Increased bradykinesia in Parkinson’s disease with

Authors: Rachel Moroney Ciska Heida Jan Geelen

Publish Date: 2008/07/10

Volume: 25, Issue: 3, Pages: 501-

PDF Link

Abstract

The present research investigates factors contributing to bradykinesia in the control of simple and complex voluntary limb movement in Parkinson’s disease PD patients The functional scheme of the basal ganglia BG–thalamocortical circuit was described by a mathematical model based on the mean firing rates of BG nuclei PD was simulated as a reduction in dopamine levels and a loss of functional segregation between two competing motor modules In order to compare model simulations with performed movements flexion and extension at the elbow joint is taken as a test case Results indicated that loss of segregation contributed to bradykinesia due to interference between competing modules and a reduced ability to suppress unwanted movements Additionally excessive neurotransmitter depletion is predicted as a possible mechanism for the increased difficulty in performing complex movements The simulation results showed that the model is in qualitative agreement with the results from movement experiments on PD patients and healthy subjects Furthermore based on changes in the firing rate of BG nuclei the model demonstrated that the effective mechanism of Deep Brain Stimulation DBS in STN may result from stimulation induced inhibition of STN partial synaptic failure of efferent projections or excitation of inhibitory afferent axons even though the underlying methods of action may be quite different for the different mechanismsParkinson’s disease PD is a chronic progressive disorder of the central nervous system characterised mainly by a difficulty in performing movements smoothly and fluently Bradykinesia or slowness of movement is one of the most debilitating symptoms of PD Experimental evidence indicates that bradykinesia is more pronounced in the execution of complex movements ie sequential or simultaneous motor tasks than in the execution of simple movements PD patients exhibit abnormal pauses between movement segments and a more pronounced movement time when a task is performed within a sequence of moves Suri et al 1998 Berardelli et al 2001 Several mechanisms have been proposed to explain the extra deficits observed in complex movements such as insufficient dopamine resources for multiple simultaneous movements difficulty in switching between movement segments due to impaired force control interference from competing motor programs and impaired preparation of movement sequences Agostino et al 2003 Levy et al 2002 Cutsuridis and Perantonis 2006 have developed a basal ganglia–cortico–spinal network model for control of voluntary arm movements by incorporating dopaminergic innervation of cells in the cortical and spinal components of the circuit The basal ganglia however were not included in this model The output of this system ie the activity of the internal part of the globus pallidus GPi was represented by a scaled step function that according to the authors initiates movement One of the conclusions of this study is that the disrupted basal ganglia output has the strongest effect on movement when dopamine levels are reducedIn the current study we have developed a computational model that simulates basal ganglia activity related to movement control under normal and parkinsonian conditions that may explain the increased difficulty to perform complex movements and even the requirement of a repetitive output from basal ganglia to complete the movementGeneral scheme of the BG–thalamocortical circuit showing the ‘direct’ ‘indirect’ and ‘hyperdirect’ pathways Excitatory glutamatergic projections are illustrated with a ‘+’ inhibitory GABAergic projections with a ‘−’ The projection from SNc to the striatum uses dopamine DA as a neurotransmitter and is inhibitory or excitatory depending on the striatal receptor to which it binds SNc Substantia nigra pars compacta STN subthalamic nucleus GPe and GPi external and internal part of the globus pallidus respectivelyDopaminergic neurons in the substantia nigra pars compacta SNc of the BG project mainly to the striatum The effect of dopamine DA is determined by the type of striatal receptor to which it binds DA increases the activity of the direct pathway via D1 receptors and decreases the activity of the indirect pathway via D2 receptors The net effect of DA is thus to reinforce the activation of the particular BG–thalamocortical circuit that has been initiated by the cortex Mink 1996 The primary pathological feature of PD is the degeneration of dopaminergic neurons in the SNc which upsets the critical balance between the direct and indirect pathways resulting in a reduction in transmission through the direct pathway and an increase in transmission through the indirect pathway This ultimately leads to an excessive inhibition of the thalamus by the GPi resulting in the symptoms of bradykinesiaThe preservation of body maps throughout the various nuclei of the BG suggests that the BG–thalamocortical circuit is characterised by individual parallel modules related to specific body parts spatially segregated in a somatotopic fashion Romanelli et al 2005 Strafella et al 2005 Furthermore single cell studies have shown that neurons in the BG are directionspecific Nambu et al 2002 and fire in relation to movement about a particular joint in a particular limb Teulings et al 1997 In neurodegenerative diseases a certain degree of distortion of the body maps occurs which is thought to lead to a loss of functional segregation between neurons in neighbouring modules It has been proposed that a loss of segregation may result in increased difficulty in inhibiting unwanted movements and facilitating desired movements Romanelli et al 2005 Strafella et al 2005Several computational models of the BG have been developed based on their predicted role in the control of movement Of the firing rate models that are directly related to the production of movement the main roles assigned to the BG are serial processing Albin et al 1989 De Long 1990 movement gating and velocity regulation ContrerasVidal and Stelmach 1995 and action selection Gurney et al 2001a b Focused selection of the desired motor program and inhibition of competing motor programs have also been proposed as an important role of the BG as the simultaneous activation of competing motor programs could cause inappropriate muscular cocontraction resulting in ineffective action Mink 1996 It is thought that during movement in addition to reinforcing the intended motor pattern a multitude of potentially competing motor mechanisms should be suppressed to prevent them from interfering with the intended movement

Keywords: