Improvement In Bradykinesia Research Articles

15.6 Anticipatory postural adjustments during shoulder flexion in Parkinson's disease and influence of levodopa

Objectives: Indications of the functional neurosurgical treatments become more and more numerous, however, few methods were used to study the mechanism of action and some discrepancies came to light. We assessed the influence of internal globus pallidus (GPI) stimulation and l-Dopa on cortical activation during the preparation and execution phases of the movement compared to clinical improvement of Parkinson's disease.Methods: We recorded the movement-related cortical potential and movement-related desynchronization.Results: The Unified Parkinson's Disease Rating Scale was improved by 46% under stimulation and 64% under stimulation with l-Dopa. Premovement desynchronization was significantly increased on central contralateral derivation under stimulation with l-Dopa and decreased on frontocentral ipsilateral derivation under stimulation with and without l-Dopa. Movement desynchronization was improved on the contralateral motor cortex under stimulation with and without l-Dopa (benefit correlated with bradykinesia improvement). The movement-related postmotor potential was significantly increased under stimulation with l-Dopa.Conclusions: GPI stimulation alone influenced the premotor cortex activation during the planning and induced a selective and focal effect on the organisation of motor cortical activity during the movement execution which may explain bradykinesia improvement. The motor cortex activation improvement under stimulation with l-Dopa concerned both the movement preparation and execution but remained very localised to the contralateral motor cortex.

Subthalamic nucleus stimulation modulates motor cortex oscillatory activity in Parkinson's disease.

In Parkinson's disease, impaired motor preparation has been related to an increased latency in the appearance of movement-related desynchronization (MRD) throughout the contralateral primary sensorimotor (PSM) cortex. Internal globus pallidus (GPi) stimulation improved movement desynchronization over the PSM cortex during movement execution but failed to improve impaired motor preparation. PET studies indicate that subthalamic nucleus (STN) stimulation partly reverses the abnormal premotor pattern of brain activation during movement. By monitoring MRD, we aimed to assess changes in premotor and PSM cortex oscillatory activity induced by bilateral STN stimulation and to compare these changes with those induced by l-dopa. Ten Parkinson's disease patients and a group of healthy, age-matched controls performed self-paced wrist flexions in each of four conditions: without either stimulation or l-dopa (the 'off' condition), with stimulation and without l-dopa (On Stim), with l-dopa and without stimulation ('on drug'), and with both stimulation and l-dopa (On Both). Compared with the Off condition, in both the On Stim and the On Drug condition the Unified Parkinson's Disease Rating Scale (UPDRS) III score decreased by about 60% and in the On Both condition it decreased by 80%. The desynchronization latency over central regions contralateral to movement and the movement desynchronization over bilateral central regions were significantly increased by stimulation and by l-dopa, with a maximal effect when the two were associated. Furthermore, desynchronization latency significantly decreased over bilateral frontocentral regions in the three treatment conditions compared with the Off condition. In Parkinson's disease, STN stimulation may induce a change in abnormal cortical oscillatory activity patterns (similar to that produced by l-dopa) by decreasing the abnormal spreading of desynchronization over frontocentral regions and increasing PSM cortex activity during movement preparation and execution, with a correlated improvement in bradykinesia. Parkinsonians under treatment displayed a desynchronization pattern close to that seen in healthy, age-matched controls, although central latencies remained shorter. The study indicates that it is possible to influence cortical reactivity related to the planning and execution of voluntary movement through the basal ganglia, and furthermore that the oscillatory activity of the PSM cortex (in addition to that of premotor areas) could be of major importance in the control of movement-associated, neural activity in Parkinson's disease.

Cerebral blood flow changes induced by subthalamic stimulation in Parkinson's disease.

The authors used PET to show that the abnormal pattern of cerebral blood flow (CBF) activation described in PD is normalized by electrical stimulation of subthalamic nucleus. Improvement in bradykinesia correlated with increase in CBF due to stimulation in the supplementary motor area and anterior cingulate cortex. Compared to unilateral stimulation, bilateral stimulation induced a greater extent of activation in bilateral cortical areas and additional bilateral activation of globus pallidus.

Lidocaine and muscimol microinjections in subthalamic nucleus reverse Parkinsonian symptoms.

Inactivation of neurones in the subthalamic nucleus (STN) of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treated monkey model of Parkinson's disease has been shown to relieve parkinsonian motor symptoms. In patients with Parkinson's disease, neurones in the STN display hyperactive firing rates and rhythmic discharge activity such as tremor-related oscillations (3-8 Hz) and synchronous high-frequency oscillations (15-30 Hz). In this study, microinjections of lidocaine (n = 4) and muscimol, a GABA(A) receptor agonist (n = 2), were performed in the STN of six patients with Parkinson's disease to determine whether the focal suppression of STN neuronal activity can lead to an improvement in tremor, bradykinesia and rigidity. We also report the first use of microelectrode recording of the effects of microinjections on neuronal activity in the human brain (n = 2). Microinjections of 10-23 microl of lidocaine produced striking improvements in bradykinesia, limb tremor and rigidity in three out of three patients. These improvements were correlated with good therapeutic effects of subsequent STN deep brain stimulation performed in the same microelectrode trajectories as these injections. The most dramatic observation following lidocaine injections was the appearance of dyskinetic limb movements. In one patient, simultaneous microelectrode recording during an injection of 3.5 microl of lidocaine demonstrated a suppression of neuronal activity at distances of < 0.9 mm from the injection site, but no suppression was observed at > or = 1.2 mm from the injection site. Microinjections of 5-10 microl of muscimol in a region with tremor-related activity resulted in suppression of limb tremor in two out of two patients. Interestingly, in one of these patients, 4 Hz oscillatory activity was diminished in a neurone recorded 1.3 mm from the injection site, but there was no reduction in the mean firing rate or 20 Hz oscillatory activity. These results demonstrate that inactivation of neuronal activity in the STN of patients with Parkinson's disease improves motor symptoms. These findings also suggest that a focal block of the STN might alter the oscillatory activity of neurones located beyond the inhibited region.

Electrical stimulation of the prelemniscal radiation in the treatment of Parkinson's disease: an old target revised with new techniques.

In the treatment of tremor and rigidity in patients with Parkinson's disease (PD), the prelemniscal radiation (RAPRL), a subthalamic bundle of fibers, is an exquisite target that can be visualized easily on ventriculograms. We sought to evaluate the effect of electrical stimulation of the RAPRL on symptoms and signs of PD in a long-term trial and to determine the localization of the stimulated area by means of stereotactic magnetic resonance imaging studies. Ten patients with PD predominantly on one side had tetrapolar electrodes stereotactically oriented through a frontal parasagittal approach to the RAPRL contralateral to the most prominent symptoms. Preoperative and postoperative evaluations at 3, 6, 9, and 12 months after surgery were performed using conventional PD scales and quantitative evaluations of tremor amplitude and reaction time. Stereotactic high-resolution magnetic resonance imaging studies with the electrodes in place were used for anatomic localization. In all patients, temporary suppression of tremor occurred when the electrodes reached the target. The most effective stimulation was obtained when the pair of contacts was placed in the RAPRL. Long-term stimulation at 130 Hz, 0.09 to 0.450 milliseconds, and 1.5 to 3.0 V produced significant improvement in tremor and rigidity and mild improvement in bradykinesia. The RAPRL is an effective target for the alleviation of tremor and rigidity in patients with PD by either lesioning or neuromodulation; however, neuromodulation has the advantage of not inducing an increase in bradykinesia. The stimulated area seems to be independent of the subthalamic nucleus.

Intermuscular coherence in Parkinson's disease: relationship to bradykinesia.

We hypothesised that bradykinesia may be partly due to the failure of the corticomuscular system to engage in high frequency oscillatory activity in Parkinson's disease (PD). In healthy subjects such oscillations are evident in coherence between active muscles at 15--30 Hz. We therefore investigated the effects of therapeutic stimulation of the basal ganglia on this coherence and related it to changes in bradykinesia in the contralateral arm. Increases in coherence at 15--30 Hz and improvements in bradykinesia upon stimulation were correlated (r = 0.564, p < 0.001). This suggests that the basal ganglia modulate oscillatory activity in the corticomuscular system and that impairment of the motor system's ability to engage in synchronised oscillations at high frequency may contribute to bradykinesia in PD.

Assessments of axial motor control during deep brain stimulation in parkinsonian patients.

We tested the hypothesis that bilateral deep brain stimulation (DBS) in the globus pallidus internus or the subthalamic nucleus improves various components of postural and oromotor function and that some of the components correlate with changes in the Unified Parkinson's Disease Rating Scale (UPDRS) in patients with Parkinson's disease. Six patients with Parkinson's disease were evaluated for four postural and two orofacial UPDRS items, and quantitative tests of posture adjustments and oromotor control were performed while the patients were on and off DBS. Measurements of postural adjustments included reactive force and latency before a voluntary step. The oromotor assessments involved velocity and amplitude changes during voluntary jaw movement. DBS significantly improved the total UPDRS motor score by an average of 44%, which included improvement of 18 to 54% in the postural and orofacial items. DBS also decreased foot lift-off latency significantly, but it produced a variable response to the preparatory postural force in the swing limb. DBS significantly improved jaw-opening velocity by 14 to 50% and jaw opening amplitude by 5 to 41%. Significant correlations for the percentage change from off and on DBS occurred among a few UPDRS items and foot lift-off latency and jaw-opening velocities. DBS in either the globus pallidus internus or the subthalamic nucleus induces improvements in bradykinesia of specific components of postural and oromotor control, which also can be measured by the postural and orofacial UPDRS items. In some Parkinson's disease patients, DBS results in improvements in force or amplitude control, although these changes are not reflected in changes in UPDRS postural and orofacial items. A battery of quantitative and clinical tests must be used to evaluate the effects of DBS on axial motor control adequately.

Gamma Knife Treatment for Movement Disorders

In this chapter the author describes his experience and that of others in the use of the Gamma Knife (Gamma Knife is a registered trademark of Elekta, Inc., Norcross, GA, USA) radiosurgical instrument to make lesions in the ventral intermediate thalamic nucleus to treat tremor of a variety of causes or in the internal segment of the globus pallidus to treat rigidity, bradykinesia, and L-dopa-induced dyskinesias in Parkinsonian patients. Patient selection for gamma knife procedures to treat movement disorders is similar to that for radiofrequency thalamotomy or deep brain stimulation except that patients of advanced age, those with other serious medical illnesses, and those utilizing anticoagulants may be treated safely with the Gamma Knife. Between 85 and 90% of patients with Parkinsonian tremor or essential tremor are rendered either tremor-free or nearly so following radiosurgical thalamotomy. These improvements are maintained in patients who have been followed between 4 and 8 years after the procedures. About 50% of patients with tremors of other origins may be improved although complete freedom from tremor has not been identified. Significant improvements in bradykinesia and rigidity occur in Parkinsonian patients, particularly in the ``off'' state, following radiosurgical pallidotomy. More than 85% of patients are rendered free of L-dopa-induced dyskinesias following radiosurgical pallidotomy. These improvements are maintained in patients followed more than 4 years after the procedures. Only 5 patients of more than 300 treated (1.7%) developed any side effects from the procedures. Radiosurgical thalamotomy and pallidotomy are effective and safe procedures for the treatment of movement disorders. For patients who take chronic anticoagulants, they may be the only form of surgical therapy available. Radiosurgical procedures are as effective as radiofrequency procedures or deep brain stimulation procedures and should be considered and presented as surgical options to patients who are surgical candidates for the treatment of movement disorders.

Voluntary movement after pallidotomy in severe Parkinson's disease.

The mechanisms of improvement in parkinsonian bradykinesia after posteroventral pallidotomy were investigated in 17 patients undergoing unilateral pallidotomy for severe Parkinson's disease. Clinical ratings of 'off' period bradykinesia demonstrated a maximal improvement of 22% 3 months postoperatively. Kinematic assessments of rapid repetitive finger and sequential arm movements were performed after overnight withdrawal of antiparkinsonian medications. There was a bilateral reduction in the inter-onset latency of a two-stage sequential arm movement and a contralateral increase in speed of arm movement after pallidotomy. There was no significant improvement postoperatively in the rhythm, amplitude or speed of repetitive finger movements. The results confirm the clinical impression that pallidotomy improves bradykinesia. This was more evident for complex limb movements, which used attentional strategies and external (visual and auditory) cues, than for repetitive fingertapping movements, which were largely internally generated. Since ablation of the pallidum can only reduce inhibitory pallidal outflow, it is unlikely to restore the normal pallidal influence on thalamocortical motor circuits. Therefore, any improvement in bradykinesia after pallidotomy must be related to mechanisms other than restoration of pallidothalamocortical connectivity. Based on the above observations, we suggest that some of the changes in motor control may be explained by the greater efficacy of external cues in facilitating movement after withdrawal of the abnormal pallidal discharge.

Bradykinesia and impairment of EEG desynchronization in Parkinson's disease.

It has been suggested that the basal ganglia control the release of cortical elements from low-frequency rhythmic idling activity during voluntary movement. This hypothesis was tested by recording the local idling rhythms of the motor cortex, the alpha and beta rhythms, in 12 untreated and treated patients with Parkinson's disease as they moved a wrist. Recordings were made after overnight withdrawal of medication and again 1 hr after levodopa. The treatment-related attenuation of the alpha and beta rhythms picked up over the cortical motor areas contralateral to the active arm correlated with the improvement in size and speed of movement effected by levodopa. The distribution and degree of attenuation depended on the complexity of the task. These results demonstrate for the first time a specific effect of levodopa on the organization of motor cortical activity in the frequency domain, an effect that correlates with improvements in bradykinesia.

Pallidotomy with the Gamma Knife: A Positive Experience

51 patients with medically refractory Parkinson’s disease underwent stereotactic posteromedial pallidotomy between August 1993 and February 1997 for treatment of bradykinesia, rigidity, and L-DOPA-induced dyskinesias. In 29 patients, the pallidotomies were performed with the Leksell Gamma Knife and in 22 they were performed with the standard radiofrequency (RF) method. Clinical assessment as well as blinded ratings of Unified Parkinson’s Disease Rating Scale (UPDRS) scores were carried out pre- and postoperatively. Mean follow-up time is 20.6 months (range 6–48) and all except 4 patients have been followed more than one year. 85 percent of patients with dyskinesias were relieved of symptoms, regardless of whether the pallidotomies were performed with the Gamma Knife or radiofrequency methods. About 2/3 of the patients in both Gamma Knife and radiofrequency groups showed improvements in bradykinesia and rigidity, although when considered as a group neither the Gamma Knife nor the radiofrequency group showed statistically significant improvements in UPDRS scores. One patient in the Gamma Knife group (3.4%) developed a homonymous hemianopsia 9 months following treatment and 5 patients (27.7%) in the radiofrequency group became transiently confused postoperatively. No other complications were seen. Gamma Knife pallidotomy is as effective as radiofrequency pallidotomy in controlling certain of the symptoms of Parkinson’s disease. It may be the only practical technique available in certain patients, such as those who take anticoagulants, have bleeding diatheses or serious systemic medical illnesses. It is a viable option for other patients as well.

Gamma knife radiosurgery as a lesioning technique in movement disorder surgery.

To increase knowledge of the safety and efficacy of the use of gamma knife radiosurgery in patients with movement disorders, the authors describe their own experience in this field and include blinded independent assessments of their results. Fifty-five patients underwent radiosurgical placement of lesions either in the thalamus (27 patients) or globus pallidus (28 patients) for treatment of movement disorders. Patients were evaluated pre- and postoperatively by a team of observers skilled in the assessment of gait and movement disorders who were blinded to the procedure performed. The observers were not associated with the surgical team and concomitantly and blindly also assessed a group of 11 control patients with Parkinson's disease who did not undergo any surgical procedures. All stereotactic lesions were made with the Leksell gamma unit using the 4-mm secondary collimator helmet and a single isocenter with maximum doses from 120 to 160 Gy. Clinical follow-up evaluation indicated that 88% of patients who underwent thalamotomy became tremor free or nearly tremor free. Statistically significant improvements in performance were noted in the independent assessments of Unified Parkinson's Disease Rating Scale (UPDRS) scores in the patients undergoing thalamotomy. Of patients undergoing pallidotomy who had exhibited levodopainduced dyskinesias, 85.7% had total or near-total relief of that symptom. Clinical assessment indicated improvements in bradykinesia and rigidity in 64.3% of patients who underwent pallidotomy. Independent blinded assessments did not reveal statistically significant improvements in Hoehn and Yahr scores or UPDRS scores. On the other hand, 64.7% of patients showed improvements in subscores of the UPDRS, including activities of daily living (58%), total contralateral score (58%), and contralateral motor scores (47%). Total ipsilateral score and ipsilateral motor scores were both improved in 59% of patients. One (1.8%) of 55 patients experienced a homonymous hemianopsia 9 months after pallidotomy due to an unexpectedly large lesion. No other complications of any kind were seen. Neuropsychological test scores that were obtained for the combined pallidotomy and thalamotomy treatment groups preoperatively and at 6 months postoperatively demonstrated an absence of cognitive morbidity. Follow-up neuroimaging confirmed correct lesion location in all patients, with a mean maximum deviation from the planned target of 1 mm in the vertical axis. Measurements of lesions at regular intervals on postoperative magnetic resonance images demonstrated considerable variability in lesion volumes. The safety and efficacy of functional lesions made with the gamma knife appear to be similar to those made with the assistance of electrophysiological guidance with open functional stereotactic procedures. Functional lesions may be made safely and accurately using gamma knife radiosurgical techniques. The efficacy is equivalent to that reported for open techniques that use radiofrequency lesioning methods with electrophysiological guidance. Complications are very infrequent with the radiosurgical method. The use of functional radiosurgical lesioning to treat movement disorders is particularly attractive in older patients and in those with major systemic diseases or coagulopathies; its use in the general movement disorder population seems reasonable as well.

Gamma knife radiosurgery as a lesioning technique in movement disorder surgery

Fifty-five patients underwent radiosurgical placement of lesions either in the thalamus (27 patients) or globus pallidus (28 patients) for treatment of movement disorders. Patients were evaluated pre- and postoperatively by a team of observers skilled in the assessment of gait and movement disorders who were blinded to the procedure performed. They were not associated with the surgical team and concomitantly and blindly also assessed a group of 11 control patients with Parkinson's disease who did not undergo any surgical procedures. All stereotactic lesions were made with the Leksell gamma unit using the 4-mm secondary collimator helmet and a single isocenter with dose maximums from 120 to 160 Gy. Clinical follow-up evaluation indicated that 88% of patients who underwent thalamotomy became tremor free or nearly tremor free. Statistically significant improvements in performance were noted in the independent assessments of Unified Parkinson's Disease Rating Scale (UPDRS) scores in the patients undergoing thalamotomy. Eighty-five and seven-tenths percent of patients undergoing pallidotomy who had exhibited levodopa-induced dyskinesias had total or near-total relief of that symptom. Clinical assessment indicated improvement of bradykinesia and rigidity in 64.3% of patients who underwent pallidotomy. Independent blinded assessments did not reveal statistically significant improvements in Hoehn and Yahr scores or UPDRS scores. On the other hand, 64.7% of patients showed improvements in subscores of the UPDRS, including activities of daily living (58%), total contralateral score (58%), and contralateral motor scores (47%). Ipsilateral total UPDRS and ipsilateral motor scores were both improved in 59% of patients. One (1.8%) of 55 patients experienced a homonymous hemianopsia 9 months after pallidotomy due to an unexpectedly large lesion. No other complications of any kind were seen. Follow-up neuroimaging confirmed correct lesion location in all patients, with a mean maximum deviation from the planned target of 1 mm in the vertical axis. Measurements of lesions at regular interals on postoperative magnetic resonance images demonstrated considerable variability in lesion volumes. The safety and efficacy of functional lesions made with the gamma knife appear to be similar to those made with the assistance of electrophysiological guidance with open functional stereotactic procedures. Functional lesions may be made safely and accurately using gamma knife radiosurgical techniques. The efficacy is equivalent to that reported for open techniques that use radiofrequency lesioning methods with electrophysiological guidance. Complications are very infrequent with the radiosurgical method. The use of functional radiosurgical lesioning to treat movement disorders is particularly attractive in older patients and those with major systemic diseases or coagulopathies; its use in the general movement disorder population seems reasonable as well.

Clinical correlates of motor performance during paced postural tasks in Parkinson's disease

Bradykinesia and hypokinesia may both play a significant role in postural instability commonly seen in patients with Parkinson's disease. We investigated which factor -movement time or movement amplitude -is the more significant limiting variable in patients with Parkinson's disease during a paced postural task. We also assessed the effect of antiparkinson medication upon these movement factors and the degree of correlation with changes in clinical performance. Subjects performed paced left-right (L-R) and forward-backward (F-B) continuous weight-shifting tasks at slow, medium and fast paces. Ten Parkinson patients were studied both OFF and ON their usual antiparkinson medication. Ten age-matched healthy controls were also tested and subsequently retested on the same schedule as the patients. Movement times and amplitudes were measured and correlated with clinical changes in UPDRS motor subscores. Parkinson patients performed similar to controls with respect to movement time, but significantly displayed underscaled (reduced) movement amplitude. Movement amplitude improved after antiparkinson medication, but remained significantly less than that of controls. Improvements in L-R movement amplitude correlated with clinical improvements in bradykinesia and postural instability, while improved F-B movement amplitude correlated only with reduced postural instability. We conclude that hypometric movement amplitude, and not abnormal movement time, is the primary abnormality observed in Parkinson patients during a paced postural task. Amplitude underscaling seems antiparkinson medication-dependent and improvement correlates with favorable clinical changes in bradykinesia and postural instability scores.

A year's experience of L-DOPA in the treatment of Parkinson's disease.

206 patients with Parkinson's disease have been treated with oral L-DOPA for periods ranging from three to twelve months. Marked or very marked improvement of bradykinesia, rigidity and tremor occurred respectively in 58.3%, 34.7% and 15% of the cases at the 3rd month of treatment; in 70.8%, 47.7% and 20% at the 6th month (80 cases); in 88%, 64.4% and 16.2% at the 9th month (34 cases). The degree of independence gained in overall behavioural performance has been recorded at three-monthly intervals and reported for the various forms of Parkinsonism (idiopathic 133 cases; arteriosclerotic 39 cases; postencephalitic 34 cases). About 78% of the patients experienced side-effects; all of them were reversible and not very important.