{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T18:05:00Z","timestamp":1791914700006,"version":"4.3.4"},"reference-count":75,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T00:00:00Z","timestamp":1768176000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,4,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Despite multiple available strategies for managing motor fluctuations in advanced Parkinson\u2019s disease, there is a continuing need for improved therapeutics. After 2\u20135 years of levodopa treatment, some patients start to experience OFF time that can last five or more hours per day. Responding to this challenge are pump-delivered infusion therapies for delivering carbidopa-levodopa or apomorphine. However, despite their ability to offer continuous dopaminergic stimulation, these options generally do not provide fluctuators with full control of daily OFF time. The complexity of managing motor fluctuations is further highlighted by the effectiveness of various non-dopaminergic adjunctive therapies for reducing OFF time in levodopa-treated patients, as shown by placebo-controlled clinical trials with adjunctive istradefylline, amantadine, zonisamide and deep brain stimulation. Other recent paradigm shifts for understanding levodopa\u2019s role in Parkinson\u2019s disease therapeutics are observations that reserpine-induced parkinsonism in mice can be reversed without its conversion to dopamine (and through levodopa-induced stimulation of ophthalmate release).<\/jats:p>\n                  <jats:p>To achieve better control of OFF time in advanced Parkinson\u2019s disease, there is a need for therapeutic strategies that act beyond the limits of today\u2019s dopaminergic therapies. Modelling brain circuitry with tools such as deterministic neural-computational analysis may provide valuable pharmacological and electrophysiological insights to better understand motor fluctuations and to inform the selection of appropriate therapeutic targets.<\/jats:p>","DOI":"10.1093\/brain\/awag002","type":"journal-article","created":{"date-parts":[[2026,1,10]],"date-time":"2026-01-10T12:38:35Z","timestamp":1768048715000},"page":"1137-1143","source":"Crossref","is-referenced-by-count":3,"title":["The persisting puzzle of OFF time in advanced Parkinson\u2019s disease"],"prefix":"10.1093","volume":"149","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4976-4445","authenticated-orcid":false,"given":"Peter A","family":"LeWitt","sequence":"first","affiliation":[{"name":"Department of Neurology, Wayne State University School of Medicine , Detroit, MI 48202 ,","place":["USA"]},{"name":"Department of Pharmacology, Wayne State University School of Medicine , Detroit, MI 48202 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