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Analyses of cerebral organoids thus far have been performed in sectioned tissue or in superficial layers due to their high scattering properties. Here, we demonstrate label-free three-photon imaging of whole, uncleared intact organoids (~2 mm depth) to assess early events of early human brain development. Optimizing a custom-made three-photon microscope to image intact cerebral organoids generated from Rett Syndrome patients, we show defects in the ventricular zone volumetric structure of mutant organoids compared to isogenic control organoids. Long-term imaging live organoids reveals that shorter migration distances and slower migration speeds of mutant radially migrating neurons are associated with more tortuous trajectories. Our label-free imaging system constitutes a particularly useful platform for tracking normal and abnormal development in individual organoids, as well as for screening therapeutic molecules via intact organoid imaging.<\/jats:p>","DOI":"10.7554\/elife.78079","type":"journal-article","created":{"date-parts":[[2022,7,14]],"date-time":"2022-07-14T04:15:17Z","timestamp":1657772117000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.78079","source":"Crossref","is-referenced-by-count":46,"title":["Label-free three-photon imaging of intact human cerebral organoids for tracking early events in brain development and deficits in Rett syndrome"],"prefix":"10.7554","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0853-2557","authenticated-orcid":true,"given":"Murat","family":"Yildirim","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/042nb2s44","id-type":"ROR","asserted-by":"publisher"}],"name":"Picower Institute of Learning and Memory, Massachusetts Institute 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