BACKGROUND: Parkinson's disease (PD) patients are deficient in time estimation. This deficit improves after dopamine (DA) treatment and it has been associated with decreased internal timekeeper speed, disruption of executive function and memory retrieval dysfunction. METHODOLOGY/FINDINGS: The aim of the present study was to explore the neurophysiologic correlates of this deficit. We performed functional magnetic resonance imaging on twelve PD patients while they were performing a time reproduction task (TRT). The TRT consisted of an encoding phase (during which visual stimuli of durations from 5 s to 16.6 s, varied at 8 levels were presented) and a reproduction phase (during which interval durations were reproduced by a button pressing). Patients were scanned twice, once while on their DA medication (ON condition) and once after medication withdrawal (OFF condition). Differences in Blood-Oxygenation-Level-Dependent (BOLD) signal in ON and OFF conditions were evaluated. The time course of activation in the brain areas with different BOLD signal was plotted. There were no significant differences in the behavioral results, but a trend toward overestimation of intervals ≤11.9 s and underestimation of intervals ≥14.1 s in the OFF condition (p<0.088). During the reproduction phase, higher activation in the precuneus was found in the ON condition (p<0.05 corrected). Time course was plotted separately for long (≥14.1 s) and short (≤11.9 s) intervals. Results showed that there was a significant difference only in long intervals, when activity gradually decreased in the OFF, but remained stable in the ON condition. This difference in precuneus activation was not found during random button presses in a control task. CONCLUSIONS/SIGNIFICANCE: Our results show that differences in precuneus activation during retrieval of a remembered duration may underlie some aspects of time perception deficit in PD patients. We suggest that DA medication may allow compensatory activation in the precuneus, which results in a more accurate retrieval of remembered interval duration.

Department of Neurology and Center of Clinical Neuroscience Charles University Prague 1st Faculty of Medicine and General University Hospital Prague Czech Republic

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Pouthas V, Perbal S. Time perception depends on accurate clock mechanisms as well as unimpaired attention and memory processes. Acta Neurobiol Exp (Wars) 2004;64:367–385. PubMed

Pastor MA, Artieda J, Jahanshahi M, Obeso JA. Time estimation and reproduction is abnormal in Parkinson's disease. Brain. 1992;115 Pt 1:211–225. PubMed

Artieda J, Pastor MA, Lacruz F, Obeso JA. Temporal discrimination is abnormal in Parkinson's disease. Brain. 1992;115 Pt 1:199–210. PubMed

Meck WH. Neuropharmacology of timing and time perception. Brain Res Cogn Brain Res. 1996;3:227–242. PubMed

Jones CR, Malone TJ, Dirnberger G, Edwards M, Jahanshahi M. Basal ganglia, dopamine and temporal processing: performance on three timing tasks on and off medication in Parkinson's disease. Brain Cogn. 2008;68:30–41. S0278-2626(08)00158-9 [pii];10.1016/j.bandc.2008.02.121 [doi] PubMed

Merchant H, Luciana M, Hooper C, Majestic S, Tuite P. Interval timing and Parkinson's disease: heterogeneity in temporal performance. Exp Brain Res. 2008;184:233–248. 10.1007/s00221-007-1097-7 [doi] PubMed

Riesen JM, Schnider A. Time estimation in Parkinson's disease: normal long duration estimation despite impaired short duration discrimination. J Neurol. 2001;248:27–35. PubMed

Schnider A, Gutbrod K, Hess CW. Motion imagery in Parkinson's disease. Brain. 1995;118(Pt 2):485–493. PubMed

Coslett HB, Wiener M, Chatterjee A. Dissociable neural systems for timing: evidence from subjects with basal ganglia lesions. PLoS One. 2010;5:e10324. 10.1371/journal.pone.0010324 [doi] PubMed PMC

Beste C, Saft C, Andrich J, Muller T, Gold R, et al. Time processing in Huntington's disease: a group-control study. PLoS One. 2007;2:e1263. 10.1371/journal.pone.0001263 [doi] PubMed PMC

Sysoeva OV, Tonevitsky AG, Wackermann J. Genetic determinants of time perception mediated by the serotonergic system. PLoS One. 2010;5 10.1371/journal.pone.0012650 [doi] PubMed PMC

Malapani C, Rakitin B, Levy R, Meck WH, Deweer B, et al. Coupled temporal memories in Parkinson's disease: a dopamine-related dysfunction. J Cogn Neurosci. 1998;10:316–331. PubMed

Koch G, Brusa L, Caltagirone C, Oliveri M, Peppe A, et al. Subthalamic deep brain stimulation improves time perception in Parkinson's disease. Neuroreport. 2004;15:1071–1073. PubMed

Koch G, Brusa L, Oliveri M, Stanzione P, Caltagirone C. Memory for time intervals is impaired in left hemi-Parkinson patients. Neuropsychologia. 2005;43:1163–1167. PubMed

Harrington DL, Haaland KY, Knight RT. Cortical networks underlying mechanisms of time perception. J Neurosci. 1998;18:1085–1095. PubMed PMC

Lewis PA, Miall RC. Brain activation patterns during measurement of sub- and supra-second intervals. Neuropsychologia. 2003;41:1583–1592. PubMed

Koch G, Oliveri M, Brusa L, Stanzione P, Torriero S, et al. High-frequency rTMS improves time perception in Parkinson disease. Neurology. 2004;63:2405–2406. PubMed

Coull JT, Cheng RK, Meck WH. Neuroanatomical and neurochemical substrates of timing. Neuropsychopharmacology. 2011;36:3–25. npp2010113 [pii];10.1038/npp.2010.113 [doi] PubMed PMC

Rubia K, Smith A. The neural correlates of cognitive time management: a review. Acta Neurobiol Exp (Wars) 2004;64:329–340. PubMed

Lewis PA, Miall RC. Distinct systems for automatic and cognitively controlled time measurement: evidence from neuroimaging. Curr Opin Neurobiol. 2003;13:250–255. PubMed

Wiener M, Turkeltaub P, Coslett HB. The image of time: a voxel-wise meta-analysis. Neuroimage. 2010;49:1728–1740. S1053-8119(09)01063-5 [pii];10.1016/j.neuroimage.2009.09.064 [doi] PubMed

Carbon M, Marie RM. Functional imaging of cognition in Parkinson's disease. Curr Opin Neurol. 2003;16:475–480. PubMed

Huang C, Mattis P, Tang C, Perrine K, Carbon M, et al. Metabolic brain networks associated with cognitive function in Parkinson's disease. Neuroimage. 2007;34:714–723. S1053-8119(06)00932-3 [pii];10.1016/j.neuroimage.2006.09.003 [doi] PubMed PMC

Cerasa A, Hagberg GE, Peppe A, Bianciardi M, Gioia MC, et al. Functional changes in the activity of cerebellum and frontostriatal regions during externally and internally timed movement in Parkinson's disease. Brain Res Bull. 2006;71:259–269. S0361-9230(06)00272-3 [pii];10.1016/j.brainresbull.2006.09.014 [doi] PubMed

Elsinger CL, Rao SM, Zimbelman JL, Reynolds NC, Blindauer KA, et al. Neural basis for impaired time reproduction in Parkinson's disease: an fMRI study. J Int Neuropsychol Soc. 2003;9:1088–1098. PubMed

Jahanshahi M, Jones CR, Zijlmans J, Katzenschlager R, Lee L, et al. Dopaminergic modulation of striato-frontal connectivity during motor timing in Parkinson's disease. Brain. 2010;133:727–745. awq012 [pii];10.1093/brain/awq012 [doi] PubMed

Yu H, Sternad D, Corcos DM, Vaillancourt DE. Role of hyperactive cerebellum and motor cortex in Parkinson's disease. Neuroimage. 2007;35:222–233. S1053-8119(06)01175-X [pii];10.1016/j.neuroimage.2006.11.047 [doi] PubMed PMC

Harrington DL, Castillo GN, Greenberg PA, Song DD, Lessig S, et al. Neurobehavioral mechanisms of temporal processing deficits in Parkinson's disease. PLoS One. 2011;6:e17461. 10.1371/journal.pone.0017461 [doi] PubMed PMC

Wackermann J. Inner and outer horizons of time experience. Span J Psychol. 2007;10:20–32. PubMed

Deuschl G, Schade-Brittinger C, Krack P, Volkmann J, Schafer H, et al. A randomized trial of deep-brain stimulation for Parkinson's disease. N Engl J Med. 2006;355:896–908. 355/9/896 [pii];10.1056/NEJMoa060281 [doi] PubMed

Jech R, Dusek P, Wackermann J, Vymazal J. Cumulative blood oxygenation-level-dependent signal changes support the ‘time accumulator’ hypothesis. Neuroreport. 2005;16:1467–1471. PubMed

Turner R, Howseman A, Rees GE, Josephs O, Friston K. Functional magnetic resonance imaging of the human brain: data acquisition and analysis. Exp Brain Res. 1998;123:5–12. PubMed

Lohmann G, Muller K, Bosch V, Mentzel H, Hessler S, et al. LIPSIA–a new software system for the evaluation of functional magnetic resonance images of the human brain. Comput Med Imaging Graph. 2001;25:449–457. S0895611101000088 [pii] PubMed

Evans AC, Marrett S, Neelin P, Collins L, Worsley K, et al. Anatomical mapping of functional activation in stereotactic coordinate space. Neuroimage. 1992;1:43–53. 1053-8119(92)90006-9 [pii] PubMed

Talairach J, Tournoux P. Co-planar Stereotaxic Atlas of the Human Brain: 3-Dimensional Proportional System - an Approach to Cerebral Imaging. New York: Thieme Medical Publishers; 1998.

Friston KJ, Holmes AP, Poline JB, Grasby PJ, Williams SC, et al. Analysis of fMRI time-series revisited. Neuroimage. 1995;2:45–53. S1053-8119(85)71007-5 [pii];10.1006/nimg.1995.1007 [doi] PubMed

Friston KJ, Frith CD, Turner R, Frackowiak RS. Characterizing evoked hemodynamics with fMRI. Neuroimage. 1995;2:157–165. S105381198571018X [pii] PubMed

Worsley KJ, Friston KJ. Analysis of fMRI time-series revisited–again. Neuroimage. 1995;2:173–181. S1053-8119(85)71023-3 [pii];10.1006/nimg.1995.1023 [doi] PubMed

Friston KJ, Josephs O, Rees G, Turner R. Nonlinear event-related responses in fMRI. Magn Reson Med. 1998;39:41–52. PubMed

Josephs O, Turner R, Friston K. Event-related f MRI. Hum Brain Mapp. 1997;5:243–248. 10.1002/(SICI)1097-0193(1997)5:4<243::AID-HBM7>3.0.CO;2-3 [doi] PubMed

Gibbon J, Malapani C, Dale CL, Gallistel C. Toward a neurobiology of temporal cognition: advances and challenges. Curr Opin Neurobiol. 1997;7:170–184. PubMed

Malapani C, Deweer B, Gibbon J. Separating storage from retrieval dysfunction of temporal memory in Parkinson's disease. J Cogn Neurosci. 2002;14:311–322. PubMed

Shea-Brown E, Rinzel J, Rakitin BC, Malapani C. A firing rate model of Parkinsonian deficits in interval timing. Brain Res. 2006;1070:189–201. PubMed

Koch G, Costa A, Brusa L, Peppe A, Gatto I, et al. Impaired reproduction of second but not millisecond time intervals in Parkinson's disease. Neuropsychologia. 2008;46:1305–1313. S0028-3932(07)00440-X [pii];10.1016/j.neuropsychologia.2007.12.005 [doi] PubMed

von Vierodt K. Der Zeitsinn nach Versuchen. Tubingen: H. Laupp; 1868.

Jazayeri M, Shadlen MN. Temporal context calibrates interval timing. Nat Neurosci. 2010;13:1020–1026. nn.2590 [pii];10.1038/nn.2590 [doi] PubMed PMC

Bueti D, Walsh V. Memory for time distinguishes between perception and action. Perception. 2010;39:81–90. PubMed

Huang C, Tang C, Feigin A, Lesser M, Ma Y, et al. Changes in network activity with the progression of Parkinson's disease. Brain. 2007;130:1834–1846. awm086 [pii];10.1093/brain/awm086 [doi] PubMed PMC

Asanuma K, Tang C, Ma Y, Dhawan V, Mattis P, et al. Network modulation in the treatment of Parkinson's disease. Brain. 2006;129:2667–2678. PubMed PMC

Goerendt IK, Lawrence AD, Mehta MA, Stern JS, Odin P, et al. Distributed neural actions of anti-parkinsonian therapies as revealed by PET. J Neural Transm. 2006;113:75–86. PubMed

Choi JK, Chen YI, Hamel E, Jenkins BG. Brain hemodynamic changes mediated by dopamine receptors: Role of the cerebral microvasculature in dopamine-mediated neurovascular coupling. Neuroimage. 2006;30:700–712. S1053-8119(05)00807-4 [pii];10.1016/j.neuroimage.2005.10.029 [doi] PubMed

Harrington DL, Boyd LA, Mayer AR, Sheltraw DM, Lee RR, et al. Neural representation of interval encoding and decision making. Brain Res Cogn Brain Res. 2004;21:193–205. PubMed

Wittmann M, van Wassenhove V, Craig AD, Paulus MP. The neural substrates of subjective time dilation. Front Hum Neurosci. 2010;4:2. 10.3389/neuro.09.002.2010 [doi] PubMed PMC

van Wassenhove V, Buonomano DV, Shimojo S, Shams L. Distortions of subjective time perception within and across senses. PLoS One. 2008;3:e1437. 10.1371/journal.pone.0001437 [doi] PubMed PMC

Cavanna AE, Trimble MR. The precuneus: a review of its functional anatomy and behavioural correlates. Brain. 2006;129:564–583. PubMed

Spreng RN, Mar RA, Kim ASN. The Common Neural Basis of Autobiographical Memory, Prospection, Navigation, Theory of Mind, and the Default Mode: A Quantitative Meta-analysis. Journal of Cognitive Neuroscience. 2009;21:489–510. PubMed

Gusnard DA, Akbudak E, Shulman GL, Raichle ME. Medial prefrontal cortex and self-referential mental activity: relation to a default mode of brain function. Proc Natl Acad Sci U S A. 2001;98:4259–4264. PubMed PMC

Raichle ME, MacLeod AM, Snyder AZ, Powers WJ, Gusnard DA, et al. A default mode of brain function. Proc Natl Acad Sci U S A. 2001;98:676–682. PubMed PMC

McKiernan KA, Kaufman JN, Kucera-Thompson J, Binder JR. A parametric manipulation of factors affecting task-induced deactivation in functional neuroimaging. J Cogn Neurosci. 2003;15:394–408. PubMed

Broyd SJ, Demanuele C, Debener S, Helps SK, James CJ, et al. Default-mode brain dysfunction in mental disorders: a systematic review. Neurosci Biobehav Rev. 2009;33:279–296. S0149-7634(08)00150-4 [pii];10.1016/j.neubiorev.2008.09.002 [doi] PubMed

Sambataro F, Murty VP, Callicott JH, Tan HY, Das S, Weinberger DR, et al. Age-related alterations in default mode network: impact on working memory performance. Neurobiol Aging. 2010;31:839–852. S0197-4580(08)00187-5 [pii];10.1016/j.neurobiolaging.2008.05.022 [doi] PubMed PMC

Kincses ZT, Johansen-Berg H, Tomassini V, Bosnell R, Matthews PM, et al. Model-free characterization of brain functional networks for motor sequence learning using fMRI. Neuroimage. 2008;39:1950–1958. PubMed

Tomasi D, Volkow ND, Wang RL, Telang F, Wang GJ, et al. Dopamine Transporters in Striatum Correlate with Deactivation in the Default Mode Network during Visuospatial Attention. Plos One. 2009;4 PubMed PMC

Stokes PRA, Rhodes RA, Grasby PM, Mehta MA. The Effects of The COMT val(108/158) met Polymorphism on BOLD Activation During Working Memory, Planning, and Response Inhibition: A Role for The Posterior Cingulate Cortex? Neuropsychopharmacology. 2011;36:763–771. PubMed PMC

Delaveau P, Salgado-Pineda P, Fossati P, Witjas T, Azulay JP, et al. Dopaminergic modulation of the default mode network in Parkinson's disease. Eur Neuropsychopharmacol. 2010;20:784–792. S0924-977X(10)00147-1 [pii];10.1016/j.euroneuro.2010.07.001 [doi] PubMed

van Eimeren T, Monchi O, Ballanger B, Strafella AP. Dysfunction of the default mode network in Parkinson disease: a functional magnetic resonance imaging study. Arch Neurol. 2009;66:877–883. 66/7/877 [pii];10.1001/archneurol.2009.97 [doi] PubMed PMC

Argyelan M, Carbon M, Ghilardi MF, Feigin A, Mattis P, et al. Dopaminergic suppression of brain deactivation responses during sequence learning. J Neurosci. 2008;28:10687–10695. 28/42/10687 [pii];10.1523/JNEUROSCI.2933-08.2008 [doi] PubMed PMC

Wackermann J, Ehm W. The dual klepsydra model of internal time representation and time reproduction. J Theor Biol. 2006;239:482–493. S0022-5193(05)00359-0 [pii];10.1016/j.jtbi.2005.08.024 [doi] PubMed