupancies are primarily accounted for by age- or disease-specific blood–brain barrier disruption is unclear, and this is an important future area of future investigation, as it has implications beyond antipsychotic prescribing.
      PubDate: 2017-02-04
       
  • Axonal neuropathy with neuromyotonia: there is a HINT
    • Authors: Peeters K; Chamova T, Tournev I, et al.
      Abstract: Recessive mutations in the gene encoding the histidine triad nucleotide binding protein 1 (HINT1) were recently shown to cause a motor-predominant Charcot–Marie–Tooth neuropathy. About 80% of the patients exhibit neuromyotonia, a striking clinical and electrophysiological hallmark that can help to distinguish this disease and to guide diagnostic screening. HINT1 neuropathy has worldwide distribution and is particularly prevalent in populations inhabiting central and south-eastern Europe. With 12 different mutations identified in more than 60 families, it ranks among the most common subtypes of axonal Charcot–Marie–Tooth neuropathy. This article provides an overview of the present knowledge on HINT1 neuropathy with the aim to increase awareness and spur interest among clinicians and researchers in the field. We propose diagnostic guidelines to recognize and differentiate this entity and suggest treatment strategies to manage common symptoms. As a recent player in the field of hereditary neuropathies, the role of HINT1 in peripheral nerves is unknown and the underlying disease mechanisms are unexplored. We provide a comprehensive overview of the structural and functional characteristics of the HINT1 protein that may guide further studies into the molecular aetiology and treatment strategies of this peculiar Charcot–Marie–Tooth subtype.
      PubDate: 2016-12-21
       
  • The yin and yang of α-synuclein-associated epigenetics in
           Parkinson’s disease
    • Authors: Pavlou MS; Pinho R, Paiva I, et al.
      Abstract: Parkinson’s disease is the second most prevalent neurodegenerative disorder. The main neuropathological hallmarks of the disease are the degeneration of dopaminergic neurons in the substantia nigra pars compacta and the accumulation of protein inclusions known as Lewy bodies. Recently, great attention has been given to the study of genes associated with both familial and sporadic forms of Parkinson’s disease. Among them, the α-synuclein gene is believed to play a central role in the disease and is, therefore, one of the most studied genes. Parkinson’s disease is a complex disorder and, as such, derives from the interaction between genetic and environmental factors. Here, we offer an update on the landscape of epigenetic-mediated regulation of gene expression that has been linked with α-synuclein and associated with Parkinson’s disease. We also provide an overview of how epigenetic modifications can influence the transcription and/or translation of the α-synuclein gene and, on the other hand, how α-synuclein function/dysfunction can, per se, affect the epigenetic landscape. Finally, we discuss how a deeper understanding of the epigenetic profile of α-synuclein may enable the development of novel therapeutic approaches for Parkinson’s disease and other synucleinopathies.
      PubDate: 2016-08-31
       
 
 
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