Dopamine Precursor Depletion in Healthy Volunteers Impairs Processing of Duration but Not Temporal Order

Abstract Studies in animals and humans have implicated the neurotransmitter dopamine in duration processing. However, very few studies have examined dopamine's involvement in other forms of temporal processing such as temporal order judgments. In a randomized within-subject placebo-controlled design, we used acute phenylalanine/tyrosine depletion (APTD) to reduce availability of the dopamine precursors tyrosine and phenylalanine in healthy human volunteers. As compared to a nutritionally balanced drink, APTD significantly impaired the ability to accurately reproduce interval duration in a temporal reproduction task. In addition, and confirming previous findings, the direction of error differed as a function of individual differences in underlying dopamine function. Specifically, APTD caused participants with low baseline dopamine precursor availability to overestimate the elapse of time, whereas those with high dopamine availability underestimated time. In contrast to these effects on duration processing, there were no significant effects of APTD on the accuracy of discriminating the temporal order of visual stimuli. This pattern of results does not simply represent an effect of APTD on motor, rather than perceptual, measures of timing because APTD had no effect on participants' ability to use temporal cues to speed RT. Our results demonstrate, for the first time in healthy volunteers, a dopaminergic dissociation in judging metrical (duration) versus ordinal (temporal order) aspects of time.

[1]  P. Cowen,et al.  Reduction of brain dopamine concentration with dietary tyrosine plus phenylalanine depletion: an [11C]raclopride PET study. , 2003, The American journal of psychiatry.

[2]  Melissa J. Allman,et al.  Pathophysiological distortions in time perception and timed performance. , 2012, Brain : a journal of neurology.

[3]  C. Benkelfat,et al.  Effects on Mood of Acute Phenylalanine/Tyrosine Depletion in Healthy Women , 2000, Neuropsychopharmacology.

[4]  L. Lopiano,et al.  Dissociation between time reproduction of actions and of intervals in patients with Parkinson’s disease , 2010, Journal of Neurology.

[5]  I. Levin,et al.  The development of time concepts in young children: the relations between duration and succession. , 1978, Child development.

[6]  J. Wearden,et al.  Scalar timing without reference memory? Episodic temporal generalization and bisection in humans. , 2001 .

[7]  Rolf Ulrich,et al.  Threshold estimation in two-alternative forced-choice (2AFC) tasks: The Spearman-Kärber method , 2004, Perception & psychophysics.

[8]  S. Sara,et al.  Orienting and Reorienting: The Locus Coeruleus Mediates Cognition through Arousal , 2012, Neuron.

[9]  Kwang-Hyuk Lee,et al.  Time perception and its neuropsychological correlates in patients with schizophrenia and in healthy volunteers , 2009, Psychiatry Research.

[10]  M. Posner,et al.  Attention and the detection of signals. , 1980, Journal of experimental psychology.

[11]  A. Nobre,et al.  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 , 1998, The Journal of Neuroscience.

[12]  A. Bakou,et al.  Distorted Multisensory Experiences of Order and Simultaneity , 2015 .

[13]  Richard B. Ivry,et al.  Double dissociation of single-interval and rhythmic temporal prediction in cerebellar degeneration and Parkinson’s disease , 2018, Proceedings of the National Academy of Sciences.

[14]  M. Gill,et al.  Impaired Temporal Resolution of Visual Attention and Dopamine Beta Hydroxylase Genotype in Attention-Deficit/Hyperactivity Disorder , 2006, Biological Psychiatry.

[15]  Patricia V Agostino,et al.  Contributions of dopaminergic signaling to timing accuracy and precision , 2016, Current Opinion in Behavioral Sciences.

[16]  Ryan D Ward,et al.  Time Distortions in Mind , 2015 .

[17]  M. Missal,et al.  How does Parkinson’s disease and aging affect temporal expectation and the implicit timing of eye movements? , 2013, Neuropsychologia.

[18]  T. McCormack,et al.  Duration judgements in patients with schizophrenia , 2003, Psychological Medicine.

[19]  A. Bond,et al.  The use of analogue scales in rating subjective feelings , 1974 .

[20]  R. Chan,et al.  Time perception deficit in children with ADHD , 2007, Brain Research.

[21]  R. Capa,et al.  Patients with schizophrenia selectively impaired in temporal order judgments , 2014, Schizophrenia Research.

[22]  D. Warden,et al.  Memory for temporal order in Schizophrenia , 1991, Biological Psychiatry.

[23]  John Gibbon,et al.  Separating Storage from Retrieval Dysfunction of Temporal Memory in Parkinson's Disease , 2002, Journal of Cognitive Neuroscience.

[24]  Monica Luciana,et al.  Interval timing and Parkinson’s disease: heterogeneity in temporal performance , 2007, Experimental Brain Research.

[25]  A. Crocker The Regulation of Motor Control: An Evaluation of the Role of Dopamine Receptors in the Substantia Nigra , 1997, Reviews in the neurosciences.

[26]  D. Oberfeld,et al.  Meta-analysis of time perception and temporal processing in schizophrenia: Differential effects on precision and accuracy. , 2017, Clinical psychology review.

[27]  W. Meck Neuropharmacology of timing and time perception. , 1996, Brain research. Cognitive brain research.

[28]  S. McKee,et al.  Spatial configurations for visual hyperacuity , 1977, Vision Research.

[29]  F. Piras,et al.  Predictive timing disturbance is a precise marker of schizophrenia , 2018, Schizophrenia Research: Cognition.

[30]  E. Stricker,et al.  Activation-induced restoration of sensorimotor functions in rats with dopamine-depleting brain lesions. , 1976, Journal of comparative and physiological psychology.

[31]  Stephen B. R. E. Brown,et al.  Effects of clonidine and scopolamine on multiple target detection in rapid serial visual presentation , 2015, Psychopharmacology.

[32]  Katya Rubia,et al.  Evidence for a pure time perception deficit in children with ADHD. , 2002, Journal of child psychology and psychiatry, and allied disciplines.

[33]  Warren H. Meck,et al.  Affinity for the dopamine D2 receptor predicts neuroleptic potency in decreasing the speed of an internal clock , 1986, Pharmacology Biochemistry and Behavior.

[34]  T. Rammsayer,et al.  Neuropharmacological Evidence for Different Timing Mechanisms in Humans , 1999, The Quarterly journal of experimental psychology. B, Comparative and physiological psychology.

[35]  Alain Dagher,et al.  Decreasing Amphetamine-Induced Dopamine Release by Acute Phenylalanine/Tyrosine Depletion: A PET/[11C]Raclopride Study in Healthy Men , 2004, Neuropsychopharmacology.

[36]  Joseph J. Paton,et al.  Midbrain dopamine neurons control judgment of time , 2016, Science.

[37]  D. Harrington,et al.  Temporal processing in the basal ganglia. , 1998, Neuropsychology.

[38]  Sven Bestmann,et al.  Learning from the past and expecting the future in Parkinsonism: Dopaminergic influence on predictions about the timing of future events , 2019, Neuropsychologia.

[39]  B. O’Donnell,et al.  Increased Timing Variability in Schizophrenia and Bipolar Disorder , 2014, PloS one.

[40]  A. Dagher,et al.  Dopaminergic Modulation of Motor Timing in Healthy Volunteers Differs as a Function of Baseline DA Precursor Availability , 2013 .

[41]  Rajeev D. S. Raizada,et al.  Challenge-Driven Attention: Interacting Frontal and Brainstem Systems , 2007, Frontiers in human neuroscience.

[42]  Karl J. Friston,et al.  Noradrenergically Mediated Plasticity in a Human Attentional Neuronal Network , 1999, NeuroImage.

[43]  D. V. von Cramon,et al.  Interval and ordinal properties of sequences are associated with distinct premotor areas. , 2001, Cerebral cortex.

[44]  Thomas H Rammsayer,et al.  Aspects of temporal information processing: A dimensional analysis , 2004, Psychological research.

[45]  S. Klein,et al.  Vernier acuity, crowding and cortical magnification , 1985, Vision Research.

[46]  P. Fraisse Perception and estimation of time. , 1984, Annual review of psychology.

[47]  E. Pöppel,et al.  A hierarchical model of temporal perception , 1997, Trends in Cognitive Sciences.

[48]  T. Rammsayer,et al.  On dopaminergic modulation of temporal information processing , 1993, Biological Psychology.

[49]  P. Cowen,et al.  Tyrosine depletion attenuates dopamine function in healthy volunteers , 2001, Psychopharmacology.

[50]  A. Nobre,et al.  The noradrenergic alpha2 agonist clonidine modulates behavioural and neuroanatomical correlates of human attentional orienting and alerting. , 2001, Cerebral cortex.

[51]  M. Jahanshahi,et al.  Contributions of the Basal Ganglia to Temporal Processing: Evidence from Parkinson’s Disease , 2014 .

[52]  S. Kish,et al.  Uneven pattern of dopamine loss in the striatum of patients with idiopathic Parkinson's disease. Pathophysiologic and clinical implications. , 1988, The New England journal of medicine.

[53]  S. Shergill,et al.  Eluding the illusion? Schizophrenia, dopamine and the McGurk effect , 2014, Front. Hum. Neurosci..

[54]  F. Vidal,et al.  Functional anatomy of timing differs for production versus prediction of time intervals , 2013, Neuropsychologia.

[55]  A. Dagher,et al.  Dopamine Precursor Depletion Impairs Timing in Healthy Volunteers by Attenuating Activity in Putamen and Supplementary Motor Area , 2012, The Journal of Neuroscience.

[56]  P. Grasby,et al.  Tyrosine depletion alters cortical and limbic blood flow but does not modulate spatial working memory performance or task‐related blood flow in humans , 2007, Human brain mapping.

[57]  S. Sara Locus Coeruleus in time with the making of memories , 2015, Current Opinion in Neurobiology.

[58]  M. Jahanshahi,et al.  Time estimation and reproduction is abnormal in Parkinson's disease. , 1992, Brain : a journal of neurology.

[59]  J A Obeso,et al.  Temporal discrimination is abnormal in Parkinson's disease. , 1992, Brain : a journal of neurology.

[60]  Thomas Rammsayer,et al.  Performance on temporal information processing as an index of general intelligence , 2007 .

[61]  N. Narayanan,et al.  Prefrontal D1 dopamine signaling is necessary for temporal expectation during reaction time performance , 2013, Neuroscience.

[62]  David M. Eagleman,et al.  Does Time Really Slow Down during a Frightening Event? , 2007, PloS one.

[63]  C. Lyoo,et al.  “Off” gait freezing and temporal discrimination threshold in patients with Parkinson disease , 2005, Neurology.

[64]  Thomas Rammsayer,et al.  Effects of Pharmacologically Induced Dopamine-Receptor Stimulation on Human Temporal Information Processing , 2009 .

[65]  T. Rammsayer,et al.  Are there dissociable roles of the mesostriatal and mesolimbocortical dopamine systems on temporal information processing in humans? , 1997, Neuropsychobiology.

[66]  W. Meck,et al.  Differential effects of clozapine and haloperidol on interval timing in the supraseconds range , 2005, Psychopharmacology.

[67]  William P. Hetrick,et al.  Temporal processing dysfunction in schizophrenia , 2008, Brain and Cognition.

[68]  W H Oldendorf,et al.  Amino acid assignment to one of three blood-brain barrier amino acid carriers. , 1976, The American journal of physiology.

[69]  Philip J. Cowen,et al.  Effect of a tyrosine-free amino acid mixture on regional brain catecholamine synthesis and release , 1999, Psychopharmacology.

[70]  F. Lopera,et al.  The cognitive structure of time estimation impairments in adults with attention deficit hyperactivity disorder , 2013, Cognitive neuropsychology.

[71]  William D. Penny,et al.  The Role of Dopamine in Temporal Uncertainty , 2016, Journal of Cognitive Neuroscience.

[72]  R. Church,et al.  The differential effects of haloperidol and methamphetamine on time estimation in the rat , 2004, Psychopharmacology.

[73]  T. O. Kvålseth Cautionary Note about R 2 , 1985 .

[74]  W. Meck,et al.  Neuroanatomical and Neurochemical Substrates of Timing , 2011, Neuropsychopharmacology.

[75]  Anita J. Jurkowski,et al.  Variable foreperiod deficits in Parkinson’s disease: Dissociation across reflexive and voluntary behaviors , 2005, Brain and Cognition.

[76]  R Tannock,et al.  Time perception deficits in attention-deficit/ hyperactivity disorder and comorbid reading difficulties in child and adolescent samples. , 2003, Journal of child psychology and psychiatry, and allied disciplines.

[77]  Jonathan D. Cohen,et al.  Role of locus coeruleus in attention and behavioral flexibility , 1999, Biological Psychiatry.

[78]  R. Cools Chemistry of the Adaptive Mind: Lessons from Dopamine , 2019, Neuron.

[79]  Warren H. Meck,et al.  Differential effects of amphetamine and haloperidol on temporal reproduction: Dopaminergic regulation of attention and clock speed , 2013, Neuropsychologia.

[80]  S. Grondin,et al.  Time perception disorders are related to working memory impairment in schizophrenia , 2012, Psychiatry Research.

[81]  B. Sahakian,et al.  Clonidine and diazepam have differential effects on tests of attention and learning , 1995, Psychopharmacology.

[82]  E. Pöppel,et al.  Temporal order judgement for auditory and visual stimuli. , 2002, Acta neurobiologiae experimentalis.

[83]  J. Horvitz,et al.  Effects of dopamine antagonists on the timing of two intervals , 2003, Pharmacology Biochemistry and Behavior.

[84]  Short-term temporal memory in idiopathic and Parkin-associated Parkinson’s disease , 2018, Scientific reports.

[85]  V. Noreika,et al.  Timing deficits in attention-deficit/hyperactivity disorder (ADHD): Evidence from neurocognitive and neuroimaging studies , 2013, Neuropsychologia.

[86]  Franck Vidal,et al.  Differential roles for parietal and frontal cortices in fixed versus evolving temporal expectations: Dissociating prior from posterior temporal probabilities with fMRI , 2016, NeuroImage.

[87]  M. D’Esposito,et al.  Inverted-U–Shaped Dopamine Actions on Human Working Memory and Cognitive Control , 2011, Biological Psychiatry.