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However, diffusion MRI to evaluate therapeutic application of mesenchymal stem cells is limited. Robust analytical techniques are required to identify potential physiological changes as a function of cell therapy in stroke. Here, we seek to establish Neurite Orientation Dispersion and Density Imaging (NODDI) as a feasible method in evaluating stroke evolution in response to cell\u2010based therapeutics.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Diffusion MRI data at 21.1T were acquired from 16 male rats. Rats were grouped randomly: na\u00efve (baseline, N = 5), stroke with injections of phosphate buffered saline (N = 6), stroke with injection of 2D human mesenchymal stem cells (hMSC, N = 5). Data were acquired on days 1, 3, 7, and 21 post\u2010surgery. DTI and NODDI maps were generated, with regions of interest placed in the ischemic hemisphere external capsule and striatum. Diffusion parameters were compared between groups each day, and within groups across hemispheres and longitudinally. Behavioral characterizations were on days 0 (pre\u2010surgery), 3, 7, 14, and 21.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The 2D hMSC preserved diffusional restriction in the external capsule compared to saline (day 1: MD,<jats:italic>P<\/jats:italic>= .4060; AD,<jats:italic>P<\/jats:italic>= .0220). NODDI indicates that hMSC may have preserved intracellular volume fractions (ICVF: day 1,<jats:italic>P<\/jats:italic>= .0086; day 3,<jats:italic>P<\/jats:italic>= .0021; day 21,<jats:italic>P<\/jats:italic>= .0383). Diffusion metrics of hMSC treated animals were comparable to na\u00efve for the external capsule.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>NODDI compliments DTI metrics, enhances interpretation of tissue outcome in ischemic stroke following hMSC application, and may be useful in evaluating or predicting therapeutic response.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mrm.28929","type":"journal-article","created":{"date-parts":[[2021,8,6]],"date-time":"2021-08-06T10:26:55Z","timestamp":1628245615000},"page":"3211-3223","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["NODDI highlights recovery mechanisms in white and gray matter in ischemic stroke following human stem cell treatment"],"prefix":"10.1002","volume":"86","author":[{"given":"F. 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