The functional anatomy of parkinsonian bradykinesia

Abstract

To investigate the difficulty that patients with Parkinson’s disease (PD) have in performing fast movements, we used H₂¹⁵O PET to study regional cerebral blood flow (rCBF) associated with performance of a simple predictive visuomanual tracking task at three different velocities. Tracking movements in PD patients (versus tracking with the eyes alone) were associated with a general underactivation of the areas normally activated by the task (sensorimotor cortex contralateral to the moving arm, bilateral dorsal premotor cortices, and ipsilateral cerebellum). Presupplementary motor cortex (pre-SMA) ipsilateral to the moving arm had greater than normal movement-related activations. Increasing movement velocity led to increased rCBF in multiple premotor and parietal cortical areas and basal ganglia in the patients as opposed to the few cerebral locations that are normally velocity-related. The functional correlates of PD bradykinesia are: (1) impaired recruitment of cortical and subcortical systems that normally regulate kinematic parameters of movement such as velocity; and (2) increased recruitment of multiple premotor areas including both regions specialized for visuomotor control (ventral premotor and parietal cortices) and some that are not (pre-SMA). The overactivation of cortical regions observed in patients may be functional correlates of compensatory mechanisms and/or impaired suppression as a facet of the primary pathophysiology of PD.

Introduction

In Parkinson’s disease (PD), loss of the dopaminergic innervation of the striatum results in akinesia and bradykinesia among other motor symptoms. The extent to which different symptoms arise from dissociable defects in the motor control apparatus remains a topic of debate. Resolution of the debate depends, first, on a careful definition of terms. Akinesia encompasses many aspects of motor control, from a paucity of spontaneous movement to lengthened response times under reaction time conditions, and impaired initiation of sequences of movement or simultaneous movements (Lakke, 1981). Although slowed and hypometric movement is often considered yet another aspect of akinesia (e.g., Paulson and Stern, 1997), numerous studies have shown that the severity of bradykinetic and akinetic symptoms varies independently Evarts et al 1981, Jordan et al 1992, Meyer 1982, van Hilten et al 1998. The peripheral correlate of bradykinesia is a reduction in the rate of change of agonist muscle force both for onset Corcos et al 1996, Hallett and Khoshbin 1980, Jordan et al 1992 and offset Jordan et al 1992, Kunesch et al 1995, Wing 1988 of muscle contraction. PD patients can modulate the level of force in agonist muscles, but they characteristically do so at lower rates than normals Corcos et al 1996, Stelmach et al 1989, Stelmach and Worringhan 1988, Teasdale et al 1990. Of note, PD patients with marked bradykinesia may show no abnormalities in the pattern of activation of task-related muscles (Godaux et al., 1992), or in movement accuracy when visual feedback is available (Adamovich et al., 2001). These studies indicate a clear dissociation between deficits in the planning, initiating, and sequencing of muscle activation patterns (akinesia) and the modulation of those activations to match the metrics of the task space (bradykinesia) (Berardelli et al., 2001).

Of the many functional imaging studies of PD, most have employed tasks that emphasize selection, initiation, and/or sequencing of discrete movements (i.e., correlates of akinesia). Playford et al. (1992) were the first to demonstrate, using H₂¹⁵O PET, that in parkinsonian patients there is a hypoactivation of the contralateral mesial premotor cortex (supplementary motor area, SMA) and dorsolateral prefrontal cortex relative to control subjects. Subsequent studies have corroborated and expanded upon this observation using PET Jahanshashi et al 1995, Samuel et al 1997a, Samuel et al 2001, SPECT (Rascol et al., 1992), and fMRI Haslinger et al 2001, Sabatini et al 2000. All of these used tasks that emphasize correlates of akinesia and working memory. Additional studies have shown that these hypoactivations are reduced following pharmacological Haslinger et al 2001, Jenkins et al 1992, Rascol et al 1992, ablative surgical (pallidotomy) Ceballos-Baumann et al 1994, Grafton et al 1994, Grafton et al 1995, Shima and Tanji 1998, or deep brain stimulation Davis et al 1997, Fukuda et al 2001, Limousin et al 1997 therapy. Despite the consistent picture these studies provide of the functional abnormalities in PD, the near universal reliance on one type of task has clouded our ability to distinguish between abnormalities that are specific to akinesia and abnormalities that might be characteristic of bradykinesia.

In a PET study of neurologically normal subjects (Turner et al., 1998), we found that brain activity was correlated with the velocity and/or rate of movement in a small subset of the regions that were activated with movement per se. Whereas wide areas of frontal and parietal lobes were activated with movement, rate-related activations were found only in contralateral primary motor cortex (M1) and globus pallidus, and in the ipsilateral cerebellum. Given that bradykinesia is a defect in scaling the motor command resulting in reduced movement velocity, we sought to determine if the velocity-related pattern of brain activity seen in normal subjects might be altered in PD. Reasoning that impaired activation of this velocity-related subcircuit may be the functional substrate for parkinsonian bradykinesia, we used H₂¹⁵O PET to study PD patients while they performed the same tracking task. The normal subjects used for comparison included those reported previously (Turner et al., 1998). Some of these results have been reported in preliminary form Turner et al 1996, Turner et al 2000.

Note that the term “velocity” is used here for the sake of simplicity. Many features of movement covary systematically with movement velocity and the present experiment did not attempt to dissociate these possible covariates. Thus, the term “movement velocity” should be understood as meaning movement velocity or one of its covariates.