Modulation of Human Time Processing by Subthalamic Deep Brain Stimulation

Timing in the range of seconds referred to as interval timing is crucial for cognitive operations and conscious time processing. According to recent models of interval timing basal ganglia (BG) oscillatory loops are involved in time interval recognition. Parkinsońs disease (PD) is a typical disease of the basal ganglia that shows distortions in interval timing. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a powerful treatment of PD which modulates motor and cognitive functions depending on stimulation frequency by affecting subcortical-cortical oscillatory loops. Thus, for the understanding of BG-involvement in interval timing it is of interest whether STN-DBS can modulate timing in a frequency dependent manner by interference with oscillatory time recognition processes. We examined production and reproduction of 5 and 15 second intervals and millisecond timing in a double blind, randomised, within-subject repeated-measures design of 12 PD-patients applying no, 10-Hz- and ≥130-Hz-STN-DBS compared to healthy controls. We found under(re-)production of the 15-second interval and a significant enhancement of this under(re-)production by 10-Hz-stimulation compared to no stimulation, ≥130-Hz-STN-DBS and controls. Milliseconds timing was not affected. We provide first evidence for a frequency-specific modulatory effect of STN-DBS on interval timing. Our results corroborate the involvement of BG in general and of the STN in particular in the cognitive representation of time intervals in the range of multiple seconds.

[1]  G. Schaltenbrand,et al.  Atlas for Stereotaxy of the Human Brain , 1977 .

[2]  J. Gibbon,et al.  Coupled Temporal Memories in Parkinson's Disease: A Dopamine-Related Dysfunction , 1998, Journal of Cognitive Neuroscience.

[3]  P. Brown Oscillatory nature of human basal ganglia activity: Relationship to the pathophysiology of Parkinson's disease , 2003, Movement disorders : official journal of the Movement Disorder Society.

[4]  T. Rammsayer,et al.  Impaired temporal discrimination in Parkinson's disease: temporal processing of brief durations as an indicator of degeneration of dopaminergic neurons in the basal ganglia. , 1997, The International journal of neuroscience.

[5]  S. Keele,et al.  Does the Cerebellum Provide a Common Computation for Diverse Tasks? A Timing Hypothesis a , 1990, Annals of the New York Academy of Sciences.

[6]  Ann M Graybiel,et al.  Neural representation of time in cortico-basal ganglia circuits , 2009, Proceedings of the National Academy of Sciences.

[7]  B Conrad,et al.  A positron emission tomographic study of subthalamic nucleus stimulation in Parkinson disease: enhanced movement-related activity of motor-association cortex and decreased motor cortex resting activity. , 1999, Archives of neurology.

[8]  A. Parent,et al.  Functional anatomy of the basal ganglia. II. The place of subthalamic nucleus and external pallidium in basal ganglia circuitry , 1995, Brain Research Reviews.

[9]  M. Yamada,et al.  [Dementia rating scale]. , 1997, Nihon rinsho. Japanese journal of clinical medicine.

[10]  Jeffrey R Binder,et al.  Neural systems supporting timing and chronometric counting: an FMRI study. , 2004, Brain research. Cognitive brain research.

[11]  Ryan D Ward,et al.  Impaired timing precision produced by striatal D2 receptor overexpression is mediated by cognitive and motivational deficits. , 2009, Behavioral neuroscience.

[12]  Viviane Pouthas,et al.  Effects of internal clock and memory disorders on duration reproductions and duration productions in patients with Parkinson’s disease , 2005, Brain and Cognition.

[13]  David J. Freedman,et al.  Representation of the Quantity of Visual Items in the Primate Prefrontal Cortex , 2002, Science.

[14]  J. Gibbon,et al.  Timing and time perception. , 1984, Annals of the New York Academy of Sciences.

[15]  A. Oliviero,et al.  Dopamine Dependency of Oscillations between Subthalamic Nucleus and Pallidum in Parkinson's Disease , 2001, The Journal of Neuroscience.

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

[17]  R. Ivry The representation of temporal information in perception and motor control , 1996, Current Opinion in Neurobiology.

[18]  R M Church,et al.  Scalar Timing in Memory , 1984, Annals of the New York Academy of Sciences.

[19]  Emanuele Lo Gerfo,et al.  Impaired reproduction of second but not millisecond time intervals in Parkinson's disease , 2008, Neuropsychologia.

[20]  J. Dostrovsky,et al.  Neuronal Oscillations in the Basal Ganglia and Movement Disorders: Evidence from Whole Animal and Human Recordings , 2004, The Journal of Neuroscience.

[21]  H. Zelaznik,et al.  Disrupted Timing of Discontinuous But Not Continuous Movements by Cerebellar Lesions , 2003, Science.

[22]  R. Ivry,et al.  The neural representation of time , 2004, Current Opinion in Neurobiology.

[23]  S. Reppert,et al.  Coordination of circadian timing in mammals , 2002, Nature.

[24]  M. Delong,et al.  Deep Brain Stimulation for Neurologic and Neuropsychiatric Disorders , 2006, Neuron.

[25]  V. Tronnier,et al.  Subthalamic nucleus stimulation affects striato-anterior cingulate cortex circuit in a response conflict task: a PET study. , 2002, Brain : a journal of neurology.

[26]  Richard S. J. Frackowiak,et al.  Changes in cerebral activity pattern due to subthalamic nucleus or internal pallidum stimulation in Parkinson's disease , 1997, Annals of neurology.

[27]  Ulrike Schroeder,et al.  Subthalamic nucleus stimulation affects a frontotemporal network: A PET study , 2003, Annals of neurology.

[28]  C. Frith,et al.  The Substantia Nigra Pars Compacta and Temporal Processing , 2006, The Journal of Neuroscience.

[29]  S. Fahn Unified Parkinson's Disease Rating Scale , 1987 .

[30]  Stephen M. Rao,et al.  Neural modulation of temporal encoding, maintenance, and decision processes. , 2010, Cerebral cortex.

[31]  Giacomo Koch,et al.  Subthalamic deep brain stimulation improves time perception in Parkinson's disease , 2004, Neuroreport.

[32]  R. Kronauer,et al.  Stability, precision, and near-24-hour period of the human circadian pacemaker. , 1999, Science.

[33]  Joachim Gross,et al.  Ten‐Hertz stimulation of subthalamic nucleus deteriorates motor symptoms in Parkinson's disease , 2004, Movement disorders : official journal of the Movement Disorder Society.

[34]  W. Meck,et al.  Cortico-striatal circuits and interval timing: coincidence detection of oscillatory processes. , 2004, Brain research. Cognitive brain research.

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

[36]  Sara Torriero,et al.  Underestimation of time perception after repetitive transcranial magnetic stimulation , 2003, Neurology.

[37]  H. Freund,et al.  The cerebral oscillatory network of parkinsonian resting tremor. , 2003, Brain : a journal of neurology.

[38]  Thomas D Parsons,et al.  Cognitive sequelae of subthalamic nucleus deep brain stimulation in Parkinson's disease: a meta-analysis , 2006, The Lancet Neurology.

[39]  F. Vidal,et al.  Activation of the supplementary motor area and of attentional networks during temporal processing , 2002, Experimental Brain Research.

[40]  L. Wojtecki,et al.  Frequency-dependent reciprocal modulation of verbal fluency and motor functions in subthalamic deep brain stimulation. , 2006, Archives of neurology.

[41]  C. Marsden,et al.  Recent Developments in Parkinson's Disease , 1986 .

[42]  W. Meck Functional and neural mechanisms of interval timing , 2003 .

[43]  M. Nicolelis,et al.  Interval timing and the encoding of signal duration by ensembles of cortical and striatal neurons. , 2003, Behavioral neuroscience.

[44]  Stephen M. Rao,et al.  The evolution of brain activation during temporal processing , 2001, Nature Neuroscience.

[45]  G. E. Alexander,et al.  Basal ganglia-thalamocortical circuits: parallel substrates for motor, oculomotor, "prefrontal" and "limbic" functions. , 1990, Progress in brain research.

[46]  R. Knight,et al.  Cortical Networks Underlying Mechanisms of Time Perception , 1998, The Journal of Neuroscience.

[47]  Catalin V. Buhusi,et al.  What makes us tick? Functional and neural mechanisms of interval timing , 2005, Nature Reviews Neuroscience.

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

[49]  Martin Wiener,et al.  Dissociable Neural Systems for Timing: Evidence from Subjects with Basal Ganglia Lesions , 2010, PloS one.

[50]  B. Rakitin,et al.  Interval Timing in the Dopamine-Depleted Basal Ganglia: From Empirical Data to Timing Theory , 2003 .

[51]  P. A. Lewis,et al.  A right hemispheric prefrontal system for cognitive time measurement , 2006, Behavioural Processes.

[52]  V. Sturm,et al.  Subthalamic Nucleus Stimulation Restores Glucose Metabolism in Associative and Limbic Cortices and in Cerebellum: Evidence from a FDG-PET Study in Advanced Parkinson's Disease , 2004, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[53]  J. Yelnik Functional anatomy of the basal ganglia , 2002, Movement disorders : official journal of the Movement Disorder Society.

[54]  G. Deuschl,et al.  A randomized trial of deep-brain stimulation for Parkinson's disease. , 2006, The New England journal of medicine.

[55]  C. Marsden,et al.  What do the basal ganglia do? , 1998, The Lancet.