Parkinson's disease patients show impaired corrective grasp control and eye-hand coupling when reaching to grasp virtual objects.

The effect of Parkinson's disease (PD) on hand-eye coordination and corrective response control during reach-to-grasp tasks remains unclear. Moderately impaired PD patients (n=9) and age-matched controls (n=12) reached to and grasped a virtual rectangular object, with haptic feedback provided to the thumb and index fingertip by two 3-degree of freedom manipulanda. The object rotated unexpectedly on a minority of trials, requiring subjects to adjust their grasp aperture. On half the trials, visual feedback of finger positions disappeared during the initial phase of the reach, when feedforward mechanisms are known to guide movement. PD patients were tested without (OFF) and with (ON) medication to investigate the effects of dopamine depletion and repletion on eye-hand coordination online corrective response control. We quantified eye-hand coordination by monitoring hand kinematics and eye position during the reach. We hypothesized that if the basal ganglia are important for eye-hand coordination and online corrections to object perturbations, then PD patients tested OFF medication would show reduced eye-hand spans and impoverished arm-hand coordination responses to the perturbation, which would be further exasperated when visual feedback of the hand was removed. Strikingly, PD patients tracked their hands with their gaze, and their movements became destabilized when having to make online corrective responses to object perturbations exhibiting pauses and changes in movement direction. These impairments largely remained even when tested in the ON state, despite significant improvement on the Unified Parkinson's Disease Rating Scale. Our findings suggest that basal ganglia-cortical loops are essential for mediating eye-hand coordination and adaptive online responses for reach-to-grasp movements, and that restoration of tonic levels of dopamine may not be adequate to remediate this coordinative nature of basal ganglia-modulated function.

Reaching to proprioceptively defined targets in Parkinson's disease: effects of deep brain stimulation therapy.

Deep brain stimulation of the subthalamic nucleus (STN DBS) provides a unique window into human brain function since it can reversibly alter the functioning of specific brain circuits. Basal ganglia-cortical circuits are thought to be excessively noisy in patients with Parkinson's disease (PD), based in part on the lack of specificity of proprioceptive signals in basal ganglia-thalamic-cortical circuits in monkey models of the disease. PD patients are known to have deficits in proprioception, but the effects are often subtle, with paradigms typically restricted to one or two joint movements in a plane. Moreover, the effects of STN DBS on proprioception are virtually unexplored. We tested the following hypotheses: first, that PD patients will show substantial deficits in unconstrained, multi-joint proprioception, and, second, that STN DBS will improve multi-joint proprioception. Twelve PD patients with bilaterally implanted electrodes in the subthalamic nucleus and 12 age-matched healthy subjects were asked to position the left hand at a location that was proprioceptively defined in 3D space with the right hand. In a second condition, subjects were provided visual feedback during the task so that they were not forced to rely on proprioception. Overall, with STN DBS switched off, PD patients showed significantly larger proprioceptive localization errors, and greater variability in endpoint localizations than the control subjects. Visual feedback partially normalized PD performance, and demonstrated that the errors in proprioceptive localization were not simply due to a difficulty in executing the movements or in remembering target locations. Switching STN DBS on significantly reduced localization errors from those of control subjects when patients moved without visual feedback relative to when they moved with visual feedback (when proprioception was not required). However, this reduction in localization errors without vision came at the cost of increased localization variability.

Finger tapping movements of Parkinson's disease patients automatically rated using nonlinear delay differential equations.

Parkinson's disease is a degenerative condition whose severity is assessed by clinical observations of motor behaviors. These are performed by a neurological specialist through subjective ratings of a variety of movements including 10-s bouts of repetitive finger-tapping movements. We present here an algorithmic rating of these movements which may be beneficial for uniformly assessing the progression of the disease. Finger-tapping movements were digitally recorded from Parkinson's patients and controls, obtaining one time series for every 10 s bout. A nonlinear delay differential equation, whose structure was selected using a genetic algorithm, was fitted to each time series and its coefficients were used as a six-dimensional numerical descriptor. The algorithm was applied to time-series from two different groups of Parkinson's patients and controls. The algorithmic scores compared favorably with the unified Parkinson's disease rating scale scores, at least when the latter adequately matched with ratings from the Hoehn and Yahr scale. Moreover, when the two sets of mean scores for all patients are compared, there is a strong (r = 0.785) and significant (p<0.0015) correlation between them.

Rhythmic movement in Parkinson's disease: effects of visual feedback and medication state.

Previous studies examining discrete movements of Parkinson's disease (PD) patients have found that in addition to performing movements that were slower than those of control participants, they exhibit specific deficits in movement coordination and in sensorimotor integration required to accurately guide movements. With medication, movement speed was normalized, but the coordinative aspects of movement were not. This led to the hypothesis that dopaminergic medication more readily compensates for intensive aspects of movement (such as speed), than for coordinative aspects (such as coordination of different limb segments) (Schettino et al., Exp Brain Res 168:186-202, 2006). We tested this hypothesis on rhythmic, continuous movements of the forearm. In our task, target peak speed and amplitude, availability of visual feedback, and medication state (on/off) were varied. We found, consistent with the discrete-movement results, that peak speed (intensive aspect) was normalized by medication, while accuracy, which required coordination of speed and amplitude modulation (coordinative aspect), was not normalized by dopaminergic treatment. However, our findings that amplitude, an intensive aspect of movement, was also not normalized by medication, suggests that a simple pathway gain increase does not act to remediate all intensive aspects of movement to the same extent. While it normalized movement peak speed, it did not normalize movement amplitude. Furthermore, we found that when visual feedback was not available, all participants (PD and controls) made faster movements. The effects of dopaminergic medication and availability of visual feedback on movement speed were additive. The finding that movement speed uniformly increased both in the PD and the control groups suggests that visual feedback may be necessary for calibration of peak speed, otherwise underestimated by the motor control system.

EEG correlates of submovements.

Numerous studies on motor control in humans and primates have suggested that the Central Nervous System (CNS) generates and controls continuous movement via discrete, elementary units of movement or submovements. While most studies are based on analysis of kinematic data, investigations of neural correlates have been lacking. To fill this gap we recorded and analyzed kinematic and high-density electroencephalographic (64-channel EEG) data from three right-handed normal adults during a reaching task that required online movement corrections. Each kinematic submovement was accompanied by stereotyped scalp maps. Furthermore, the peaks of event-related potentials (ERP) recorded at electrode C1 (over contralateral motor cortex) were time-locked to kinematic submovement peaks. These results provide further evidence for the hypothesis that the CNS generates and controls continuous movement via discrete submovements. Applications include design of quantitative outcome metrics for motor disorders of neurological origin such as stroke and Parkinson's disease.

Non-monotonicity on a spatio-temporally defined cyclic task: evidence of two movement types?

We tested 23 healthy participants who performed rhythmic horizontal movements of the elbow. The required amplitude and frequency ranges of the movements were specified to the participants using a closed shape on a phase-plane display, showing angular velocity versus angular position, such that participants had to continuously control both the speed and the displacement of their forearm. We found that the combined accuracy in velocity and position throughout the movement was not a monotonic function of movement speed. Our findings suggest that specific combinations of required movement frequency and amplitude give rise to two distinct types of movements: one of a more rhythmic nature, and the other of a more discrete nature.

Deep brain stimulation of the subthalamic nucleus facilitates coordination of hand preshaping in Parkinson's disease.

Several studies have found that Parkinson's disease (PD) disrupts the organization of complex motor sequences regardless of the influence of parkinsonian medications. A clear candidate for the neural bases of such deficits, which we term "coordinative," is the failure to integrate propioceptive and visual information by cortico-striatal circuits in a timed fashion. Recent reports, however, have indicated that deep-brain stimulation of the subthalamic nucleus (STN DBS) may result in an improvement in coordinative deficits beyond the amelioration of "intensive deficits" such as bradykinesia and scaling errors. The present study examined the spatio-temporal organization underlying the shaping of the hand during reaching to grasp objects differing in shape. Six PD patients ON and OFF their STN DBS when OFF their concomitant medications and six age-matched controls participated in this study. STN DBS improved the coordination involved in preshaping the hand while grasping. We discuss these results in light of our earlier work with PD patients on and off dopamine replacement therapy.

Probabilistic reversal learning is impaired in Parkinson's disease.

In many everyday settings, the relationship between our choices and their potentially rewarding outcomes is probabilistic and dynamic. In addition, the difficulty of the choices can vary widely. Although a large body of theoretical and empirical evidence suggests that dopamine mediates rewarded learning, the influence of dopamine in probabilistic and dynamic rewarded learning remains unclear. We adapted a probabilistic rewarded learning task originally used to study firing rates of dopamine cells in primate substantia nigra pars compacta [Morris G, Nevet A, Arkadir D, Vaadia E, Bergman H (2006) Midbrain dopamine neurons encode decisions for future action. Nat Neurosci 9:1057-1063] for use as a reversal learning task with humans. We sought to investigate how the dopamine depletion in Parkinson's disease (PD) affects probabilistic reward learning and adaptation to a reversal in reward contingencies. Over the course of 256 trials subjects learned to choose the more favorable from among pairs of images with small or large differences in reward probabilities. During a subsequent otherwise identical reversal phase, the reward probability contingencies for the stimuli were reversed. Seventeen PD patients of mild to moderate severity were studied off of their dopaminergic medications and compared to 15 age-matched controls. Compared to controls, PD patients had distinct pre- and post-reversal deficiencies depending upon the difficulty of the choices they had to learn. The patients also exhibited compromised adaptability to the reversal. A computational model of the subjects' trial-by-trial choices demonstrated that the adaptability was sensitive to the gain with which patients weighted pre-reversal feedback. Collectively, the results implicate the nigral dopaminergic system in learning to make choices in environments with probabilistic and dynamic reward contingencies.

Dopamine replacement therapy does not restore the ability of Parkinsonian patients to make rapid adjustments in motor strategies according to changing sensorimotor contexts.

The ability of dopamine replacement to restore rapid motor adjustments in Parkinson's disease (PD) was investigated. Medicated and non-medicated patients performed finger-to-nose movements while simultaneously bending the trunk forward, without vision. Trunk motion was blocked unexpectedly, necessitating rapid adjustments in arm trajectories. Patients exhibited irregular hand paths, plateaus in hand velocity, and prolonged movement times, which were significantly greater in perturbed trials. Medication improved kinematics but perturbation-induced disturbances persisted and did not approximate the levels of non-perturbed trials nor those of controls. Dopaminergic replenishment in PD may therefore have limited restorative benefits for rapid context-specific motor control.

Deficits in adaptive upper limb control in response to trunk perturbations in Parkinson's disease.

The ability of patients with Parkinson's disease (PD) to compensate for unexpected perturbations remains relatively unexplored. To address this issue PD subjects were required to compensate at the arm for an unexpected mechanical perturbation of the trunk while performing a trunk-assisted reach. Twelve healthy and nine PD subjects (off medication) performed trunk-assisted reaching movements without vision or knowledge of results to a remembered target in the ipsilateral (T1) or contralateral (T2) workspace. On 60% of the trials trunk motion was unrestrained (free condition). On the remaining 40% of randomly selected trials trunk motion was arrested at movement onset (blocked condition). If subjects appropriately changed arm joint angles to compensate for the trunk arrest, there should be spatial and temporal invariance in the hand trajectories and in the endpoint errors across conditions. The control group successfully changed their arm configuration in a context-dependent manner which resulted in invariant hand trajectory profiles across the free and blocked conditions. More so, they initiated these changes rapidly after the trunk perturbation (group mean 70 ms). Some PD subjects were unable to maintain invariant hand paths and movement errors across conditions. Their hand velocity profiles were also more variable relative to those of the healthy subjects in the blocked-trunk trials but not in the free-trunk trials. Furthermore, the latency of compensatory changes in arm joint angles in movements toward T1 was longer in the PD group (group mean 153 ms). Finally, PD subjects' arm and trunk were desynchronized at movement onset, confirming our previous findings and consistent with PD patients' known problems in the sequential or parallel generation of different movement components. The findings that individual PD subjects were unsuccessful or delayed in producing context-dependent responses at the arm to unexpected perturbations of the trunk suggests that the basal ganglia are important nodes in the organization of adaptive behavior.

A virtual reality based exercise system for hand rehabilitation post-stroke: transfer to function.

We present preliminary results from a virtual reality (VR)-based system for hand rehabilitation that uses a CyberGlove and a Rutgers Master II-ND haptic glove. This system trains finger range of motion, finger flexion speed, independence of finger motion and finger strength. Eight chronic post-stroke subjects participated. In keeping with variability in both the lesion site and in initial upper extremity function, each subject showed improvement on a unique combination of movement parameters in VR training. These improvements transferred to gains on clinical tests, as well as to significant reductions in task completion times for the prehension of real objects. These results are indicative of the potential feasibility of this exercise system for rehabilitation in patients with hand dysfunction resulting from neurological impairment.

Arm-trunk coordination in the absence of proprioception.

During trunk-assisted reaching to targets placed within arm's length, the influence of trunk motion on the hand trajectory is compensated for by changes in the arm configuration. The role of proprioception in this compensation was investigated by analyzing the movements of 2 deafferented and 12 healthy subjects. Subjects reached to remembered targets (placed approximately 80 degrees ipsilateral or approximately 45 degrees contralateral to the sagittal midline) with an active forward movement of the trunk produced by hip flexion. In 40% of randomly selected trials, trunk motion was mechanically blocked. No visual feedback was provided during the experiment. The hand trajectory and velocity profiles of healthy subjects remained invariant whether or not the trunk was blocked. The invariance was achieved by changes in arm interjoint coordination that, for reaches toward the ipsilateral target, started as early as 50 ms after the perturbation. Both deafferented subjects exhibited considerable, though incomplete, compensation for the effects of the perturbation. Compensation was more successful for reaches to the ipsilateral target. Both deafferented subjects showed invariance between conditions (unobstructed or blocked trunk motion) in their hand paths to the ipsilateral target, and one did to the contralateral target. For the other deafferented subject, hand paths in the two types of trials began to deviate after about 50% into the movement, because of excessive elbow extension. In movements to the ipsilateral target, when deafferented subjects compensated successfully, the changes in arm joint angles were initiated as early as 50 ms after the trunk perturbation, similar to healthy subjects. Although the deafferented subjects showed less than ideal compensatory control, they compensated to a remarkably large extent given their complete loss of proprioception. The presence of partial compensation in the absence of vision and proprioception points to the likelihood that not only proprioception but also vestibulospinal pathways help mediate this compensation.

Virtual reality-based post-stroke hand rehabilitation.

A VR-based system using a CyberGlove and a Rutgers Master II-ND haptic glove was used to rehabilitate four post-stroke patients in the chronic phase. Each patient had to perform a variety of VR exercises to reduce impairments in their finger range of motion, speed, fractionation and strength. Patients exercised for about two hours per day, five days a week for three weeks. Results showed that three of the patients had gains in thumb range (50-140%) and finger speed (10-15%) over the three weeks trial. All four patients had significant improvement in finger fractionation (40-118%). Gains in finger strength were modest, due in part to an unexpected hardware malfunction. Two of the patients were measured against one-month post intervention and showed good retention. Evaluation using the Jebsen Test of Hand Function showed a reduction of 23-28% in time completion for two of the patients (the ones with the higher degrees of impairment). A prehension task was performed 9-40% faster for three of the patients after the intervention illustrating transfer of their improvement to a functional task.

Virtual reality-enhanced stroke rehabilitation.

A personal computer (PC)-based desktop virtual reality (VR) system was developed for rehabilitating hand function in stroke patients. The system uses two input devices, a CyberGlove and a Rutgers Master II-ND (RMII) force feedback glove, allowing user interaction with a virtual environment. This consists of four rehabilitation routines, each designed to exercise one specific parameter of hand movement: range, speed, fractionation or strength. The use of performance-based target levels is designed to increase patient motivation and individualize exercise difficulty to a patient's current state. Pilot clinical trials have been performed using the above system combined with noncomputer tasks, such as pegboard insertion or tracing of two-dimensional (2-D) patterns. Three chronic stroke patients used this rehabilitation protocol daily for two weeks. Objective measurements showed that each patient showed improvement on most of the hand parameters over the course of the training. Subjective evaluation by the patients was also positive. This technical report focuses on this newly developed technology for VR rehabilitation.

Automatic orienting of visuospatial attention in Parkinson's disease.

The basal ganglia are involved in not only motor behavior, but also other more cognitive processes, such as attention. We tested Parkinson's disease (PD) patients in a task that measures reflexive orienting of spatial attention. Seven patients with idiopathic PD and eight control subjects performed a covert orienting task where spatial attention was directed by means of exogenous cues (luminance increments) with no predictive validity for target position. The subjects' task was to make a speeded saccade to a visual target, which appeared a variable time after onset of the cue either in the cued or an uncued spatial position. There was no overall difference between PD patients and control subjects in terms of the initial facilitation following reflexive cues, and later inhibition of return (IOR). However, PD patients differed from control subjects in two important respects. First, they were significantly faster than were control subjects on this reflexive visual-orienting task. Second, disease severity correlated with attentional performance; more advanced patients showed less initial facilitation but greater IOR. Thus PD patients show better performance on a reflexive saccade task and, for more advanced patients, greater IOR than control subjects. These findings are consistent with the possibility that reflexive attentional processes in PD patients may be more active.

The interaction of visual and proprioceptive inputs in pointing to actual and remembered targets in Parkinson's disease.

We previously reported that Parkinson's disease patients could point with their eyes closed as accurately as normal subjects to targets in three-dimensional space that were initially presented with full vision. We have now further restricted visual information in order to more closely examine the individual and combined influences of visual information, proprioceptive feedback, and spatial working memory on the accuracy of Parkinson's disease patients. All trials were performed in the dark. A robot arm presented a target illuminated by a light-emitting diode at one of five randomly selected points composing a pyramidal array. Subjects attempted to "touch" the target location with their right finger in one smooth movement in three conditions: dark, no illumination of arm or target during movement; movement was to the remembered target location after the robot arm retracted; finger, a light-emitting diode on the pointing fingertip was visible during the movement but the target was extinguished; again, movement was to the remembered target location; and target, the target light-emitting diode remained in place and visible throughout the trial but there was no vision of the arm. In the finger condition, there is no need to use visual-proprioceptive integration, since the continuously visualized fingertip position can be compared to the remembered location of the visual target. In the target condition, the subject must integrate the current visible target with arm proprioception, while in the dark condition, the subject must integrate current proprioception from the arm with the remembered visual target. Parkinson's disease patients were significantly less accurate than controls in both the dark and target conditions, but as accurate as controls in the finger condition. Parkinson's disease patients, therefore, were selectively impaired in those conditions (target and dark) which required integration of visual and proprioceptive information in order to achieve accurate movements. In contrast, the patients' normal accuracy in the finger condition indicates that they had no substantial deficits in their relevant spatial working memory. Final arm configurations were significantly different in the two subject groups in all three conditions, even in the finger condition where mean movement endpoints were not significantly different. Variability of the movement endpoints was uniformly increased in Parkinson's disease patients across all three conditions. The current study supports an important role for the basal ganglia in the integration of proprioceptive signals with concurrent or remembered visual information that is needed to guide movements. This role can explain much of the patients' dependence on visual information for accuracy in targeted movements. It also underlines what may be an essential contribution of the basal ganglia to movement, the integration of afferent information that is initially processed through multiple, discrete modality-specific pathways, but which must be combined into a unified and continuously updated spatial model for effective, accurate movement.

Hand trajectory invariance in reaching movements involving the trunk.

Movements of different body segments may be combined in different ways to achieve the same motor goal. How this is accomplished by the nervous system was investigated by having subjects make fast pointing movements with the arm in combination with a forward bending of the trunk that was unexpectedly blocked in some trials. Subjects moved their hand above the surface of a table without vision from an initial position near the midline of the chest to remembered targets placed within the reach of the arm in either the ipsi- or contralateral workspace. In experiment 1, subjects were instructed to make fast arm movements to the target without corrections whether or not the trunk was arrested. Only minor changes were found in the hand trajectory and velocity profile in response to the trunk arrest, and these changes were seen only late in the movement. In contrast, the patterns of the interjoint coordination substantially changed in response to the trunk arrest, suggesting the presence of compensatory arm-trunk coordination minimizing the deflections from the hand trajectory regardless of whether the trunk is recruited or mechanically blocked. Changes in the arm interjoint coordination in response to the trunk arrest could be detected kinematically at a minimal latency of 50 ms. This finding suggests a rapid reflex compensatory mechanism driven by vestibular and/or proprioceptive afferent signals. In experiment 2, subjects were required, as soon as they perceived the trunk arrest, to change the hand motion to the same direction as that of the trunk. Under this instruction, subjects were able to initiate corrections only after the hand approached or reached the final position. Thus, centrally mediated compensatory corrections triggered in response to the trunk arrest were likely to occur too late to maintain the observed invariant hand trajectory in experiment 1. In experiment 3, subjects produced similar pointing movements, but to a target that moved together with the trunk. In these body-oriented pointing movements, the hand trajectories from trials in which the trunk was moving or arrested were substantially different. The same trajectories represented in a relative frame of reference moving with the trunk were virtually identical. We conclude that hand trajectory invariance can be produced in an external spatial (experiment 1) or an internal trunk-centered (experiment 3) frame of reference. The invariance in the external frame of reference is accomplished by active compensatory changes in the arm joint angles nullifying the influence of the trunk motion on the hand trajectory. We suggest that to make a transition to the internal frame of reference, control systems suppress this compensation. One of the hypotheses opened to further experimental testing is that the integration of additional (trunk) degrees of freedom into movement is based on afferent (proprioceptive, vestibular) signals stemming from the trunk motion and transmitted to the arm muscles.

Procedural motor learning in Parkinson's disease.

We have been investigating motor control and learning in parkinsonian subjects. In the current study, we sought to explore the existence of deficits in procedural motor learning, which is a form of implicit motor learning where skill improves over repetitive blocks of trials. We sought to determine, in particular, whether any such deficit is accentuated during specific types or phases of learning. We would expect that those specific learning tasks would require the greatest participation of the basal ganglia. Numerous studies have found that Parkinson's disease (PD) patients may show deficits in learning. Combined with information about basal ganglia neuronal connections and activity, this led some investigators to suggest that one of the key functions of the basal ganglia is to facilitate learning. To investigate these learning deficits, we used a robotic device to generate conservative force fields that disturbed the subjects' arm movements, thereby generating a "virtual mechanical environment" that subjects learned to manipulate. Movements were successively grouped into blocks comprising five different conditions: motor performance, early learning, late learning, negative transfer, and aftereffect motor performance. Our results with eight right-handed PD subjects and nine age-matched controls showed a relative decrease in the rate of learning for the PD patients in all blocks, but greater differences emerged between groups during novelty phases of learning. In particular, the difference in performance during the negative transfer condition reached statistical significance, suggesting that the basal ganglia might be a key center for "switching" motor patterns. Our results support the hypothesis that deficiencies in procedural motor learning are characteristic of PD. They add to existing evidence which has suggested a key role for the basal ganglia when new sensorimotor mappings are required by novel task environments. Better understanding of these deficits should facilitate the rehabilitation of PD patients.

The timing of arm-trunk coordination is deficient and vision-dependent in Parkinson's patients during reaching movements.

The role of the basal ganglia in the coordination of different body segments and utilization of motor synergies was investigated by analyzing reaching movements to remembered three-dimensional (3D) targets in patients with Parkinson's disease (PD). Arm movements were produced alone or in combination with a forward bending of the trunk, with or without visual feedback. Movements in PD patients were more temporally segmented, as evidenced by irregular changes in tangential velocity profiles. In addition, the relative timing in the onsets and offsets of fingertip and trunk motions were substantially different in PD patients than in control subjects. While the control subjects synchronized both onsets and offsets, the PD patients had large mean intervals between the onsets and offsets of the fingertip and trunk motions. Moreover, PD patients showed substantially larger trial-to-trial variability in these intervals. The degree of synchronization in PD patients gradually increased during the movement under the influence of visual feedback. The mean and variability of the intersegmental intervals decreased as the fingertip approached the target. This improvement in timing occurred even though the separate variability in the timing of arm and trunk motions was not reduced by vision. In combined movements, even without vision, the PD patients were able to achieve normal accuracy, suggesting they were able to use the same movement synergies as normals to control the multiple degrees of freedom involved in the movements and to compensate for the added trunk movement. However, they were unable to recruit these synergies in the stereotyped manner characteristic of healthy subjects. These results suggest that the basal ganglia are involved in the temporal coordination of movement of different body segments and that related timing abnormalities may be partly compensated by vision. Abnormal intersegmental timing may be a highly sensitive indicator of a deficient ability to assemble complex movements in patients with basal-ganglia dysfunction. This abnormality may be apparent even when the overall movement goal of reaching a target is preserved and normal movement synergies appear to be largely intact.

A novel quantitative method for 3D measurement of Parkinsonian tremor.

OBJECTIVE: To demonstrate the usefulness of a three dimensional (3D) motion analysis system for the quantitative measurement of tremor in patients with Parkinson's disease (PD). METHODS: Six PD patients with hand tremors were studied using a system that employed 3D electromagnetic position sensors to measure the actual, cumulative displacement of the tremoring finger. Patients were studied in different hand positions and activating conditions before and 30, 60, 90 and 120 min after intake of Pramipexole, a dopamine agonist known to reduce tremor. Tremor amplitude and frequency, before and after drug intake, were compared using Mann-Whitney U test and Wilcoxon rank test, respectively. RESULTS: The motion analysis system allowed discrimination of tremor related events from movement artifact and allowed the calculation of real world movement of the finger tremor despite altered hand positions and orientation. Average 3D tremor frequency ranged from 3.71 to 4.34 Hz. Median tremor amplitude (total distance traveled per 5 s interval) decreased with drug from 4.9 to 1.6 cm for resting tremor, 4.5 to 3.7 cm for postural tremor, 3.4 to 3.3 cm for precision tremor, 10.2 to 3.3 cm for tapping activation and 108.6 to 5.7 cm for counting activation. CONCLUSIONS: Our method of 3D analysis provides a robust, single quantitative measure of tremor amplitude that is intuitive and likely to reflect the functional impact of tremor. This methodology should be useful in comparing tremor across patients and in measuring the efficacy of therapeutic interventions.