A neural network model of Parkinson's disease bradykinesia

Parkinson's disease (PD) is caused by dopamine (DA) depletion consequent to cell degeneration in the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA). Although computational analyses of PD have focused on DA depletion in DA-recipient parts of the basal ganglia, there is also extensive DAergic innervation of the frontal and parietal cortex as well as the spinal cord. To understand PD bradykinesia, a comprehensive network model is needed to study how patterns of DA depletion at key cellular sites in the basal ganglia, cortex and spinal cord contribute to disordered neuronal and spinal cord activity and other PD symptoms. We extend a basal ganglia-cortico-spinal circuit for control of voluntary arm movements by incorporating DAergic innervation of cells in the cortical and spinal components of the circuit. The resultant model simulates successfully several of the main reported effects of DA depletion on neuronal, electromyographic (EMG), and movement parameters of PD bradykinesia.

[1]  J. Weil-Fugazza,et al.  Dorsal and ventral dopaminergic innervation of the spinal cord: Functional implications , 1993, Brain Research Bulletin.

[2]  K. Hagbarth,et al.  Grouped spindle and electromyographic responses to abrupt wrist extension movements in man , 1981, The Journal of physiology.

[3]  J. Kaas,et al.  Topography and collateralization of the dopaminergic projections to motor and lateral prefrontal cortex in owl monkeys , 1992, The Journal of comparative neurology.

[4]  A. Grace,et al.  The control of firing pattern in nigral dopamine neurons: single spike firing , 1984, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[5]  D. Signorini,et al.  Neural networks , 1995, The Lancet.

[6]  S. Grossberg,et al.  Cortical networks for control of voluntary arm movements under variable force conditions. , 1998, Cerebral cortex.

[7]  C. Fromm,et al.  Sensory response properties of pyramidal tract neurons in the precentral motor cortex and postcentral gyrus of the rhesus monkey , 2004, Experimental Brain Research.

[8]  M L Latash,et al.  Organizing principles for single joint movements: V. Agonist-antagonist interactions. , 1992, Journal of neurophysiology.

[9]  W. Weiner,et al.  Parkinson's Disease and Nonpharmacologic Treatment Programs , 1989, Journal of the American Geriatrics Society.

[10]  P. Voorn,et al.  Development of Dopamine - Containing Systems in the CNS , 1992 .

[11]  R. Roth,et al.  MPTP reduces dopamine and norepinephrine concentrations in the supplementary motor area and cingulate cortex of the primate , 1990, Neuroscience Letters.

[12]  J. Deniau,et al.  Disinhibition as a basic process in the expression of striatal functions , 1990, Trends in Neurosciences.

[13]  M. Savasta,et al.  Autoradiographic distribution of the D1 agonist [3H]SKF 38393, in the rat brain and spinal cord. Comparison with the distribution of D2 dopamine receptors , 1986, Neuroscience.

[14]  A. Lees.  Clinical Neurophysiology in Parkinsonism , 1986 .

[15]  C. Ghez,et al.  Trajectory control in targeted force impulses , 1987, Experimental Brain Research.

[16]  D. Humphrey,et al.  Separate cortical systems for control of joint movement and joint stiffness: reciprocal activation and coactivation of antagonist muscles. , 1983, Advances in neurology.

[17]  M. McGlamery.  Mammalian Muscle Receptors and Their Central Actions , 1973 .

[18]  E. Bizzi,et al.  Human arm trajectory formation. , 1982, Brain : a journal of neurology.

[19]  A. Grace,et al.  The control of firing pattern in nigral dopamine neurons: burst firing , 1984, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[20]  J C Rothwell,et al.  The behaviour of the long-latency stretch reflex in patients with Parkinson's disease , 1983, Journal of neurology, neurosurgery, and psychiatry.

[21]  Karl M. Newell,et al.  Variability and Motor Control , 1993 .

[22]  L. Tremblay,et al.  Effects of dopamine agonists on the spontaneous activity of globus pallidus neurons in monkeys with MPTP-induced parkinsonism , 1991, Brain Research.

[23]  M. Hallett,et al.  A physiological mechanism of bradykinesia. , 1980, Brain : a journal of neurology.

[24]  T. Sejnowski,et al.  A Computational Model of How the Basal Ganglia Produce Sequences , 1998, Journal of Cognitive Neuroscience.

[25]  R. Tanaka,et al.  Disorder in reciprocal innervation upon initiation of voluntary movement in patients with Parkinson's disease , 2004, Experimental Brain Research.

[26]  Y. Lamarre,et al.  Discharge properties of area 5 neurones during arm movements triggered by sensory stimuli in the monkey , 1984, Brain Research.

[27]  J. Cooke,et al.  Movement-related phasic muscle activation. I. Relations with temporal profile of movement. , 1990, Journal of neurophysiology.

[28]  A. Björklund,et al.  Evidence for a major spinal cord projection from the diencephalic A11 dopamine cell group in the rat using transmitter-specific fluorescent retrograde tracing , 1979, Brain Research.

[29]  J. Abbs,et al.  Orofacial motor control impairment in Parkinson's disease , 1987, Neurology.

[30]  B. Berger,et al.  Regional and laminar distribution of the dopamine and serotonin innervation in the macaque cerebral cortex: A radioautographic study , 1988, The Journal of comparative neurology.

[31]  D. Woodbury,et al.  Penetration of 14C-inulin and 14C-sucrose into brain, cerebrospinal fluid, and skeletal muscle of developing rats , 2004, Experimental Brain Research.

[32]  T. Ebner,et al.  Effects of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP)-induced hemiparkinsonism on the kinematics of a two-dimensional, multijoint arm movement in the rhesus monkey , 1992, Neuroscience.

[33]  Stephen Grossberg,et al.  How laminar frontal cortex and basal ganglia circuits interact to control planned and reactive saccades , 2004, Neural Networks.

[34]  G. Stelmach,et al.  Interlimb coordination in Parkinson's disease , 1992, Movement disorders : official journal of the Movement Disorder Society.

[35]  Stephen Grossberg,et al.  Adaptive neural networks for control of movement trajectories invariant under speed and force rescaling , 1991 .

[36]  K. Hagbarth,et al.  Muscle spindle activity in alternating tremor of Parkinsonism and in clonus. , 1975, Journal of neurology, neurosurgery, and psychiatry.

[37]  C. Marsden,et al.  Performance of simultaneous movements in patients with Parkinson's disease. , 1986, Brain : a journal of neurology.

[38]  P S Goldman-Rakic,et al.  Widespread origin of the primate mesofrontal dopamine system. , 1998, Cerebral cortex.

[39]  G. Stelmach,et al.  Force production characteristics in Parkinson's disease , 1989, Experimental Brain Research.

[40]  F. Horak,et al.  Influence of globus pallidus on arm movements in monkeys. I. Effects of kainic acid-induced lesions. , 1984, Journal of neurophysiology.

[41]  M. Hallett,et al.  Ballistic flexion movements of the human thumb. , 1979, The Journal of physiology.

[42]  H. Dr,et al.  Separate cortical systems for control of joint movement and joint stiffness: reciprocal activation and coactivation of antagonist muscles. , 1983 .

[43]  B. Bioulac,et al.  MPTP primate model of Parkinson's disease: a mechanographic and electromyographic study , 1985, Brain Research.

[44]  J. Chalmers,et al.  Direct projection of catecholamine (presumably dopamine)-containing neurons from hypothalamus to spinal cord , 1979, Neuroscience Letters.

[45]  L Proteau,et al.  Determining movement onsets from temporal series. , 1993, Journal of motor behavior.

[46]  Rajesh Pahwa,et al.  Stroke , 1987, Neurology.

[47]  C. Ghez,et al.  Trajectory control in targeted force impulses , 1987, Experimental Brain Research.

[48]  R. Watts,et al.  The role of motor cortex in the pathophysiology of voluntary movement deficits associated with parkinsonism. , 1992, Neurologic clinics.

[49]  J. Rothwell,et al.  Strength in Parkinson's disease: Relationshp to rate of force generation and clinical status , 1996, Annals of neurology.

[50]  A. Benazzouz,et al.  MPTP induced hemiparkinsonism in monkeys: behavioral, mechanographic, electromyographic and immunohistochemical studies , 2004, Experimental Brain Research.

[51]  M. Yoshida,et al.  A new dopaminergic terminal plexus in the ventral horn of the rat spinal cord. Immunohistochemical studies at the light and electron microscopic levels , 1990, Experientia.

[52]  P. Delwaide,et al.  Short‐latency autogenic inhibition in patients with parkinsonian rigidity , 1991, Annals of neurology.

[53]  T. Tzschentke.  Pharmacology and behavioral pharmacology of the mesocortical dopamine system , 2001, Progress in Neurobiology.

[54]  G. Stelmach,et al.  Movement accuracy constraints in Parkinson’s disease patients , 2000, Neuropsychologia.

[55]  A. Grace,et al.  The tonic/phasic model of dopamine system regulation: its relevance for understanding how stimulant abuse can alter basal ganglia function. , 1995, Drug and alcohol dependence.

[56]  A. W. Wiegner,et al.  Role of agonist and antagonist muscles in fast arm movements in man , 2004, Experimental Brain Research.

[57]  J C Rothwell,et al.  Scaling of the size of the first agonist EMG burst during rapid wrist movements in patients with Parkinson's disease. , 1986, Journal of neurology, neurosurgery, and psychiatry.

[58]  C Ghez,et al.  Trajectory control in targeted force impulses , 2004, Experimental Brain Research.

[59]  D. Geschwind,et al.  Distribution of major neurotransmitter receptors in the motor and somatosensory cortex of the rhesus monkey , 1989, Neuroscience.

[60]  L. Tremblay,et al.  Responses of pallidal neurons to striatal stimulation in monkeys with MPTP-induced parkinsonism , 1989, Brain Research.

[61]  J. Seal,et al.  Neuronal Activity in Area 4 and Movement Parameters Recorded in Trained Monkeys After Unilateral Lesion of the Substantia Nigra , 1983 .

[62]  E. Henneman.  Relation between size of neurons and their susceptibility to discharge. , 1957, Science.

[63]  K. Flowers.  Visual "closed-loop" and "open-loop" characteristics of voluntary movement in patients with Parkinsonism and intention tremor. , 1976, Brain : a journal of neurology.

[64]  Peter Redgrave,et al.  A computational model of action selection in the basal ganglia. I. A new functional anatomy , 2001, Biological Cybernetics.

[65]  S. Gentleman,et al.  Spinal cord dopaminergic neurons: Evidence for an uncrossed nigrospinal pathway , 1979, Neuropharmacology.

[66]  Daniel Bullock,et al.  Chapter 11 Vite and Flete: Neural Modules for Trajectory Formation and Postural Control , 1989 .

[67]  Gibberd Fb.  The management of Parkinson's disease. , 1986 .

[68]  T. Hattori,et al.  Single thalamic dopaminergic neurons project to both the neocortex and spinal cord , 1988, Brain Research.

[69]  J. Dormand,et al.  A family of embedded Runge-Kutta formulae , 1980 .

[70]  Y. Agid,et al.  Reduction of cortical dopamine, noradrenaline, serotonin and their metabolites in Parkinson's disease , 1983, Brain Research.

[71]  Peter Redgrave,et al.  A computational model of action selection in the basal ganglia. II. Analysis and simulation of behaviour , 2001, Biological Cybernetics.

[72]  D. Jacobowitz,et al.  A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[73]  B. Bioulac,et al.  Modifications of precentral cortex discharge and EMG activity in monkeys with MPTP-induced lesions of DA nigral neurons , 2004, Experimental Brain Research.

[74]  C. Ghez,et al.  Trajectory control in targeted force impulses , 2004, Experimental Brain Research.

[75]  S. Grossberg,et al.  A neural model of cerebellar learning for arm movement control: cortico-spino-cerebellar dynamics. , 1997, Learning & memory.

[76]  D. McCrea.  Can sense be made of spinal interneuron circuits , 1992 .

[77]  R. Young.  Tremor in relation to certain other movement disorders , 1984 .

[78]  J. Cooke,et al.  Movement-related phasic muscle activation. II. Generation and functional role of the triphasic pattern. , 1990, Journal of neurophysiology.

[79]  J. Desmedt.  Motor control mechanisms in health and disease , 1983 .

[80]  J. Morrison,et al.  Brainstem dopaminergic neurons project to monkey parietal cortex , 1988, Neuroscience Letters.

[81]  G. Stelmach,et al.  Parkinsonian arm movements as altered by task difficulty. , 1996, Parkinsonism & related disorders.

[82]  J. Cooke,et al.  Initial agonist burst duration depends on movement amplitude , 2004, Experimental Brain Research.

[83]  D. Bullock,et al.  How Spinal Neural Networks Reduce Discrepancies between Motor Intention and Motor Realization , 1991 .

[84]  P. Goldman-Rakic,et al.  Characterization of the dopaminergic innervation of the primate frontal cortex using a dopamine-specific antibody. , 1993, Cerebral cortex.

[85]  J. Kalaska,et al.  A comparison of movement direction-related versus load direction- related activity in primate motor cortex, using a two-dimensional reaching task , 1989, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[86]  S. Grossberg,et al.  Neural dynamics of planned arm movements: emergent invariants and speed-accuracy properties during trajectory formation. , 1988, Psychological review.

[87]  N. Bathien,et al.  Reciprocal continuous inhibition in rigidity of Parkinsonism. , 1977, Journal of neurology, neurosurgery, and psychiatry.

[88]  E. Henneman.  The size-principle: a deterministic output emerges from a set of probabilistic connections. , 1985, The Journal of experimental biology.

[89]  JM Tepper,et al.  GABAA receptor-mediated inhibition of rat substantia nigra dopaminergic neurons by pars reticulata projection neurons , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[90]  A P Georgopoulos,et al.  On the relations between the direction of two-dimensional arm movements and cell discharge in primate motor cortex , 1982, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[91]  J. Contreras-Vidal.  The gating functions of the basal ganglia in movement control. , 1999, Progress in brain research.

[92]  J Jacquy,et al.  Parkinsonian bradykinesia is due to depression in the rate of rise of muscle activity , 1992, Annals of neurology.

[93]  B. Berger,et al.  Alterations of dopaminergic and noradrenergic innervations in motor cortex in parkinson's disease , 1991, Annals of neurology.

[94]  J. Penney,et al.  The functional anatomy of basal ganglia disorders , 1989, Trends in Neurosciences.

[95]  John G. Taylor,et al.  Analysis of recurrent cortico-basal ganglia-thalamic loops for working memory , 2000, Biological Cybernetics.

[96]  R. Roth,et al.  Dopaminergic neurons: effect of antipsychotic drugs and amphetamine on single cell activity. , 1973, The Journal of pharmacology and experimental therapeutics.

[97]  E. Bézard,et al.  Compensatory mechanisms in experimental and human Parkinsonism: towards a dynamic approach , 1998, Progress in Neurobiology.

[98]  J. Abbs,et al.  Task-dependent variations in parkinsonian motor impairments. , 1991, Brain : a journal of neurology.

[99]  Stephen Grossberg,et al.  Emergence of tri-phasic muscle activation from the nonlinear interactions of central and spinal neural network circuits , 1992 .

[100]  J. Kalaska,et al.  Parietal area 5 neuronal activity encodes movement kinematics, not movement dynamics , 2004, Experimental Brain Research.

[101]  José Luis Contreras-Vidal,et al.  A neural model of basal ganglia-thalamocortical relations in normal and parkinsonian movement , 1995, Biological Cybernetics.