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Despite extensive experience, however, the precise target of optimal stimulation and the relationship between site of stimulation and alleviation of individual signs remains unclear. We examined whether machine learning could predict the benefits in specific Parkinsonian signs when informed by precise locations of stimulation. We studied 275 Parkinson\u2019s disease patients who underwent subthalamic nucleus deep brain stimulation between 2003 and 2018. We selected pre-deep brain stimulation and best available post-deep brain stimulation scores from motor items of the Unified Parkinson's Disease Rating Scale (UPDRS-III) to discern sign-specific changes attributable to deep brain stimulation. Volumes of tissue activated were computed and weighted by (i) tremor, (ii) rigidity, (iii) bradykinesia and (iv) axial signs changes. Then, sign-specific sites of optimal (\u2018hot spots\u2019) and suboptimal efficacy (\u2018cold spots\u2019) were defined. These areas were subsequently validated using machine learning prediction of sign-specific outcomes with in-sample and out-of-sample data (n\u2009=\u200951 subthalamic nucleus deep brain stimulation patients from another institution). Tremor and rigidity hot spots were largely located outside and dorsolateral to the subthalamic nucleus whereas hot spots for bradykinesia and axial signs had larger overlap with the subthalamic nucleus. Using volume of tissue activated overlap with sign-specific hot and cold spots, support vector machine classified patients into quartiles of efficacy with \u226592% accuracy. The accuracy remained high (68\u201398%) when only considering volume of tissue activated overlap with hot spots but was markedly lower (41\u201372%) when only using cold spots. The model also performed poorly (44\u201348%) when using only stimulation voltage, irrespective of stimulation location. Out-of-sample validation accuracy was \u226596% when using volume of tissue activated overlap with the sign-specific hot and cold spots. In two independent datasets, distinct brain areas could predict sign-specific clinical changes in Parkinson\u2019s disease patients with subthalamic nucleus deep brain stimulation. With future prospective validation, these findings could individualize stimulation delivery to optimize quality of life improvement.<\/jats:p>","DOI":"10.1093\/braincomms\/fcab027","type":"journal-article","created":{"date-parts":[[2021,3,9]],"date-time":"2021-03-09T15:12:50Z","timestamp":1615302770000},"source":"Crossref","is-referenced-by-count":30,"title":["Sign-specific stimulation \u2018hot\u2019 and \u2018cold\u2019 spots in Parkinson\u2019s disease validated with machine learning"],"prefix":"10.1093","volume":"3","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6942-5195","authenticated-orcid":false,"given":"Alexandre","family":"Boutet","sequence":"first","affiliation":[{"name":"Joint Department of Medical Imaging, University of Toronto, Toronto, ON, Canada"},{"name":"University Health Network, Toronto, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0995-8226","authenticated-orcid":false,"given":"Jurgen","family":"Germann","sequence":"additional","affiliation":[{"name":"University Health Network, Toronto, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dave","family":"Gwun","sequence":"additional","affiliation":[{"name":"University Health Network, Toronto, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Loh","sequence":"additional","affiliation":[{"name":"University Health Network, Toronto, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gavin J B","family":"Elias","sequence":"additional","affiliation":[{"name":"University Health Network, Toronto, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3153-1045","authenticated-orcid":false,"given":"Clemens","family":"Neudorfer","sequence":"additional","affiliation":[{"name":"University Health Network, Toronto, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Paff","sequence":"additional","affiliation":[{"name":"University Health Network, Toronto, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0695-6025","authenticated-orcid":false,"given":"Andreas","family":"Horn","sequence":"additional","affiliation":[{"name":"Department of Neurology, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, and Berlin Institute of Health, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea A","family":"Kuhn","sequence":"additional","affiliation":[{"name":"Department of Neurology, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Freie Universit\u00e4t Berlin, Humboldt-Universit\u00e4t zu Berlin, and Berlin Institute of Health, Germany"},{"name":"Berlin School of Mind and Brain, Humboldt-Universit\u00e4t zu Berlin, Germany"},{"name":"Deutsches Zentrum f\u00fcr Neurodegenerative Erkrankungen, Berlin, Germany"},{"name":"Neurocure Cluster of Excellence, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renato P","family":"Munhoz","sequence":"additional","affiliation":[{"name":"Edmond J. Safra Program in Parkinson\u2019s Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, UHN, Division of Neurology, University of Toronto, Toronto, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suneil K","family":"Kalia","sequence":"additional","affiliation":[{"name":"University Health Network, Toronto, ON, Canada"},{"name":"Department of Neurosurgery, University of Toronto, Toronto, ON, Canada"},{"name":"Krembil Brain Institute, Toronto, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6278-4929","authenticated-orcid":false,"given":"Mojgan","family":"Hodaie","sequence":"additional","affiliation":[{"name":"University Health Network, Toronto, ON, Canada"},{"name":"Department of Neurosurgery, University of Toronto, Toronto, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter","family":"Kucharczyk","sequence":"additional","affiliation":[{"name":"Joint Department of Medical Imaging, University of Toronto, Toronto, ON, Canada"},{"name":"University Health Network, Toronto, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5346-0180","authenticated-orcid":false,"given":"Alfonso","family":"Fasano","sequence":"additional","affiliation":[{"name":"Edmond J. Safra Program in Parkinson\u2019s Disease, Morton and Gloria Shulman Movement Disorders Clinic, Toronto Western Hospital, UHN, Division of Neurology, University of Toronto, Toronto, ON, Canada"},{"name":"Center for Advancing Neurotechnological Innovation to Application (CRANIA), Toronto, ON, Canada"},{"name":"Krembil Brain Institute, Toronto, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andres M","family":"Lozano","sequence":"additional","affiliation":[{"name":"University Health Network, Toronto, ON, Canada"},{"name":"Department of Neurosurgery, University of Toronto, Toronto, ON, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,3,10]]},"reference":[{"issue":"3","key":"2021041304334065100_fcab027-B1","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1016\/j.neuron.2013.01.020","article-title":"Probing and regulating dysfunctional circuits using deep brain 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