Long-term follow-up of globus pallidus chronic stimulation in advanced Parkinson's disease.

To assess the long-term follow-up of the globus pallidus internus (GPi) stimulation, six patients were evaluated every year by using the Unified Parkinson's Disease Rating Scale (UPDRS). Three years postoperatively, GPi stimulation led to a significant improvement of dyskinesia severity (50%, P = 0.05) and activities of daily living (subscore of quality of life scale, 9%, P = 0.05). However, the improvement induced by chronic pallidal stimulation on the mean daily duration in the off state was lost at the last assessment.     

Striatopallidonigral degeneration in Pick's disease: a clinicopathological study of 41 cases

Summary The frequency and degree of stiatopallidonigral (SPN) degeneration were examined in 41 autopsy cases of Pick's disease. Based on the degree of SPN degeneration, these cases were arranged into four groups: 1) group I (severely degenerate; 19.5%), 2) group II (moderately degenerate; 22.0%), 3) group III (mildly degenerate; 36.5%), and 4) group IV (non-degenerate; 22.0%). 17 of the 41 cases had a definite (moderate to severe) SPN degeneration. The striatum, especially the caudate nucleus, was most frequently and most severely affected, while the internal segment of the globus pallidus was least frequently and least severely affected. In general, the oral portions of the SPN nuclei were more severely involved. In addition, in the putamen and globus pallidus the dorsomedial portions adjacent to the internal capsule were apt to be affected more markedly than the other portions. In the substantia nigra the degeneration tended to be more predominant in the pars reticulata than in the pars compacta, although both were usually involved. In addition, the medial to central portions of the substantia nigra were more vulnerable. In comparing the severely and moderately degenerate groups (groups I and II) with the mildly and non degenerate groups (groups III and IV), the former had more female cases, longer duration of illness, and more third-stage cases. In addition, the former contained more cases with lower brain weight and (predominant) frontal atrophy type, and more atypical cases without Pick bodies, or with symmetrical pyramidal tract degeneration or with combined traumatic lesions. It is notable that in all cases with definite SPN degeneration no extrapyramidal involuntary movements had been detected.     

Distinct changes in evoked and resting globus pallidus activity in early and late Parkinson's disease experimental models

The main clinical manifestations of Parkinson's disease are caused by alterations of basal ganglia activity that are tied in with the progressive loss of mesencephalic dopaminergic neurons. Recent theoretical and modeling studies have suggested that changes in resting neuronal activity occurred later in the course of the disease than those evoked by phasic cortical input. However, there is no empirical support for this proposal. Here we report a marked increase in the responsiveness of globus pallidus neurons to electrical motor cortex stimulation, in the absence of noticeable changes in resting activity, in anesthetized rats that had consistently shown a deficit in forelimb use during behavioral testing before the experiments, and had approximately 45% dopamine neurons spared in the substantia nigra. Pallidal neurons were also over-responsive to motor cortex stimulation and lost spatial selectivity for cortical inputs in rats with extensive nigrostriatal damage. After partial lesions, over-responsiveness was mainly due to an increased proportion of neurons showing excitatory responses, while extensive lesions led to an increased likelihood of inhibitory responding neurons. Changes in resting neuronal activity, comprising pauses disrupting tonic discharge, occurred across different global brain states, including an activated condition which shares similarities with natural patterns of cortical activity seen in awake states and rapid eye-movement sleep, but only after massive nigrostriatal degeneration. These results suggest that a loss of functional segregation and an abnormal temporal encoding of phasic cortical inputs by globus pallidus neurons may contribute to inducing early motor impairment in Parkinson's disease.     

Pallidal GABA and chorea in Huntington's disease

Summary Neurochemical correlates of chorea in Huntington's disease were studied using striatal and pallidal tissue taken post mortem from patients with mild and severe chorea. While GABA was decreased in all these areas in Huntington's disease, patients with mild chorea had significantly less GABA in the medial pallidum than did those with severe chorea. There was no relationship between the degree of chorea and concentrations of dopamine or its metabolite. Thus the chorea of Huntington's disease may relate to the balance of residual GABAergic innervation between specific areas of the basal ganglia, consistent with primate models of dyskinesias.     

Differential localization of GABA(A) receptor subunits in relation to rat striatopallidal and pallidopallidal synapses

As a central integrator of basal ganglia function, the external segment of the globus pallidus (GP) plays a critical role in the control of voluntary movement. The GP is composed of a network of inhibitory GABA-containing projection neurons which receive GABAergic input from axons of the striatum (Str) and local collaterals of GP neurons. Here, using electrophysiological techniques and immunofluorescent labeling we have investigated the differential cellular distribution of α1, α2 and α3 GABA(A) receptor subunits in relation to striatopallidal (Str-GP) and pallidopallidal (GP-GP) synapses. Electrophysiological investigations showed that zolpidem (100 nm; selective for the α1 subunit) increased the amplitude and the decay time of both Str-GP and GP-GP IPSCs, indicating the presence of the α1 subunits at both synapses. However, the application of drugs selective for the α2, α3 and α5 subunits (zolpidem at 400 nm, L-838,417 and TP003) revealed differential effects on amplitude and decay time of IPSCs, suggesting the nonuniform distribution of non-α1 subunits. Immunofluorescence revealed widespread distribution of the α1 subunit at both soma and dendrites, while double- and triple-immunofluorescent labeling for parvalbumin, enkephalin, gephyrin and the γ2 subunit indicated strong immunoreactivity for GABA(A) α3 subunits in perisomatic synapses, a region mainly targeted by local axon collaterals. In contrast, immunoreactivity for synaptic GABA(A) α2 subunits was observed in dendritic compartments where striatal synapses are preferentially located. Due to the kinetic properties which each GABA(A) α subunit confers, this distribution is likely to contribute differentially to both physiological and pathological patterns of activity.     

A Golgi analysis of the primate globus pallidus. I. Inconstant processes of large neurons, other neuronal types, and afferent axons

The present paper is a Golgi study, with high-power lenses, of the primate globus pallidus. Two kinds of inconstant processes of large neurons are first described: complex endings and thin processes. Complex endings are thick apparatuses terminally located on dendrites having many appendages of various types. Contacts were observed not only between striatal axons and these complex endings but also between complex endings and the soma, dendritic stems, dendritic portions or complex endings of other large pallidal neurons. Thin processes were usually beaded, very thin, and arose from any part of the dendritic tree. Contacts were seen between them and soma or dendrites of other large neurons. These thin processes were very similar to initial axonal collaterals and together constitute a common pool of processes. Complex endings and thin processes were essentially observed in the lateral nucleus of the pallidum where they apparently are evenly distributed inside the nucleus but randomly distributed on individual neurons. Two neuronal types other than large pallidal neurons were isolated: the smallest were considered to be local circuit neurons, while intermediate-sized neurons might be the origin of a particular efference. Many striatal axons gave no branches over long distances and collaterals were of two types and most frequently were short (less than 50 micron). Larger axonal arborization were rarely encountered. In addition to parallel contacts, numerous very short ones were observed. All these contacts between striatal axons and dendrites of large pallidal neurons seem to be irregularly distributed.     

Baroreflex sensitivity and power spectral analysis in different extrapyramidal syndromes

Cardiac autonomic abnormalities have been described in Parkinson’s disease and other extrapyramidal syndromes. To investigate baroreflex sensitivity as an important risk marker of cardiovascular mortality in patients with Parkinson’s disease and other extrapyramidal syndromes. We recorded continuously blood pressure, ECG and respiration in 35 patients with multiple system atrophy (MSA), 32 patients with progressive supranuclear palsy (PSP), 46 patients with idiopathic Parkinson’s disease (PD) and in 27 corresponding healthy subjects (Con). Recordings of 2 min at rest were used to calculate baroreflex and spectral analysis of heart rate and systolic blood pressure. Resting baroreflex sensitivity (BRS) was significantly lower in the MSA and the PSP group but not in the PD group in comparison to the Con group. With increasing Hoehn & Yahr stage, BRS significantly decreased in all patient groups. In spectral analysis, all patient groups had a significantly lower relative low frequency (LF)-band power than the healthy controls. Patients with extrapyramidal disorders frequently demonstrate pathologically decreased BRS values and abnormalities of spectral analysis. This may have fundamental impact on the cardiovascular prognosis of patients with extrapyramidal disease.     

Effects of unilateral subthalamic and pallidal deep brain stimulation on fine motor functions in Parkinson's disease.

Deep brain stimulation (DBS) is an effective treatment for selected patients with disabling Parkinson's disease (PD). The two main targets are the subthalamic nucleus (STN) and the globus pallidus internus (GPi), although it has not been established whether stimulation at one target is superior to the other. This prospective randomized study assessed the effects of unilateral DBS of the STN versus GPi on fine motor skills in 33 patients with advanced PD. Stimulation of either the STN (18 subjects) or GPi (15 subjects) in the off medication state significantly improved movement time and dexterity, but had little or no effect on reaction time. Overall, the extent of improvement did not differ between the two targets. The degree of improvement in movement time, but not dexterity, was correlated with the extent of preoperative medication responsiveness. Our findings suggest that DBS of the STN or GPi results in a similar improvement in hand movements at short-term follow-up. Preoperative medication responsiveness predicts improvement in some but not other motor tasks.     

Oscillatory nature of human basal ganglia activity: relationship to the pathophysiology of Parkinson's disease.

Alterations of basal ganglia physiology in parkinsonism may consist of two elements, an increase in the firing rate of neurones and a change in the pattern of synchronisation of discharges between neurones. Recent findings suggest the presence of two principal modes of synchronised activity within the human subthalamo-pallidal-thalamo-cortical circuit, at <30 Hz and >60 Hz. These oscillations are dynamically and systematically modulated by task, thereby suggesting a functional role in movement. More importantly, the two frequency modes are inversely affected by movement, consistent with opposing actions, and differentially expressed according to the prevailing level of dopaminergic activity. It is argued that the balance between these modes determines the effects of basal ganglia-thalamocortical projections on the motor areas of the cortex. The lower frequency oscillations facilitate slow idling rhythms in the motor areas of the cortex, whereas synchronisation at high frequency restores dynamic task-related cortical ensemble activity in the gamma band.     

Bilateral globus pallidus internus deep brain stimulation in tardive dyskinesia: a case report.

The clinical response of a 53-year-old woman with tardive dyskinesia treated with bilateral globus pallidus interna deep brain stimulation is described. At 18 months follow-up, her Burke-Fahn-Marsden Dystonia Rating Scale score fell from 52 (preoperative) to 21 (60% improvement).     

情感障碍病人锥体外系症状横断面分析

探索住院情感障碍病人锥体外系症状的发生率,并研究这些症状与药物和其它因素的关系。方法 用Ｓｉｍｐｓｏｎ锥体外系症状量表评定帕金森氏征,静坐不能,肌张力障碍和ＴＤ。结果 震颤,运动减少,静坐不能,肌张力障碍,ＴＤ发生率分别为３０．７％,１３．６％,１０．３％,１．７％和１３．６％。运动减少与年龄有关;静坐不能与抗抑郁药有关;ＴＤ与抗精神病药,锂盐及年龄显著相关。     

Walking ability after implantation of a pallidal stimulator: analysis of plantar force distribution in patients with Parkinson's disease

This preliminary study aimed to analyse the roll-off of the foot during gait before and after implantation of a unilateral pallidal electrode in severely affected patients with Parkinson’s disease (PD). Five subjects were tested in a gait laboratory during the “on” phase of the medication cycle. Spatiotemporal variables demonstrated a pronounced increase of stride length and gait speed in three patients. Plantar force distribution and roll-off was considerably improved in one patient, which was not replicated in others. Gait analysis highlighted the variable effects found after surgery with a pallidal stimulator and might contribute to future studies into the effect of surgical procedures in PD.     

Long‐term results of a multicenter study on subthalamic and pallidal stimulation in Parkinson's disease

We report the 5 to 6 year follow‐up of a multicenter study of bilateral subthalamic nucleus (STN) and globus pallidus internus (GPi) deep brain stimulation (DBS) in advanced Parkinson's disease (PD) patients. Thirty‐five STN patients and 16 GPi patients were assessed at 5 to 6 years after DBS surgery. Primary outcome measure was the stimulation effect on the motor Unified Parkinson's Disease Rating Scale (UPDRS) assessed with a prospective cross‐over double‐blind assessment without medications (stimulation was randomly switched on or off). Secondary outcomes were motor UPDRS changes with unblinded assessments in off‐ and on‐medication states with and without stimulation, activities of daily living (ADL), anti‐PD medications, and dyskinesias. In double‐blind assessment, both STN and GPi DBS were significantly effective in improving the motor UPDRS scores (STN, P < 0.0001, 45.4%; GPi, P = 0.008, 20.0%) compared with off‐stimulation, regardless of the sequence of stimulation. In open assessment, both STN‐ and GPi‐DBS significantly improved the off‐medication motor UPDRS when compared with before surgery (STN, P < 0.001, 50.5%; GPi, P = 0.002, 35.6%). Dyskinesias and ADL were significantly improved in both groups. Anti‐PD medications were significantly reduced only in the STN group. Adverse events were more frequent in the STN group. These results confirm the long‐term efficacy of STN and GPi DBS in advanced PD. Although the surgical targets were not randomized, there was a trend to a better outcome of motor signs in the STN‐DBS patients and fewer adverse events in the GPi‐DBS group. © 2010 Movement Disorder Society     

Distribution of histamine H3-receptor binding in the normal human basal ganglia: comparison with Huntington's and Parkinson's disease cases

It is now widely recognized that histamine acts as a neurotransmitter in the mammalian central nervous system. Three selective histamine receptors have been described, all of which are present in the basal ganglia. This study is a detailed, quantitative, autoradiographical examination of the densities of histamine H3-receptors in coronal sections of human basal ganglia, using the selective ligand [3H]-(R)-alpha-methylhistamine. [3H]-(R)-alpha-methylhistamine binding was highest within the external and internal segments of the globus pallidus together with the substantia nigra. High levels were also found in the striatum, where density was significantly higher (P < 0.05) at a pre-, as opposed to post-, anterior commissure coronal level. Within the striatum, binding was noticeably higher in both the nucleus accumbens and acetylcholinesterase-deficient striosomes, while being undetectable in the subthalamic nucleus and very low in both the ventroanterior and ventrolateral thalamic nuclei. An intermediate level of binding, often with a laminar distribution, was seen in the insular cortex. [3H]-(R)-alpha-methylhistamine binding was also examined in both Parkinson's disease and Huntington's disease. No difference from control receptor density was found in any area examined in Parkinson's disease, while values were significantly lower in caudate (P < 0.001), putamen (P < 0.001), external (P < 0.001) and internal (P < 0.05) globus pallidus, although not the insular cortex, in Huntington's disease cases. These data suggest that H3-receptors are present upon striatonigral projection neurons of the direct and indirect movement pathways thus providing histaminergic control over the activity of both these circuits.     

Effects of stereotactic neurosurgery on postural instability and gait in Parkinson's disease.

Postural instability and gait disability (PIGD) are disabling signs of Parkinson's disease. Stereotactic surgery aimed at the internal globus pallidus (GPi) or subthalamic nucleus (STN) might improve PIGD, but the precise effects remain unclear. We performed a systematic review of studies that examined the effects of GPi or STN surgery on PIGD. Most studies examined the effects of bilateral GPi stimulation, bilateral STN stimulation, and unilateral pallidotomy; we, therefore, only performed a meta-analysis on these studies. Bilateral GPi stimulation, bilateral STN stimulation, and to a lesser extent, unilateral pallidotomy significantly improved PIGD, and more so during the ON phase than during the OFF phase.     

Late emergence of synchronized oscillatory activity in the pallidum during progressive Parkinsonism

Parkinson's disease is known to result from basal ganglia dysfunction. Electrophysiological recordings in parkinsonian patients and animals have shown the emergence of abnormal synchronous oscillatory activity in the cortico-basal ganglia network in the pathological condition. In addition, previous studies pointed out an altered response pattern during movement execution in the pallidum of parkinsonian animals. To investigate the dynamics of these changes during disease progression and to relate them to the onset of the motor symptoms, we recorded spontaneous and movement-related neuronal activity in the internal pallidum of nonhuman primates during a progressive dopamine depletion process. Parkinsonian motor symptoms appeared progressively during the intoxication protocol, at the end of which both animals displayed severe akinesia, rigidity and postural abnormalities. Spontaneous firing rates did not vary significantly after intoxication. During the early phase of the protocol, voluntary movements were significantly slowed down and delayed. At the same time, the neuronal response to movement execution was modified and inhibitory responses disappeared. In contrast, the unitary and collective dynamic properties of spontaneous neuronal activity, as revealed by spectral and correlation analysis, remained unchanged during this period. Spontaneous correlated activity increased later, after animals became severely bradykinetic, whereas synchronous oscillatory activity appeared only after major motor symptoms developed. Thus, a causality between the emergence of synchronous oscillations in the pallidum and main parkinsonian motor symptoms seems unlikely. The pathological disruption of movement-related activity in the basal ganglia appears to be a better correlate at least to bradykinesia and stands as the best candidate to account for this motor symptom.     

Long descending direct projection from the basal ganglia to the spinal cord: a revival of the extrapyramidal concept

Our retrograde fluorescent labeling study shows that a distinct cell group of the subthalamic nucleus, posited in the basal ganglia, directly sends long descending axons contralaterally to the upper cervical segments (C1-C5) of the spinal cord in the rat. A large population (60-70%) of these subthalamic cells projecting to contralateral spinal levels give off axonal branches innervating the ipsilateral globus pallidus. Now, the classical concept of the 'extrapyramidal' motor system needs to be reconsidered. Furthermore, our results may provide a morphological substrate for the onset of a violent form of dyskinesia, 'hemiballism', which occurs in the contralateral limbs both clinically and experimentally following discrete lesions in the subthalamic nucleus or its fiber connections with the globus pallidus.     

Randomised, double-blind, placebo-controlled trial to assess the potential of cannabinoid receptor stimulation in the treatment of dystonia.

Cannabis may have medicinal uses in a variety of diseases. The neural mechanisms underlying dystonia involve abnormalities within the basal ganglia-in particular, overactivity of the lateral globus pallidus (GPl). Cannabinoid receptors are located presynaptically on GABA terminals within the GPi, where their activation reduces GABA reuptake. Cannabinoid receptor stimulation may thus reduce overactivity of the GPl and thereby reduce dystonia. A double-blind, randomised, placebo-controlled, crossover study using the synthetic cannabinoid receptor agonist nabilone in patients with generalised and segmental primary dystonia showed no significant reduction in dystonia following treatment with nabilone.