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We previously showed that the N\u2010methyl\u2010D\u2010aspartate receptor antagonist ketamine was able to prevent deleterious consequences of SD in brain slices, under conditions of metabolic compromise. The current study aimed to extend these observations into an in vivo stroke model, to test whether gradients of metabolic capacity lead to differential accumulation of calcium (Ca\n                    <jats:sup>2+<\/jats:sup>\n                    ) following SD. In addition, we tested whether ketamine protects vulnerable tissuewhile allowing SD to propagate through surrounding undamaged tissue. Focal lesions were generated using a distal middle cerebral artery occlusion in mice, and clusters of SD were generated at 20\u2009min intervals with remote microinjection of potassium chloride. SDs invading peri\u2010infarct regions had significantly different consequences, depending on the distance from the infarct core. Proximal to the lesion, Ca\n                    <jats:sup>2+<\/jats:sup>\n                    transients were extended, as compared with responses in better\u2010perfused tissue more remote from the lesion. Extracellular potential shifts were also longer and hyperemia responses were reduced in proximal regions following SDs. Consistent with in vitro studies, ketamine, at concentrations that did not abolish the propagation of SD, reduced the accumulation of intracellular Ca\n                    <jats:sup>2+<\/jats:sup>\n                    in proximal regions following an SD wave. These findings suggest that deleterious consequences of SD can be targeted in vivo, without requiring outright block of SD initiation and propagation.\n                    <jats:boxed-text content-type=\"graphic\" position=\"anchor\">\n                      <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15923-fig-0005-m.png\">\n                        <jats:alt-text>image<\/jats:alt-text>\n                      <\/jats:graphic>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1111\/jnc.15923","type":"journal-article","created":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T14:15:26Z","timestamp":1692627326000},"page":"855-867","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Ketamine improves neuronal recovery following spreading depolarization in peri\u2010infarct tissues"],"prefix":"10.1111","volume":"168","author":[{"given":"Katelyn M.","family":"Reinhart","sequence":"first","affiliation":[{"name":"Department of Neurosciences University of New Mexico School of Medicine  Albuquerque New Mexico USA"},{"name":"Department of Neurology University of Utah School of Medicine  Salt Lake City Utah USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell A.","family":"Morton","sequence":"additional","affiliation":[{"name":"Department of Neurosciences University of New Mexico School of Medicine  Albuquerque New Mexico USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"K. 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