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      Selective vulnerability of inhibitory networks in multiple sclerosis

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          Abstract

          In multiple sclerosis (MS), a chronic demyelinating disease of the central nervous system, neurodegeneration is detected early in the disease course and is associated with the long-term disability of patients. Neurodegeneration is linked to both inflammation and demyelination, but its exact cause remains unknown. This gap in knowledge contributes to the current lack of treatments for the neurodegenerative phase of MS. Here we ask if neurodegeneration in MS affects specific neuronal components and if it is the result of demyelination. Neuropathological examination of secondary progressive MS motor cortices revealed a selective vulnerability of inhibitory interneurons in MS. The generation of a rodent model of focal subpial cortical demyelination reproduces this selective neurodegeneration providing a new preclinical model for the study of neuroprotective treatments.

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          The online version contains supplementary material available at 10.1007/s00401-020-02258-z.

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          Most cited references49

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          QuPath: Open source software for digital pathology image analysis

          QuPath is new bioimage analysis software designed to meet the growing need for a user-friendly, extensible, open-source solution for digital pathology and whole slide image analysis. In addition to offering a comprehensive panel of tumor identification and high-throughput biomarker evaluation tools, QuPath provides researchers with powerful batch-processing and scripting functionality, and an extensible platform with which to develop and share new algorithms to analyze complex tissue images. Furthermore, QuPath’s flexible design makes it suitable for a wide range of additional image analysis applications across biomedical research.
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            Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions.

            Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system that causes motor, sensory, and cognitive deficits. The present study characterized demyelinated lesions in the cerebral cortex of MS patients. One hundred twelve cortical lesions were identified in 110 tissue blocks from 50 MS patients. Three patterns of cortical demyelination were identified: Type I lesions were contiguous with subcortical white matter lesions; Type II lesions were small, confined to the cortex, and often perivascular; Type III lesions extended from the pial surface to cortical layer 3 or 4. Inflammation and neuronal pathology were studied in tissue from 8 and 7 patients, respectively. Compared to white matter lesions, cortical lesions contained 13 times fewer CD3-positive lymphocytes (195 vs 2,596/mm3 of tissue) and 6 times fewer CD68-positive microglia/macrophages (11,948 vs 67,956/mm3 of tissue). Transected neurites (both axons and dendrites) occurred at a density of 4,119/mm3 in active cortical lesions, 1,107/mm3 in chronic active cortical lesions, 25/mm3 in chronic inactive cortical lesions, 8/mm3 in myelinated MS cortex, and 1/mm3 in control cortex. In active and chronic active cortical lesions, activated microglia closely apposed and ensheathed apical dendrites, neurites, and neuronal perikarya. In addition, apoptotic neurons were increased significantly in demyelinated cortex compared to myelinated cortex. These data support the hypothesis that demyelination, axonal transection, dendritic transection, and apoptotic loss of neurons in the cerebral cortex contribute to neurological dysfunction in MS patients.
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              The Role of GABA in Human Motor Learning

              Results There is considerable variability in motor learning behavior across individuals [7], and the present study aimed to test whether some of this variability could be explained by variation in responsiveness of the GABA system, because GABA modulation plays an important role in learning [1–4]. As a measure of GABA responsiveness, we used magnetic resonance spectroscopy (MRS) to quantify changes in GABA concentration following anodal transcranial direct current stimulation (tDCS), a noninvasive technique that decreases GABA within the motor cortex [5], increases cortical excitability [8], and enhances short-term learning [9]. We predicted that individuals who show less tDCS-mediated GABA modulation would show less behavioral evidence of motor learning and less modulation of fMRI responses during learning. Subjects participated in three experimental sessions on different days. The first two sessions were MRS sessions, during which GABA-edited spectra were acquired before and after 10 min of tDCS. In the third session, subjects performed an explicit sequence learning task during fMRI, and no tDCS was applied. Motor Behavior Motor learning was assessed via change in reaction times to a visually cued explicit sequence learning task performed with the four fingers of the right hand during fMRI acquisition in session 3. All subjects showed a significant reduction in reaction times across successive learning blocks (Figure 1A; repeated-measures analysis of variance, main effect of BLOCK F(15,150) = 19.95; p  2.0 and a (corrected) cluster significance threshold of p = 0.01.
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                Author and article information

                Contributors
                anna.williams@ed.ac.uk
                Journal
                Acta Neuropathol
                Acta Neuropathol
                Acta Neuropathologica
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0001-6322
                1432-0533
                15 January 2021
                15 January 2021
                2021
                : 141
                : 3
                : 415-429
                Affiliations
                [1 ]GRID grid.4305.2, ISNI 0000 0004 1936 7988, Centre for Regenerative Medicine, Institute for Regeneration and Repair, , University of Edinburgh, ; Edinburgh, EH16 4UU UK
                [2 ]GRID grid.4305.2, ISNI 0000 0004 1936 7988, Centre for Discovery Brain Sciences, , University of Edinburgh, ; Edinburgh, EH8 9XD UK
                [3 ]GRID grid.419239.4, ISNI 0000 0000 8583 7301, Leibniz-Institut Für Polymerforschung Dresden E.V, ; Max Bergmann Center of Biomaterials Dresden, Hohe Straße 6, 01069 Dresden, Germany
                [4 ]GRID grid.4305.2, ISNI 0000 0004 1936 7988, UK Dementia Research Institute, , University of Edinburgh, ; Edinburgh, EH8 9JZ UK
                [5 ]GRID grid.5600.3, ISNI 0000 0001 0807 5670, School of Pharmacy and Pharmaceutical Sciences, , Cardiff University, ; Cardiff, CF10 3NB UK
                [6 ]GRID grid.4305.2, ISNI 0000 0004 1936 7988, Simons Initiative for the Developing Brain, , University of Edinburgh, ; Edinburgh, EH8 9XD UK
                [7 ]GRID grid.4305.2, ISNI 0000 0004 1936 7988, Patrick Wild Centre for Autism Research, , University of Edinburgh, ; Edinburgh, EH8 9XD UK
                Author information
                https://orcid.org/0000-0002-7529-8492
                https://orcid.org/0000-0003-1980-9873
                https://orcid.org/0000-0002-1364-8629
                https://orcid.org/0000-0003-0189-3448
                https://orcid.org/0000-0002-4256-9639
                https://orcid.org/0000-0003-2530-0598
                https://orcid.org/0000-0002-5214-2604
                https://orcid.org/0000-0002-6329-382X
                Article
                2258
                10.1007/s00401-020-02258-z
                7882577
                33449171
                6bf3f0bf-eb08-4c6e-b39d-b236469dd298
                © The Author(s) 2021

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 12 October 2020
                : 21 December 2020
                : 22 December 2020
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100000381, Multiple Sclerosis Society;
                Funded by: FundRef http://dx.doi.org/10.13039/100010663, H2020 European Research Council;
                Award ID: 681181
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award ID: 320041273
                Award ID: 320041273
                Award ID: 320041273
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100014370, Simons Foundation Autism Research Initiative;
                Award ID: 529085
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100000265, Medical Research Council;
                Funded by: Multiple Sclerosis Society uk
                Funded by: Dementia Research Initiative
                Categories
                Original Paper
                Custom metadata
                © Springer-Verlag GmbH Germany, part of Springer Nature 2021

                Neurology
                multiple sclerosis,neurodegeneration,interneurons,myelin,synapses
                Neurology
                multiple sclerosis, neurodegeneration, interneurons, myelin, synapses

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