{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T23:51:57Z","timestamp":1768002717944,"version":"3.49.0"},"reference-count":61,"publisher":"MIT Press - Journals","issue":"1","content-domain":{"domain":["direct.mit.edu"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2016,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The temporal preparation of motor responses to external events (temporal preparation) relies on internal representations of the accumulated elapsed time (temporal representations) before an event occurs and on estimates about its most likely time of occurrence (temporal expectations). The precision (inverse of uncertainty) of temporal preparation, however, is limited by two sources of uncertainty. One is intrinsic to the nervous system and scales with the length of elapsed time such that temporal representations are least precise for longest time durations. The other is external and arises from temporal variability of events in the outside world. The precision of temporal expectations thus decreases if events become more variable in time. It has long been recognized that the processing of time durations within the range of hundreds of milliseconds (interval timing) strongly depends on dopaminergic (DA) transmission. The role of DA for the precision of temporal preparation in humans, however, remains unclear. This study therefore directly assesses the role of DA in the precision of temporal preparation of motor responses in healthy humans. In a placebo-controlled double-blind design using a selective D2-receptor antagonist (sulpiride) and D1\/D2 receptor antagonist (haloperidol), participants performed a variable foreperiod reaching task, under different conditions of internal and external temporal uncertainty. DA blockade produced a striking impairment in the ability of extracting temporal expectations across trials and on the precision of temporal representations within a trial. Large Weber fractions for interval timing, estimated by fitting subjective hazard functions, confirmed that this effect was driven by an increased uncertainty in the way participants were experiencing time. This provides novel evidence that DA regulates the precision with which we process time when preparing for an action.<\/jats:p>","DOI":"10.1162\/jocn_a_00880","type":"journal-article","created":{"date-parts":[[2015,9,24]],"date-time":"2015-09-24T13:20:13Z","timestamp":1443100813000},"page":"96-110","update-policy":"https:\/\/doi.org\/10.1162\/mitpressjournals.corrections.policy","source":"Crossref","is-referenced-by-count":46,"title":["The Role of Dopamine in Temporal Uncertainty"],"prefix":"10.1162","volume":"28","author":[{"given":"Alessandro","family":"Tomassini","sequence":"first","affiliation":[{"name":"1University College London"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diane","family":"Ruge","sequence":"additional","affiliation":[{"name":"1University College London"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joseph M.","family":"Galea","sequence":"additional","affiliation":[{"name":"1University College London"},{"name":"2University of Birmingham"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William","family":"Penny","sequence":"additional","affiliation":[{"name":"1University College London"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sven","family":"Bestmann","sequence":"additional","affiliation":[{"name":"1University College London"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"281","published-online":{"date-parts":[[2016,1,1]]},"reference":[{"key":"2021073020583018800_R1","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1093\/brain\/115.1.199","article-title":"Temporal discrimination is abnormal in Parkinson's disease","volume":"115","author":"Artieda","year":"1992","journal-title":"Brain"},{"key":"2021073020583018800_R2","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/0042-6989(64)90031-8","article-title":"Dark-adaptation: A new hypothesis","volume":"4","author":"Barlow","year":"1964","journal-title":"Vision Research"},{"key":"2021073020583018800_R3","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.neuron.2012.03.016","article-title":"Not noisy, just wrong: The role of suboptimal inference in behavioral variability","volume":"74","author":"Beck","year":"2012","journal-title":"Neuron"},{"key":"2021073020583018800_R4","first-page":"199","article-title":"The time-course of preparation: Confirmatory results with visual and auditory warning signals","volume":"120","author":"Bertelson","year":"1969","journal-title":"Acta Psychologica"},{"key":"2021073020583018800_R5","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1162\/jocn_a_00706","article-title":"The role of dopamine in motor flexibility","volume":"27","author":"Bestmann","year":"2015","journal-title":"Journal of Cognitive Neurosciences"},{"key":"2021073020583018800_R6","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/0140-6736(92)91108-K","article-title":"Striatal dopamine D2-receptor blockade by typical and atypical neuroleptics","volume":"339","author":"Br\u00fccke","year":"1992","journal-title":"Lancet"},{"key":"2021073020583018800_R7","doi-asserted-by":"crossref","first-page":"4343","DOI":"10.1523\/JNEUROSCI.2254-09.2010","article-title":"Encoding of temporal probabilities in the human brain","volume":"30","author":"Bueti","year":"2010","journal-title":"Journal of Neuroscience"},{"key":"2021073020583018800_R8","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.beproc.2013.02.015","article-title":"Time-scale invariance as an emergent property in a perceptron with realistic, noisy neurons","volume":"95","author":"Buhusi","year":"2013","journal-title":"Behavioral Processes"},{"key":"2021073020583018800_R39","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1038\/nrn1764","article-title":"What makes us tick? Functional and neural mechanisms of interval timing","volume":"6","author":"Buhusi","year":"2005","journal-title":"Nature Reviews Neuroscience"},{"key":"2021073020583018800_R9","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1080\/13803390490918318","article-title":"Intraindividual variability as a marker of neurological dysfunction: A comparison of Alzheimer's disease and Parkinson's disease","volume":"28","author":"Burton","year":"2006","journal-title":"Journal of Clinical and Experimental Neuropsychology"},{"key":"2021073020583018800_R10","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1038\/nn.3743","article-title":"Direct and indirect pathways of basal ganglia: A critical reappraisal","volume":"17","author":"Calabresi","year":"2014","journal-title":"Nature Neuroscience"},{"key":"2021073020583018800_R11","volume-title":"Statistical power analysis for the behavioral sciences","author":"Cohen","year":"1988"},{"key":"2021073020583018800_R12","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/npp.2010.113","article-title":"Neuroanatomical and neurochemical substrates of timing","volume":"36","author":"Coull","year":"2011","journal-title":"Neuropsychopharmacology"},{"key":"2021073020583018800_R13","doi-asserted-by":"crossref","first-page":"7426","DOI":"10.1523\/JNEUROSCI.18-18-07426.1998","article-title":"Where and when to pay attention: The neural systems for directing attention to spatial locations and to time intervals as revealed by both PET and fMRI","volume":"18","author":"Coull","year":"1998","journal-title":"Journal of Neuroscience"},{"key":"2021073020583018800_R14","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.ijpsycho.2009.10.009","article-title":"Timing is everything: Neural response dynamics during syllable processing and its relation to higher-order cognition in schizophrenia and healthy comparison subjects","volume":"75","author":"Dale","year":"2010","journal-title":"International Journal of Psychophysiology"},{"key":"2021073020583018800_R15","doi-asserted-by":"crossref","first-page":"261","DOI":"10.2165\/00003088-200241040-00003","article-title":"Clinical pharmacokinetic and pharmacodynamic properties of drugs used in the treatment of Parkinson's disease","volume":"41","author":"Deleu","year":"2002","journal-title":"Clinical Pharmacokinetics"},{"key":"2021073020583018800_R16","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1037\/h0046860","article-title":"Effects of foreperiod, foreperiod variability, and probability of stimulus occurrence on simple reaction time","volume":"62","author":"Drazin","year":"1961","journal-title":"Journal of Experimental Psychology"},{"key":"2021073020583018800_R17","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1038\/nn.2159","article-title":"The temporal precision of reward prediction in dopamine neurons","volume":"11","author":"Fiorillo","year":"2008","journal-title":"Nature Neuroscience"},{"key":"2021073020583018800_R18","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1162\/0898929052880093","article-title":"Dynamic dopamine modulation in the basal ganglia: A neurocomputational account of cognitive deficits in medicated and nonmedicated Parkinsonism","volume":"17","author":"Frank","year":"2005","journal-title":"Journal of Cognitive Neuroscience"},{"key":"2021073020583018800_R19","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1037\/0735-7044.120.3.497","article-title":"A mechanistic account of striatal dopamine function in human cognition: Psychopharmacological studies with cabergoline and haloperidol","volume":"120","author":"Frank","year":"2006","journal-title":"Behavioral Neuroscience"},{"key":"2021073020583018800_R20","doi-asserted-by":"crossref","first-page":"e1002327","DOI":"10.1371\/journal.pcbi.1002327","article-title":"Dopamine, affordance and active inference","volume":"8","author":"Friston","year":"2012","journal-title":"PLoS Computational Biology"},{"key":"2021073020583018800_R21","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1523\/JNEUROSCI.3621-11.2012","article-title":"Action reprogramming in Parkinson's disease: Response to prediction error is modulated by levels of dopamine","volume":"32","author":"Galea","year":"2012","journal-title":"Journal of Neuroscience"},{"key":"2021073020583018800_R22","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1152\/jn.1981.46.4.725","article-title":"Spatial trajectories and reaction times of aimed movements: Effects of practice, uncertainty, and change in target location","volume":"46","author":"Georgopoulos","year":"1981","journal-title":"Journal of Neurophysiology"},{"key":"2021073020583018800_R23","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1037\/0033-295X.84.3.279","article-title":"Scalar expectancy theory and Weber's law in animal timing","volume":"84","author":"Gibbon","year":"1977","journal-title":"Psychological Review"},{"key":"2021073020583018800_R24","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.2466\/pms.1968.27.3f.1023","article-title":"Reaction time to onset and termination of lights and sounds","volume":"27","author":"Goldstone","year":"1968","journal-title":"Perceptual and Motor Skills"},{"key":"2021073020583018800_R25","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1111\/j.1469-8986.2008.00722.x","article-title":"Separation of phasic arousal and expectancy effects in a speeded reaction time task via fMRI","volume":"46","author":"Hackley","year":"2009","journal-title":"Psychophysiology"},{"key":"2021073020583018800_R26","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1038\/1124","article-title":"Dopamine neurons report an error in the temporal prediction of reward during learning","volume":"1","author":"Hollerman","year":"1998","journal-title":"Nature Neuroscience"},{"key":"2021073020583018800_R27","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1038\/nn1386","article-title":"A representation of the hazard rate of elapsed time in macaque area LIP","volume":"8","author":"Janssen","year":"2005","journal-title":"Nature Neuroscience"},{"key":"2021073020583018800_R61","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.bandc.2004.09.008","article-title":"Variable foreperiod in Pakinson's disease: Dissociation across reflexive and behaviors","volume":"58","author":"Jurkowski","year":"2005","journal-title":"Brain and Cognition"},{"key":"2021073020583018800_R28","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1037\/h0049152","article-title":"Reaction time as a function of foreperiod duration and variability","volume":"58","author":"Karlin","year":"1959","journal-title":"Journal of Experimental Psychology"},{"key":"2021073020583018800_R29","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1037\/h0042317","article-title":"Time uncertainty in simple reaction time","volume":"51","author":"Klemmer","year":"1956","journal-title":"Journal of Experimental Psychology"},{"key":"2021073020583018800_R30","doi-asserted-by":"crossref","first-page":"1894","DOI":"10.1038\/npp.2011.75","article-title":"Neuromodulatory neurotransmitters influence LTP-like plasticity in human cortex: A pharmaco-TMS study","volume":"36","author":"Korchounov","year":"2011","journal-title":"Neuropsychopharmacology"},{"key":"2021073020583018800_R31","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/j.neuropsychologia.2012.09.014","article-title":"Differential effects of amphetamine and haloperidol on temporal reproduction: Dopaminergic regulation of attention and clock speed","volume":"51","author":"Lake","year":"2013","journal-title":"Neuropsychologia"},{"key":"2021073020583018800_R33","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.bandc.2004.09.005","article-title":"Chronic treatment with haloperidol induces deficits in working memory and feedback effects of interval timing","volume":"58","author":"Lustig","year":"2005","journal-title":"Brain and Cognition"},{"key":"2021073020583018800_R34","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.cogbrainres.2004.06.012","article-title":"Cortico-striatal circuits and interval timing: Coincidence detection of oscillatory processes","volume":"21","author":"Matell","year":"2004","journal-title":"Brain Research, Cognitive Brain Research"},{"key":"2021073020583018800_R35","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/0926-6410(96)00009-2","article-title":"Neuropharmacology of timing and time perception","volume":"3","author":"Meck","year":"1996","journal-title":"Cognitive Brain Research"},{"key":"2021073020583018800_R36","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.brainres.2006.06.031","article-title":"Neuroanatomical localization of an internal clock: A functional link between mesolimbic, nigrostriatal, and mesocortical dopaminergic systems","volume":"1109","author":"Meck","year":"2006","journal-title":"Brain Research"},{"key":"2021073020583018800_R59","doi-asserted-by":"crossref","first-page":"20726","DOI":"10.1073\/pnas.1211258109","article-title":"Prefrontal D1 dopamine signaling is required for temporal control","volume":"109","author":"Narayanan","year":"2012","journal-title":"Proceedings of the National Academy of Sciences"},{"key":"2021073020583018800_R60","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1016\/j.neuron.2006.10.021","article-title":"Top-down control of motor cortex ensembles by dorsomedial prefrontal cortex","volume":"52","author":"Narayanan","year":"2006","journal-title":"Neuron"},{"key":"2021073020583018800_R38","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1037\/0033-2909.89.1.133","article-title":"Foreperiod and simple reaction time","volume":"89","author":"Niemi","year":"1981","journal-title":"Psychological Bulletin"},{"key":"2021073020583018800_R40","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/0306-3623(82)90088-X","article-title":"The pharmacology of Sulpiride\u2014A dopamine receptor antagonist","volume":"13","author":"O'Connor","year":"1982","journal-title":"General Pharmacology"},{"key":"2021073020583018800_R41","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.neuroscience.2013.09.057","article-title":"Prefrontal D1 dopamine signaling is necessary for temporal expectation during reaction time performance","volume":"255","author":"Parker","year":"2013","journal-title":"Neuroscience"},{"key":"2021073020583018800_R42","doi-asserted-by":"crossref","first-page":"e18203","DOI":"10.1371\/journal.pone.0018203","article-title":"Implicit, predictive timing draws upon the same scalar representation of time as explicit timing","volume":"6","author":"Piras","year":"2011","journal-title":"PLoS One"},{"key":"2021073020583018800_R43","doi-asserted-by":"crossref","first-page":"2848","DOI":"10.1152\/jn.00224.2007","article-title":"Slow brain potential and oscillatory EEG manifestations of impaired temporal preparation in Parkinson's disease","volume":"98","author":"Praamstra","year":"2007","journal-title":"Journal of Neurophysiology"},{"key":"2021073020583018800_R44","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1159\/000118549","article-title":"Is there a common dopaminergic basis of time perception and reaction time?","volume":"21","author":"Rammsayer","year":"1989","journal-title":"Neuropsychobiology"},{"key":"2021073020583018800_R45","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/0301-0511(93)90018-4","article-title":"On dopaminergic modulation of temporal information processing","volume":"36","author":"Rammsayer","year":"1993","journal-title":"Biological Psychology"},{"key":"2021073020583018800_R46","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1159\/000119328","article-title":"Are there dissociable roles of the mesostriatal and mesolimbocortical dopamine systems on temporal information processing in humans?","volume":"35","author":"Rammsayer","year":"1997","journal-title":"Neuropsychobiology"},{"key":"2021073020583018800_R47","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1037\/0033-2909.114.3.510","article-title":"Methods for dealing with reaction time outliers","volume":"114","author":"Ratcliff","year":"1993","journal-title":"Psychological Bulletin"},{"key":"2021073020583018800_R48","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1080\/026432998381078","article-title":"Evidence for movement preprogramming and on line control in differentially impaired patients with Parkinson's disease","volume":"15","author":"Reed","year":"1998","journal-title":"Cognitive Neuropsychology"},{"key":"2021073020583018800_R49","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1163\/156856803322467572","article-title":"Pointing errors in immediate and delayed conditions in unilateral optic ataxia","volume":"16","author":"Revol","year":"2003","journal-title":"Spatial Vision"},{"key":"2021073020583018800_R37","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1016\/j.neuroimage.2013.08.065","article-title":"Bayesian model selection for group studies\u2014Revisited","volume":"84","author":"Rigoux","year":"2014","journal-title":"Neuroimage"},{"key":"2021073020583018800_R50","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1016\/0306-4522(84)90014-9","article-title":"Responses of striatal neurons in the behaving monkey. 3. Effects of iontophoretically applied dopamine on normal responsiveness","volume":"12","author":"Rolls","year":"1984","journal-title":"Neuroscience"},{"key":"2021073020583018800_R58","doi-asserted-by":"crossref","first-page":"1593","DOI":"10.1126\/science.275.5306.1593","article-title":"A neural substrate of prediction and reward","volume":"275","author":"Schultz","year":"1997","journal-title":"Science"},{"key":"2021073020583018800_R51","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.bandc.2007.01.005","article-title":"The effect of Parkinson's disease on time estimation as a function of stimulus duration range and modality","volume":"64","author":"Smith","year":"2007","journal-title":"Brain and Cognition"},{"key":"2021073020583018800_R32","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1016\/j.neuroimage.2009.03.025","article-title":"Bayesian model selection for group studies","volume":"46","author":"Stephan","year":"2009","journal-title":"Neuroimage"},{"key":"2021073020583018800_R52","first-page":"1","article-title":"Dissecting neural responses to temporal prediction, attention and memory: Effects of reward learning and interoception on time perception","volume":"25","author":"Tomasi","year":"2014","journal-title":"Cerebral Cortex"},{"key":"2021073020583018800_R53","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1007\/s00221-011-2821-x","article-title":"Anticipation of future events improves the ability to estimate elapsed time","volume":"214","author":"Tsunoda","year":"2011","journal-title":"Experimental Brain Research"},{"key":"2021073020583018800_R54","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1162\/jocn.2009.21098","article-title":"When time shapes behavior: fMRI evidence of brain correlates of temporal monitoring","volume":"21","author":"Vallesi","year":"2009","journal-title":"Journal of Cognitive Neuroscience"},{"key":"2021073020583018800_R55","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1093\/cercor\/bhj163","article-title":"Role of the prefrontal cortex in the foreperiod effect: TMS evidence for dual mechanisms in temporal preparation","volume":"17","author":"Vallesi","year":"2007","journal-title":"Cerebral Cortex"},{"key":"2021073020583018800_R57","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1038\/35083500","article-title":"Dopamine responses comply with assumptions of formal learning theory","volume":"412","author":"Waelti","year":"2001","journal-title":"Nature"},{"key":"2021073020583018800_R56","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1007\/s002130050834","article-title":"The in vivo effects of olanzapine and other antipsychotic agents on receptor occupancy and antagonism of dopamine D1, D2, D3, 5HT 2A and muscarinic receptors","volume":"141","author":"Zhang","year":"1999","journal-title":"Psychopharmacology"}],"container-title":["Journal of Cognitive Neuroscience"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/direct.mit.edu\/jocn\/article-pdf\/28\/1\/96\/1950358\/jocn_a_00880.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/direct.mit.edu\/jocn\/article-pdf\/28\/1\/96\/1950358\/jocn_a_00880.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,31]],"date-time":"2021-07-31T00:59:45Z","timestamp":1627693185000},"score":1,"resource":{"primary":{"URL":"https:\/\/direct.mit.edu\/jocn\/article\/28\/1\/96\/28428\/The-Role-of-Dopamine-in-Temporal-Uncertainty"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,1,1]]},"references-count":61,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,1,1]]},"published-print":{"date-parts":[[2016,1,1]]}},"URL":"https:\/\/doi.org\/10.1162\/jocn_a_00880","relation":{},"ISSN":["0898-929X","1530-8898"],"issn-type":[{"value":"0898-929X","type":"print"},{"value":"1530-8898","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2016,1]]},"published":{"date-parts":[[2016,1,1]]}}}