Deep Brain Stimulation of the Cortico-Basal Ganglia Network Enhances Cognitive Flexibility and Ameliorates Exploration Anomalies in a Primate Schizophrenia Model

Deep Brain Stimulation of the Cortico-Basal Ganglia Network Enhances Cognitive Flexibility and Ameliorates Exploration Anomalies in a Primate Schizophrenia Model | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Deep Brain Stimulation of the Cortico-Basal Ganglia Network Enhances Cognitive Flexibility and Ameliorates Exploration Anomalies in a Primate Schizophrenia Model Nir Asch, Noa Rahamim, Uri Werner-Reiss, Zvi Israel, Hagai Bergman This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5094090/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 28 May, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract Learning thrives on cognitive flexibility and exploration. Subjects with schizophrenia have impaired cognitive flexibility and maladaptive exploration patterns. The basal ganglia-dorsolateral prefrontal cortex (BG-DLPFC) network plays a significant role in learning processes. However, how this network maintains cognitive flexibility and exploration patterns and what alters these patterns in schizophrenia remains elusive. Using a combination of extracellular recordings, pharmacological manipulations, macro-stimulation techniques, and adaptive reinforcement learning modeling, we show that in the nonhuman primate (NHP), the external segment of the globus pallidus (GPe, the central nucleus of the BG network) modulates cognitive flexibility and exploration patterns. We found that chronic, low-dose administration of N-methyl-D-aspartate receptor (NMDA-R) antagonist, phencyclidine (PCP), decreases directed exploration but increases random exploration, as seen in schizophrenia. However, low-frequency GPe macro-stimulation restores the balance of both exploration types. Our findings suggest that schizophrenia symptoms reflect abnormal BG-DLPFC balance, and GPe stimulation may be advantageous for these patients. Biological sciences/Neuroscience/Diseases of the nervous system/Schizophrenia Biological sciences/Neuroscience/Computational neuroscience/Learning algorithms Biological sciences/Neuroscience/Learning and memory/Working memory Biological sciences/Neuroscience/Cognitive neuroscience/Attention Full Text Additional Declarations There is NO Competing Interest. Supplementary Files ExtendedDataNNsubbmission.pdf Cite Share Download PDF Status: Published Journal Publication published 28 May, 2025 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5094090","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":359876537,"identity":"c2e37ef7-b0ff-4cd5-81e4-c08b419f7376","order_by":0,"name":"Nir 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Our findings suggest that schizophrenia symptoms reflect abnormal BG-DLPFC balance, and GPe stimulation may be advantageous for these patients.","manuscriptTitle":"Deep Brain Stimulation of the Cortico-Basal Ganglia Network Enhances Cognitive Flexibility and Ameliorates Exploration Anomalies in a Primate Schizophrenia Model","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-22 02:57:55","doi":"10.21203/rs.3.rs-5094090/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"e584b0a1-8a5f-486f-9e56-f283658d268c","owner":[],"postedDate":"October 22nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":38298092,"name":"Biological sciences/Neuroscience/Diseases of the nervous system/Schizophrenia"},{"id":38298093,"name":"Biological sciences/Neuroscience/Computational neuroscience/Learning algorithms"},{"id":38298094,"name":"Biological sciences/Neuroscience/Learning and memory/Working memory"},{"id":38298095,"name":"Biological sciences/Neuroscience/Cognitive neuroscience/Attention"}],"tags":[],"updatedAt":"2025-05-29T07:05:29+00:00","versionOfRecord":{"articleIdentity":"rs-5094090","link":"https://doi.org/10.1038/s41467-025-60044-5","journal":{"identity":"nature-communications","isVorOnly":false,"title":"Nature Communications"},"publishedOn":"2025-05-28 04:00:00","publishedOnDateReadable":"May 28th, 2025"},"versionCreatedAt":"2024-10-22 02:57:55","video":"","vorDoi":"10.1038/s41467-025-60044-5","vorDoiUrl":"https://doi.org/10.1038/s41467-025-60044-5","workflowStages":[]},"version":"v1","identity":"rs-5094090","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5094090","identity":"rs-5094090","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}