Neurophysiological correlates of bradykinesia in Parkinson’s disease

Many neurophysiological abnormalities have been described in the primary motor cortex of patients with Parkinson's disease. However, it is unclear whether there is any relationship between them and bradykinesia, one of the cardinal motor features of the condition. In the present study we aimed to investigate whether objective measures of bradykinesia in Parkinson's disease have any relationship with neurophysiological measures in primary motor cortex as assessed by means of transcranial magnetic stimulation techniques. Twenty-two patients with Parkinson's disease and 18 healthy subjects were enrolled. Objective measurements of repetitive finger tapping (amplitude, speed and decrement) were obtained using a motion analysis system. The excitability of primary motor cortex was assessed by recording the input/output curve of the motor-evoked potentials and using a conditioning-test paradigm for the assessment of short-interval intracortical inhibition and facilitation. Plasticity-like mechanisms in primary motor cortex were indexed according to the amplitude changes in motor-evoked potentials after the paired associative stimulation protocol. Patients were assessed in two sessions, i.e. OFF and ON medication. A canonical correlation analysis was used to test for relationships between the kinematic and neurophysiological variables. Patients with Parkinson's disease tapped more slowly and with smaller amplitude than normal, and displayed decrement as tapping progressed. They also had steeper input/output curves, reduced short-interval intracortical inhibition and a reduced response to the paired associative stimulation protocol. Within the patient group, bradykinesia features correlated with the slope of the input/output curve and the after-effects of the paired associative stimulation protocol. Although dopaminergic therapy improved movement kinematics as well as neurophysiological measures, there was no relationship between them. In conclusion, neurophysiological changes in primary motor cortex relate to bradykinesia in patients with Parkinson's disease, although other mechanisms sensitive to dopamine levels must also play a role.

[1]  M. Hallett,et al.  Transcranial magnetic stimulation techniques in clinical investigation , 2002, Neurology.

[2]  R. Carson,et al.  Modulation of human corticospinal excitability by paired associative stimulation , 2013, Front. Hum. Neurosci..

[3]  S. Rossi,et al.  Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research , 2009, Clinical Neurophysiology.

[4]  G. Fink,et al.  Dopaminergic modulation of motor network dynamics in Parkinson’s disease , 2015, Brain : a journal of neurology.

[5]  Francesca Morgante,et al.  Motor cortex plasticity in Parkinson's disease and levodopa-induced dyskinesias. , 2006, Brain : a journal of neurology.

[6]  Robert Iansek,et al.  The sequence effect and gait festination in Parkinson disease: Contributors to freezing of gait? , 2006, Movement disorders : official journal of the Movement Disorder Society.

[7]  A. Aertsen,et al.  Spiking activity propagation in neuronal networks: reconciling different perspectives on neural coding , 2010, Nature Reviews Neuroscience.

[8]  Alfredo Berardelli,et al.  The effect of L-dopa in Parkinson’s disease as revealed by neurophysiological studies of motor and sensory functions , 2017, Expert review of neurotherapeutics.

[9]  R. Tibshirani Regression Shrinkage and Selection via the Lasso , 1996 .

[10]  J. Rothwell,et al.  Transcranial magnetic stimulation follow‐up study in early Parkinson's disease: A decline in compensation with disease progression? , 2015, Movement disorders : official journal of the Movement Disorder Society.

[11]  M. Hallett,et al.  Abnormal facilitation of the response to transcranial magnetic stimulation in patients with Parkinson's disease , 1994, Neurology.

[12]  Jun B. Ding,et al.  Motor learning in animal models of Parkinson's disease: Aberrant synaptic plasticity in the motor cortex , 2017, Movement disorders : official journal of the Movement Disorder Society.

[13]  Jean-Pascal Lefaucheur,et al.  Motor cortex dysfunction revealed by cortical excitability studies in Parkinson's disease: influence of antiparkinsonian treatment and cortical stimulation , 2005, Clinical Neurophysiology.

[14]  C. MacKinnon,et al.  Pathways mediating abnormal intracortical inhibition in Parkinson's disease , 2005, Annals of neurology.

[15]  R. Turner,et al.  Primary motor cortex of the parkinsonian monkey: differential effects on the spontaneous activity of pyramidal tract-type neurons. , 2011, Cerebral cortex.

[16]  G. Deuschl,et al.  MDS clinical diagnostic criteria for Parkinson's disease , 2015, Movement disorders : official journal of the Movement Disorder Society.

[17]  P. Remy,et al.  Core assessment program for surgical interventional therapies in Parkinson's disease (CAPSIT‐PD) , 1999, Movement disorders : official journal of the Movement Disorder Society.

[18]  P. Brown,et al.  Beta band stability over time correlates with Parkinsonian rigidity and bradykinesia , 2012, Experimental Neurology.

[19]  Michael C. Ridding,et al.  Consensus paper on short-interval intracortical inhibition and other transcranial magnetic stimulation intracortical paradigms in movement disorders , 2008, Brain Stimulation.

[20]  M. Hallett,et al.  Characteristics of the sequence effect in Parkinson's disease , 2010, Movement disorders : official journal of the Movement Disorder Society.

[21]  Peter Brown,et al.  Subthalamic beta dynamics mirror Parkinsonian bradykinesia months after neurostimulator implantation , 2017, Movement disorders : official journal of the Movement Disorder Society.

[22]  J. Jankovic,et al.  Movement Disorder Society‐sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS‐UPDRS): Scale presentation and clinimetric testing results , 2008, Movement disorders : official journal of the Movement Disorder Society.

[23]  Ulf Ziemann,et al.  Interference of short-interval intracortical inhibition (SICI) and short-interval intracortical facilitation (SICF) , 2008, Clinical Neurophysiology.

[24]  Alfredo Berardelli,et al.  Bradykinesia in early and advanced Parkinson's disease , 2016, Journal of the Neurological Sciences.

[25]  M. Hallett,et al.  The Sequence Effect in De Novo Parkinson’s Disease , 2011, Journal of movement disorders.

[26]  Pablo Mir,et al.  Distinguishing SWEDDs patients with asymmetric resting tremor from Parkinson's disease: A clinical and electrophysiological study , 2010, Movement disorders : official journal of the Movement Disorder Society.

[27]  D Curran-Everett,et al.  Multiple comparisons: philosophies and illustrations. , 2000, American journal of physiology. Regulatory, integrative and comparative physiology.

[28]  A. Berardelli,et al.  Impairment of individual finger movements in Parkinson's disease , 2003, Movement disorders : official journal of the Movement Disorder Society.

[29]  N Accornero,et al.  Sequential arm movements in patients with Parkinson's disease, Huntington's disease and dystonia. , 1992, Brain : a journal of neurology.

[30]  Robert Chen,et al.  Increased motor cortical facilitation and decreased inhibition in Parkinson disease , 2013, Neurology.

[31]  U. Ziemann,et al.  Hysteresis effects on the input–output curve of motor evoked potentials , 2009, Clinical Neurophysiology.

[32]  K. Stefan,et al.  Modulation of associative human motor cortical plasticity by attention. , 2004, Journal of neurophysiology.

[33]  Francesca Morgante,et al.  Impairments of speed and amplitude of movement in Parkinson's disease: A pilot study , 2009, Movement disorders : official journal of the Movement Disorder Society.

[34]  S. Rossi,et al.  Non-invasive electrical and magnetic stimulation of the brain, spinal cord, roots and peripheral nerves: Basic principles and procedures for routine clinical and research application. An updated report from an I.F.C.N. Committee , 2015, Clinical Neurophysiology.

[35]  J. Rothwell,et al.  Functional reorganization of sensorimotor cortex in early Parkinson disease , 2012, Neurology.

[36]  S. Meunier,et al.  Early, severe and bilateral loss of LTP and LTD-like plasticity in motor cortex (M1) in de novo Parkinson’s disease , 2012, Clinical Neurophysiology.

[37]  J. Cummings,et al.  The Montreal Cognitive Assessment, MoCA: A Brief Screening Tool For Mild Cognitive Impairment , 2005, Journal of the American Geriatrics Society.

[38]  J. Rothwell,et al.  Are studies of motor cortex plasticity relevant in human patients with Parkinson’s disease? , 2016, Clinical Neurophysiology.

[39]  I Litvan,et al.  The FAB: A frontal assessment battery at bedside , 2000, Neurology.

[40]  A. Beck,et al.  An inventory for measuring depression. , 1961, Archives of general psychiatry.

[41]  Robert Chen,et al.  Differential response of speed, amplitude, and rhythm to dopaminergic medications in Parkinson's disease , 2011, Movement disorders : official journal of the Movement Disorder Society.

[42]  R. Inzelberg,et al.  Changes in excitability of motor cortical circuitry in patients with parkinson's disease , 1995, Annals of neurology.

[43]  T. Mima,et al.  Differences in Dopaminergic Modulation to Motor Cortical Plasticity between Parkinson's Disease and Multiple System Atrophy , 2013, PloS one.

[44]  J. Obeso,et al.  Compensatory mechanisms in Parkinson's disease: Circuits adaptations and role in disease modification , 2017, Experimental Neurology.

[45]  Alexander L Green,et al.  Subthalamic Nucleus Local Field Potential Activity Helps Encode Motor Effort Rather Than Force in Parkinsonism , 2015, The Journal of Neuroscience.

[46]  W. Poewe,et al.  Fatigue rating scales critique and recommendations by the Movement Disorders Society task force on rating scales for Parkinson's disease , 2010, Movement disorders : official journal of the Movement Disorder Society.

[47]  C. Clarke,et al.  Systematic review of levodopa dose equivalency reporting in Parkinson's disease , 2010, Movement disorders : official journal of the Movement Disorder Society.

[48]  M. Hallett,et al.  Pathophysiology of bradykinesia in Parkinson's disease. , 2001, Brain : a journal of neurology.

[49]  T. Mima,et al.  Altered plasticity of the human motor cortex in Parkinson's disease , 2006, Annals of neurology.

[50]  L. Cohen,et al.  A temporally asymmetric Hebbian rule governing plasticity in the human motor cortex. , 2003, Journal of neurophysiology.

[51]  M. Nitsche,et al.  Dose-Dependent Nonlinear Effect of l-DOPA on Paired Associative Stimulation-Induced Neuroplasticity in Humans , 2011, The Journal of Neuroscience.

[52]  R. Turner,et al.  Primary motor cortex of the parkinsonian monkey: altered encoding of active movement. , 2016, Brain : a journal of neurology.

[53]  A. Albanese,et al.  Validation of the Italian version of the Movement Disorder Society—Unified Parkinson’s Disease Rating Scale , 2013, Neurological Sciences.

[54]  C. Civardi,et al.  Transcranial magnetic stimulation and Parkinson’s disease , 2002, Brain Research Reviews.

[55]  H. Hotelling Relations Between Two Sets of Variates , 1936 .

[56]  Masashi Hamada,et al.  Cerebellar modulation of human associative plasticity , 2012, The Journal of physiology.

[57]  A. Antonini,et al.  EFNS/MDS‐ES recommendations for the diagnosis of Parkinson's disease , 2013, European journal of neurology.

[58]  Alastair J. Noyce,et al.  Technologies Assessing Limb Bradykinesia in Parkinson’s Disease , 2017, Journal of Parkinson's disease.

[59]  Tipu Aziz,et al.  Frequency specific activity in subthalamic nucleus correlates with hand bradykinesia in Parkinson's disease , 2013, Experimental Neurology.

[60]  E. Kunesch,et al.  Paired associative stimulation. , 2004, Supplements to Clinical neurophysiology.

[61]  Jungsu S. Oh,et al.  Neural correlates of progressive reduction of bradykinesia in de novo Parkinson's disease. , 2014, Parkinsonism & related disorders.

[62]  M. Nitsche,et al.  Dosage‐dependent non‐linear effect of l‐dopa on human motor cortex plasticity , 2010, The Journal of physiology.

[63]  A. Berardelli,et al.  Repetitive magnetic stimulation of cortical motor areas in Parkinson's disease: Implications for the pathophysiology of cortical function , 2002, Movement disorders : official journal of the Movement Disorder Society.

[64]  Tipu Aziz,et al.  Complementary roles of different oscillatory activities in the subthalamic nucleus in coding motor effort in Parkinsonism☆ , 2013, Experimental Neurology.

[65]  A. Berardelli,et al.  Lack of LTP-like plasticity in primary motor cortex in Parkinson's disease , 2011, Experimental Neurology.

[66]  P. Calabresi,et al.  Early synaptic dysfunction in Parkinson's disease: Insights from animal models , 2016, Movement disorders : official journal of the Movement Disorder Society.

[67]  D. Heldman,et al.  Clinician versus machine: reliability and responsiveness of motor endpoints in Parkinson's disease. , 2014, Parkinsonism & related disorders.

[68]  S. Meunier,et al.  Motor cortex plasticity can indicate vulnerability to motor fluctuation and high L-DOPA need in drug-naïve Parkinson's disease. , 2017, Parkinsonism & related disorders.