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Neural Eng."],"published-print":{"date-parts":[[2026,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    <jats:italic>Objective.<\/jats:italic>\n                    Determining the intricate structure and function of neural circuits requires the ability to precisely manipulate circuit activity. Two-photon holographic optogenetics has emerged as a powerful tool for achieving this via flexible excitation of user-defined neural ensembles. However, the precision of two-photon optogenetics has been constrained by off-target stimulation (OTS), an effect where proximal non-target neurons can be unintentionally activated due to imperfect spatial confinement of light onto target neurons. New approaches are therefore needed to resolve the OTS problem.\n                    <jats:italic>Approach.<\/jats:italic>\n                    Here, we introduce a real-time computational method for mitigating OTS that first empirically samples each neuron\u2019s sensitivity to stimulation at proximal locations, and then optimizes stimulation sites using a fast, interpretable model based on adaptive non-negative basis function regression (NBFR).\n                    <jats:italic>Main results.<\/jats:italic>\n                    NBFR is highly scalable, completing model fitting for hundreds of neurons in just a few seconds and then optimizing stimulation sites in several hundred milliseconds per stimulus\u2014fast enough for most closed-loop behavioral experiments. We characterize the performance of our approach in both simulations and\n                    <jats:italic>in vivo<\/jats:italic>\n                    experiments in mouse hippocampus, showing its efficacy under realistic experimental conditions.\n                    <jats:italic>Significance.<\/jats:italic>\n                    Our results thus establish NBFR-based photostimulus optimization as an important addition to an emerging computational toolkit for precise yet scalable holographic optogenetics.\n                  <\/jats:p>","DOI":"10.1088\/1741-2552\/ae4925","type":"journal-article","created":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T10:10:33Z","timestamp":1774433433000},"page":"026015","update-policy":"https:\/\/doi.org\/10.1088\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Computational optimization of two-photon holographic stimulation sites\n                    <i>in vivo<\/i>"],"prefix":"10.1088","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1805-0180","authenticated-orcid":true,"given":"Marcus A","family":"Triplett","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0981-9592","authenticated-orcid":true,"given":"Edgar","family":"B\u00e4umler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7060-658X","authenticated-orcid":false,"given":"Alex","family":"Prodan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3027-9260","authenticated-orcid":true,"given":"Rokas","family":"Stonis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7351-5820","authenticated-orcid":false,"given":"Darcy S","family":"Peterka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2673-8957","authenticated-orcid":false,"given":"Michael","family":"H\u00e4usser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0276-7032","authenticated-orcid":false,"given":"Liam","family":"Paninski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"266","published-online":{"date-parts":[[2026,3,25]]},"reference":[{"key":"jneae4925bib1","doi-asserted-by":"publisher","DOI":"10.1101\/2023.03.02.530875","type":"other","article-title":"Probing inter-areal computations with a cellular resolution two-photon holographic mesoscope","author":"Abdeladim","year":"2023"},{"key":"jneae4925bib2","doi-asserted-by":"publisher","first-page":"1356","DOI":"10.1038\/s41593-021-00902-9","type":"journal-article","article-title":"Probing neural codes with two-photon holographic optogenetics","volume":"24","author":"Adesnik","year":"2021","journal-title":"Nat. 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