In vivo MRI is sensitive to remyelination in a nonhuman primate model of multiple sclerosis
- National Institute of Neurological Disorders and Stroke, United States
- University of Pittsburgh, United States
- National Institute of Mental Health, United States
- Vertex Phamaceuticals Inc, United States
- Cedars-Sinai Medical Center, United States
Abstract
Remyelination is crucial to recover from inflammatory demyelination in multiple sclerosis (MS). Investigating remyelination in vivo using magnetic resonance imaging (MRI) is difficult in MS, where collecting serial short-interval scans is challenging. Using experimental autoimmune encephalomyelitis (EAE) in common marmosets, a model of MS that recapitulates focal cerebral inflammatory demyelinating lesions, we investigated whether MRI is sensitive to, and can characterize, remyelination. In 6 animals followed with multisequence 7-tesla MRI, 31 focal lesions, predicted to be demyelinated or remyelinated based on signal intensity on proton density-weighted images, were subsequently assessed with histopathology. Remyelination occurred in 4 of 6 marmosets and 45% of lesions. Radiological-pathological comparison showed that MRI had high statistical sensitivity (100%) and specificity (90%) for detecting remyelination. This study demonstrates the prevalence of spontaneous remyelination in marmoset EAE and the ability of in vivo MRI to detect it, with implications for preclinical testing of pro-remyelinating agents.
Data availability
All of the 6 marmosets' serial in vivo MRI images, including all the sequences used for analysis and figure generation, were uploaded in an easily accessible format (NIFTI). The file names are titled with the corresponding animal # used in the manuscript, as well as the date of MRI acquisition. All the Iba1 and PLP immunohistochemistry stains have been uploaded as well.
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Author details
Funding
National Institutes of Health (Intramural Research Program)
- Nathanael J Lee
Adelson Family Foundation
- Maxime Donadieu
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: The study was performed under the guideline and in accordance with the National Institutes of Health IACUC. Specifically, the neuroethics committee of the National Institutes of Neurological Diseases and Stroke formally went through our manuscript prior to submission on salient topics including minimization of pain, justification of number of animals and the sex ratio, dosing of methylprednisone based on available human data. All procedures were performed under anesthesia to minimize discomfort and pain. Animals were housed in pairs or triplets to maximize social interactions and well-being. The institutional IACUC protocol number is #1308.
Copyright
This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
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In vivo MRI is sensitive to remyelination in a nonhuman primate model of multiple sclerosis
eLife 12:e73786.
https://doi.org/10.7554/eLife.73786
Further reading
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When holding visual information temporarily in working memory (WM), the neural representation of the memorandum is distributed across various cortical regions, including visual and frontal cortices. However, the role of stimulus representation in visual and frontal cortices during WM has been controversial. Here, we tested the hypothesis that stimulus representation persists in the frontal cortex to facilitate flexible control demands in WM. During functional MRI, participants flexibly switched between simple WM maintenance of visual stimulus or more complex rule-based categorization of maintained stimulus on a trial-by-trial basis. Our results demonstrated enhanced stimulus representation in the frontal cortex that tracked demands for active WM control and enhanced stimulus representation in the visual cortex that tracked demands for precise WM maintenance. This differential frontal stimulus representation traded off with the newly-generated category representation with varying control demands. Simulation using multi-module recurrent neural networks replicated human neural patterns when stimulus information was preserved for network readout. Altogether, these findings help reconcile the long-standing debate in WM research, and provide empirical and computational evidence that flexible stimulus representation in the frontal cortex during WM serves as a potential neural coding scheme to accommodate the ever-changing environment.
