帕金森病内侧苍白球和丘脑腹外侧核神经细胞放电特点与临床症状的关系

目的：探讨帕金森病（PD）患者内侧苍白球（GPi）和丘脑腹外侧核团（Vop／Vim）细胞电活动与PD症状的关系。方法：24例患者在接受手术的同时采集细胞电活动（GPi：12个,Vop／Vim：12个）和记录肢体肌电图（EMG）。应用单细胞分析,峰阃隔（ISI）、ISI变异系数（CV）和ISI直方图等方法进行分析。用统一帕金森评分量表（UPDRS）进行疗效评估。结果：199个GPi神经元中,33个（16．6％）为与震颤相关放电活动,136个（68．3％）为紧张性放电活动,30个（15．1％）为不规则放电活动。223个Vop／Vim神经元中,110个（49．3％）为与震颤相关的放电活动,49个（22％）为紧张性放电活动,64个（28．7％）为不规则放电活动。ISI分析发现GPi神经元放电频率为78Hz（n=92）而Vop／Vim为24Hz（n=107）。方差分析显示GPi和Vop／Vim的上述三种不同放电模式神经元的数量之间比较差异有统计学意义（P〈0．05）。UPDRS显示,术后GPi对震颤、僵直和运动迟缓的疗效分别为63％、83％和64％;而Vop／Vim术后对震颤、僵直和运动迟缓的疗效分别为94％、66％和49％,提示GPi对僵直改善明显,而Vim对震颤改善显著（P〈0．05）。结论：GPi和Vop／Vim中不同放电模式的神经元可能与PD运动症状有内在联系,支持PD病理生理模型。     

Neuronal firing rates and patterns in the globus pallidus internus of patients with cervical dystonia differ from those with Parkinson's disease

Cervical dystonia (CD) is a movement disorder that involves involuntary turning and twisting of the neck caused by abnormal muscle contraction. Deep brain stimulation (DBS) in the globus pallidus internus (GPi) is used to treat both CD and the motor symptoms of Parkinson's disease (PD). It has been suggested that the differing motor symptoms in CD and PD may arise from a decreased GPi output in CD and elevation of output in PD. To test this hypothesis, extracellular recordings of GPi neuronal activity were obtained during stereotactic surgery for the implantation of DBS electrodes in seven idiopathic CD and 14 PD patients. The mean GPi neuronal firing rate recorded from CD patients was lower than that in PD patients (P < 0.001; means +/- SE: 71.4 +/- 2.2 and 91.7 +/- 3.0 Hz, respectively). Furthermore, GPi neurons fired in a more irregular pattern consisting of more frequent and longer pauses in CD compared with PD patients. When comparisons were done based on locations of recordings, these differences in firing rates and patterns were limited to the ventral portion of the GPi. In contrast, no difference in firing rate or pattern was observed in the globus pallidus externus between the two groups. These findings suggest that alterations in both firing rate and firing pattern may underlie the differing motor symptoms associated with these two movement disorders.     

Microstimulation-induced inhibition of neuronal firing in human globus pallidus

Neurosurgical treatment of Parkinson's disease (PD) frequently employs chronic high-frequency deep brain stimulation (DBS) within the internal segment of globus pallidus (GPi) and can very effectively reduce L-dopa-induced dyskinesias and bradykinesia, but the mechanisms are unknown. The present study examined the effects of microstimulation in GPi on the activity of neurons close to the stimulation site. Recordings were made from GPi using two fixed or independently controlled microelectrodes, with the electrode tips usually approximately 250 or >600 micrometer apart in PD patients undergoing stereotactic exploration to localize the optimal site for placement of a lesion or DBS electrode. The spontaneous activity of nearly all of the cells (22/23) recorded in GPi in three patients was inhibited by microstimulation at currents typically <10 microA (0.15-ms pulses at 5 Hz). The inhibition had a duration of 10-25 ms at threshold. These findings suggest that microstimulation within GPi preferentially excites the axon terminals of striatal and/or external pallidal neurons causing release of GABA and inhibition of GPi neurons.     

Comparison of MPTP-induced changes in spontaneous neuronal discharge in the internal pallidal segment and in the substantia nigra pars reticulata in primates

 The basal ganglia are currently viewed as components of segregated corticosubcortical reentrant circuits. One of these circuits, the ”motor” circuit, is critically involved in the development of parkinsonian motor signs. Current pathophysiologic models postulate that parkinsonism is associated with increased activity in the basal ganglia output nuclei. The neuronal activity in the motor portion of one of these output nuclei, the internal segment of the globus pallidus (GPi), has been characterized in detail in intact and parkinsonian animals, but the neuronal activity in the second major basal ganglia output nucleus, the substantia nigra pars reticulata (SNr), has received far less attention. This study in primates represents a comparison of the effects of parkinsonism, induced by injections of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), on the neuronal discharge in the GPi and SNr. These electrophysiologic recording experiments were carried out in three African green and two rhesus monkeys. One hundred and twenty-four neurons were recorded in the GPi before treatment with MPTP, and 93 neurons thereafter. In the SNr, 55 cells were recorded before treatment with MPTP, and 41 cells thereafter. MPTP induced a non-significant increase in the average discharge rate and a significant decrease in the median interspike interval length (ISI) in the GPi (by 13%), whereas no changes were detected in either parameter in the SNr. The average ISI distributions were markedly asymmetric in both structures, and could be modeled by a logarithmic normal distribution. With the MPTP treatment, the mode of the ISI distribution fell by 24% in the GPi (P≤0.01), whereas it did not change significantly in the SNr. An algorithm that detects burst discharges in the raw ISI data (based on the method by Legendy and Salcman) detected a significant increase in the proportion of action potentials that participated in bursts of discharge in both structures (increase by 257% in the GPi, and by 67% in the SNr). Power spectral and autocorrelation analysis revealed that treatment with MPTP increased the proportion of cells with oscillatory burst patterns at 3–8 Hz in both structures (from 0.8% to 27% of all neurons in the GPi, and from none to 10% in the SNr). The results show that neuronal discharge in the SNr is affected in parkinsonism, but that the changes in the SNr are less pronounced then those seen in the GPi. Received: 3 March 1998 / Accepted: 15 October 1998     

Single-unit analysis of the pallidum, thalamus and subthalamic nucleus in parkinsonian patients

Microelectrode-guided stereotactic operations performed in 29 parkinsonian patients allowed the recording of 86 cells located in the globus pallidus and 563 in thalamic nuclei. In the globus pallidus, the average firing rate was significantly higher in the internal (91+/-52 Hz) than in the external (60+/-21 Hz) subdivision. This difference was further accentuated when the average firing rate in the external subdivision was compared with that of the internal part of the internal subdivision (114+/-30 Hz). A rhythmic modulation in globus pallidus activities was observed in 19.7% of the cells, and this only during rest tremor episodes. In these cases, modulation frequency of unit activities was not statistically different from the rest tremor frequency (average: 4.6+/-0.5 vs 4. 4+/-0.4 Hz, respectively). In the medial thalamus, four types of unit activities could be defined. A sporadic type was mainly found in the parvocellular division of the mediodorsal nucleus (96.8% of the cells recorded) and in the centre median-parafascicular complex (74.2%). Two other types of activities characterized by random or rhythmic bursts fulfilling the extracellular criteria of low-threshold calcium spike bursts were concentrated in the central lateral nucleus (62.3%) and the paralamellar division of the mediodorsal nucleus (34.1%). These activities could be recorded independently of the presence of a rest tremor. When a tremor episode occurred, the rhythmic low-threshold calcium spike bursts had an interburst frequency similar to rest tremor frequency, although they were not synchronized with it. The fourth type, the so-called tremor locked, was also characterized by rhythmic bursts which, however, did not display low-threshold calcium spike burst properties. These bursts occurred only when a rest tremor was present and was in-phase with the electromyographic bursts. All tremor-locked cells were located in the centre median-parafascicular complex. In the lateral thalamus, cells exhibiting random or rhythmic low-threshold calcium spike bursts were found preponderantly in the ventral anterior nucleus (53.4%) and in the ventral lateral anterior nucleus (52.7%). Tremor-locked units were confined to the ventral division of the ventral lateral posterior nucleus (35.4%). None of the random or rhythmic low-threshold calcium spike bursting units responded to somatosensory stimuli or voluntary movements, either in the medial or in the lateral thalamus. The presence of low-threshold calcium spike bursts at the thalamic level, together with the paucity (8%) of responses to voluntary movements compared to what is found in normal non-human primates, demonstrate a pathological state of inhibition due to the overactivity of the internal subdivision of the globus pallidus units. Activities of the thalamic cells producing low-threshold calcium spike bursts are not synchronized with each other or with the tremor. However, this does not exclude a causal role of these activities in the generation of tremor. Indeed, it has been demonstrated that even random electrical stimulations of the rolandic cortex in parkinsonian patients induce tremor episodes, probably due to the triggering of rhythmic, low-threshold calcium spike-dependent, thalamocortical activities. Similarly, low-threshold calcium spike bursts could be at the origin of rigidity and dystonia through an activation of the supplementary motor area and of akinesia when reaching the pre-supplementary motor area.We conclude that the intrinsic oscillatory properties of individual neurons, combined with the dynamic properties of the thalamocortical circuitry, are responsible for the three cardinal parkinsonian symptoms.     

Differences in neuronal firing rates in pallidal and cerebellar receiving areas of thalamus in patients with Parkinson's disease, essential tremor, and pain

The motor symptoms of Parkinson's disease (PD) are thought to result from increased inhibitory outflow from the basal ganglia to the pallidal receiving areas of thalamus (ventral oral anterior and posterior-Voa,Vop). To test this hypothesis, we examined the firing rates of neurons in pallidal and cerebellar receiving areas of thalamus in five PD patients and compared them to those of neurons in comparable regions of motor thalamus in two other patient groups where hyperactivity of GPi is not believed to occur [essential tremor (ET), pain]. Neuronal recordings were made during microelectrode-guided functional stereotactic neurosurgery. The mean spontaneous firing rate (MSFR) of neurons classified as voluntary neurons and presumed to be in pallidal receiving areas of thalamus in PD patients [7.4 +/- 1.0 (SE) Hz] was significantly lower (P < 0.01) than in the ET (18.1 +/- 3.0 Hz) and pain (19.0 +/- 1.9Hz) groups. In contrast, the MSFR of neurons classified as kinesthetic and presumed to be primarily in the cerebellar receiving area of thalamus (ventral intermediate-Vim), although some are probably in the deep shell region of the ventrocaudal nucleus (VPLa), was significantly greater in ET patients (25.8 +/- 3.5 Hz) than in the PD (14.3 +/- 1.6 Hz; P < 0.01) and pain (16.1 +/- 1.5 Hz; P < 0.05) groups. Similar findings were obtained when the neurons were grouped according to their estimated locations in Voa/Vop and Vim of motor thalamus. These data provide support for the prediction of the classical pathophysiological model of PD and moreover suggest that pathophysiology in the cerebello-thalamo-cortical pathway may be a possible cause of tremor in ET patients.     

High-frequency microstimulation in human globus pallidus and substantia nigra

Deep brain stimulation of the basal ganglia and other brain regions has been used successfully to treat a variety of neurological disorders. However, the mechanisms by which it works, remain unclear. In a previous study, we showed that locally delivered single current pulses delivered from a nearby microelectrode are sufficient to inhibit firing in the internal globus pallidus for tens of milliseconds. The GPi and the substantia nigra pars reticulata are the output nuclei of the basal ganglia and share many anatomical and physiological features. The goal of the current study was to examine the after-effects of trains of high-frequency microstimulation on neuronal firing in the GPi of Parkinson’s disease and dystonia patients as well as in the SNr of PD patients. Microelectrode recordings and microstimulation were performed in a total of 57 patients during stereotactic surgery. We found that firing in the GPi and SNr is inhibited for several hundreds of milliseconds following the end of a short, 200 Hz high-frequency train delivered through the recording electrode (e.g., on average 618 ms when stimulating in the SNr with a 0.5 s train of 4 μA pulses at 200 Hz). Inhibition duration usually increased with increasing current intensity, train frequency and generally peaked for trains of 1–2 s, while it decreased with increasing train durations. Statistical analysis with general linear models revealed a significant linear relationship between current intensity and inhibition duration in all nuclei and patient groups. There was also a significant relationship between train frequency and inhibition duration in the SNr and GPi of PD patients and between train duration and inhibition duration in the GPi of PD patients. There was no significant difference in inhibition duration across patient groups but the current threshold for inhibition was significantly different in the SNr compared to the GPi. The characteristics of the inhibition observed are consistent with stimulation-induced GABA release following activation of the GABAergic afferents in the SNr and GPi. The findings suggest that high-frequency microstimulation of the GPi and SNr depresses local neuronal activity and synaptic transmission, and such mechanisms may contribute to the therapeutic effects of DBS.     

Neuronal discharge patterns in the Globus Pallidus pars interna in a patient with Parkinson’s disease and hemiballismus secondary to subthalamotomy

Alterations in the basal ganglia-thalamocortical “motor” circuit activity, have been proposed to explain many features associated with hypokinetic and hyperkinetic movement disorders. We describe the firing pattern of the globus pallidus pars interna in a Parkinson disease’s patient who developed Hemichorea-Ballismus subsequent to ipsilateral subthalamotomy, and compare findings to those from PD patients submitted to pallidotomy while in the OFF-medication state. Single units obtained from extracellular recordings were extracted and mean discharge frequency, interspike interval and coefficient of variation (defined as Tonicity Score) were computed. Discharge density histograms, analysis of distribution and spectral analysis were also performed. Mean firing frequency showed no significant difference between PD patients in the OFF state and the patient we report. However, a significant difference in tonicity was found for this patient characterized by a regular, non-bursting firing pattern. The findings indicate that in HB caused by lesions to STN in the parkinsonian state, GPi firing rates can be similar to and firing pattern more regular than those observed in GPi of PD patients OFF-medication with intact STN.     

Effects of apomorphine on subthalamic nucleus and globus pallidus internus neurons in patients with Parkinson's disease.

This study examines the effect of apomorphine (APO), a nonselective D(1)- and D(2)-dopamine receptor agonist, on the firing activity of neurons in the subthalamic nucleus (STN) and internal segment of the globus pallidus (GPi) in patients with Parkinson's disease (PD). Single-unit microelectrode recordings were conducted in 13 patients undergoing implantation of deep brain stimulation electrodes in STN and 6 patients undergoing a pallidotomy. Doses of APO (2.5-8 mg) were sufficient to produce an ON state, but not intended to induce dyskinetic movements. Following baseline recordings from a single neuron, APO was administered and the activity of the neuron followed for an average of 15 min. The spontaneous discharge of neurons encountered before (n = 309), during (n = 146, 10-60 min), and after the effect of APO had waned (n = 127, >60 min) was also sampled, and the response to passive joint movements was noted. In both nuclei, APO increased the overall proportion of spikes in burst discharges (as detected with Poisson "surprise" analysis), and a greater proportion of cells with an irregular discharge pattern was observed. APO significantly decreased the overall firing rates of GPi neurons (P < 0.01), but there was no change in the overall firing rate of neurons in the STN (P = 0.68). However, the mean firing rates of STN neurons during APO-induced movements (choreic or dystonic dyskinesias) that occurred in four patients were significantly lower than OFF-period baseline values (P < 0.05). Concurrent with a reduction in limb tremor, the percentage of cells with tremor-related activity (TCs) was found to be significantly reduced from 19 to 6% in the STN and 14 to 0% in the GPi following APO administration. APO also decreased the firing rate of STN TCs (P < 0.05). During the OFF state, more than 15% of neurons tested (STN = 93, GPi = 63) responded to passive movement of two or more joints. After APO, this proportion decreased significantly to 7% of STN cells and 4% of GPi cells (STN = 28, GPi = 26). These findings suggest that the APO-induced amelioration of parkinsonian symptoms is not solely due to a decrease in overall activity in the GPi or STN as predicted by the current model of basal ganglia function in PD.     

Spontaneous activity of individual neurons in the human ventrolateral thalamus during changes in the functional state of the brain

Background spike activity of 235 cells of the integrative subcortical motor center, i.e., the ventrolateral nucleus of the thalamus, were analyzed in nonanesthetized human brains during stereotaxic surgery in patients with various forms of Parkinson’s disease. Previous data on the existence of two major types of neurons with convergent properties in the ventrolateral nucleus were confirmed. These cell types are: 1) cells with irregular occasional activity, with a tendency for spikes to group into the frequency ranges 5±1 and 10–30 Hz (type A cells, 74%), and 2) cells with constant rhythmic (3–6 Hz) generation of short volleys of discharges, with an interval structure similar to that of low-threshold Ca²⁺-dependent volley activity (type B, 26%). This is the first report demonstrating that changes in the functional state of the brain (after repeated movement trials, in transient anesthesia) are accompanied by transiently occurring transformations of the initial irregular activity of A cells into a rhythmic, volley-like pattern whose interval structure was in some cases similar to the spike activity of B cells. Differences in the localizations of A and B neurons in the ventrolateral nucleus are described, along with differences in the correlation characteristics of their background spike activity with the pathological features of Parkinson’s disease (tremor, rigidity). The nature of the two types of convergent neurons in the ventrolateral nucleus is discussed, and a basis is laid for the importance of the functional factor in understanding the transformation of, their background spike activity, due to the properties of cell membranes and intercellular and interstructure interactions in conditions of the living nonanesthetized human brain. Laboratory of Human Cellular Neurophysiology, Institute of Chemical Physics, Russian Academy of Sciences. Academician N. N. Burdenko Institute of Neurosurgery, Russian Academy of Medical Sciences, 4 Kosygin Street, Moscow 117977, Russia. Translated from Rossiiski Fiziologicheskii, Zhurnal imeni I. M. Sechenova, Vol. 83, No. 8, pp. 24–32. August, 1997.     

Firing rates of pallidal neurons are similar in Huntington’s and Parkinson’s disease patients

According to the now classical basal ganglia–thalamocortical circuitry model, the chorea of Huntingtons disease (HD) and the hypokinesia in Parkinsons disease (PD) are explained by a decrease in the inhibitory output (reduced firing rates) from the globus pallidus internus (GPi) in HD and increased output in PD. Differences between firing patterns might also be a factor contributing to the different symptoms, however. To test the predictions of the model we examined neuronal firing rates and patterns in two HD patients and 14 PD patients. Single-cell, microelectrode recordings were obtained from awake patients undergoing stereotactic surgery for implantation of deep brain stimulating (DBS) electrodes in the GPi. The mean neuronal firing rate in the GPi of HD patients was 81.8±4.3 Hz (mean±SEM), which was not significantly different from that in PD patients (89.9±3.0 Hz). Firing pattern analyses using measurements of burst index, coefficient of variation, and percentage participation of spikes in bursts revealed, however, that GPi neurons in HD patients fired in a more regular pattern (fewer bursts) than in PD patients. These results suggest that the rate-based model does not adequately explain the motor abnormalities present in the two HD patients studied. Furthermore, the findings did reveal a difference between firing patterns in the HD and PD groups, thereby supporting the role of altered firing patterns in the pathophysiology of these diseases.     

Single-neuron analysis of human thalamus in patients with intention tremor and other clinical signs of cerebellar disease

Tremor that occurs as a result of a cerebellar lesion, cerebellar tremor, is characteristically an intention tremor. Thalamic activity may be related to cerebellar tremor because transmission of some cerebellar efferent signals occurs via the thalamus and cortex to the periphery. We have now studied thalamic neuronal activity in a cerebellar relay nucleus (ventral intermediate-Vim) and a pallidal relay nucleus (ventralis oral posterior-Vop) during thalamotomy in patients with intention tremor and other clinical signs of cerebellar disease (tremor patients). The activity of single neurons and the simultaneous electromyographic (EMG) activity of the contralateral upper extremity in tremor patients performing a pointing task were analyzed by spectral cross-correlation analysis. EMG spectra during intention tremor often showed peaks of activity in the tremor-frequency range (1.9-5.8 Hz). There were significant differences in thalamic neuronal activity between tremor patients and controls. Neurons in Vim and Vop had significantly lower firing rates in tremor patients than in patients undergoing thalamic surgery for pain (pain controls). Other studies have shown that inputs to Vim from the cerebellum are transmitted through excitatory connections. Therefore the present results suggest that tremor in these tremor patients is associated with deafferentation of the thalamus from cerebellar efferent pathways. The thalamic X EMG cross-correlation functions were studied for cells located in Vim and Vop. Neuronal and EMG activity were as likely to be significantly correlated for cells in Vim as for those in Vop. Cells in Vim were more likely to have a phase lag relative to EMG than were cells in Vop. In monkeys, cells in the cerebellar relay nucleus of the thalamus, corresponding to Vim, are reported to lead movement during active oscillations at the wrist. In view of these monkey studies, the present results suggest that cells in Vim are deafferented and have a phase lag relative to tremor that is not found in normal active oscillations. The difference in phase of thalamic spike X EMG activity between Vim and Vop may contribute to tremor because lesions of pallidum or Vop are reported to relieve cerebellar tremor.     

The impact of ventrolateral thalamotomy on tremor and voluntary motor behavior in patients with Parkinson’s disease

A preferred target for parkinsonian tremor alleviation is the ventrolateral (VL) thalamus. The goal of the present study is to determine how lesions involving the presumed cerebellar and pallidal recipient areas of the “motor” thalamus would alter the tremor and motor behavior of ten patients with Parkinson’s disease (PD). Tremor amplitude, power dispersion (a measure of sharpness of the power spectrum of tremor), and power distribution were quantified using a laser displacement sensor prior to, and a week after, VL thalamotomy. As well, the impact of surgery on tremor seen during movement was quantified in a manual-tracking (MT) task. Tremor-induced noise (a measure of the amount of tremor present during movement) and ERROR (difference between subject’s performance and target) were quantified. Finally, bradykinesia was assessed with a rapid alternating movement (RAM) task. Duration, range, and amplitude irregularity of wrist pronation–supination cycles were computed. Both motor tasks were quantified using a highly sensitive forearm rotational sensor. Healthy age-matched control subjects were also tested. Magnetic resonance images with an integrated atlas of thalamic nuclei were used to confirm lesion location. Results show that the lesions were centered upon the posterior portion of the ventral lateral (VLp) nucleus of the thalamus, included the posterior part of the ventral lateral anterior nucleus (VLa), and extended posteriorly to encroach upon the most rostral sector of the sensory ventral posterior nucleus (VPLa). VL thalamotomy significantly decreased tremor amplitude in all cases. Power dispersion was increased significantly so that it became similar to that of control subjects. Changes in power distribution indicate that thalamotomy selectively targeted PD tremor oscillations. Tremor detected during the MT task was also markedly decreased, becoming similar to that of controls. Patients also showed significant decrease in ERROR during MT. RAM duration and range were not significantly modified by the surgery, and patients’ performance remained impaired compared to healthy control subjects. Collectively, these results suggest that lesions involving the presumed “cerebellar” and “pallidal” recipient sectors of the motor thalamus do not worsen bradykinesia, suggesting that neural circuits other than the pallido-thalamo-cortical loop may be involved in slowness of movement in PD. A review of alternate pathways is presented.     

Internal pallidal neuronal activity during mild drug-related dyskinesias in Parkinson's disease: decreased firing rates and altered firing patterns

The neuronal basis of hyperkinetic movement disorders has long been unclear. We now test the hypothesis that changes in the firing pattern of neurons in the globus pallidus internus (GPi) are related to dyskinesias induced by low doses of apomorphine in patients with advanced Parkinson's disease (PD). During pallidotomy for advanced PD, the activity of single neurons was studied both before and after administration of apomorphine at doses just adequate to induce dyskinesias (21 neurons, 17 patients). After the apomorphine injection, these spike trains demonstrated an initial fall in firing from baseline. In nine neurons, the onset of on was simultaneous with that of dyskinesias. In these spike trains, the initial fall in firing rate preceded and was larger than the fall at the onset of on with dyskinesias. Among the three neurons in which the onset of on occurred before that of dyskinesias, the firing rate did not change at the time of onset of dyskinesias. After injection of apomorphine, dyskinesias during on with dyskinesias often fluctuated between transient periods with dyskinesias and those without. Average firing rates were not different between these two types of transient periods. Transient periods with dyskinesias were characterized by interspike interval (ISI) independence, stationary spike trains, and higher variability of ISIs. A small but significant group of neurons demonstrated recurring ISI patterns during transient periods of on with dyskinesias. These results suggest that mild dyskinesias resulting from low doses of apomorphine are related to both low GPi neuronal firing rates and altered firing patterns.     

Features of the spike activity of globus pallidus neurons and pallido-thalamic functional interactions during targeted verbally cued movements in humans

This paper reports the results of an analysis of evoked spike activity in neurons of the human globus pallidus during performance of a targeted verbally cued movement, along with a comparison with the results of previous experiments on evoked spike activity of neurons in the reticular and ventrolateral thalamic nuclei in an identical test, recorded during stereotaxic surgery with a microelectrode technique in patients with Parkinson’s disease. The following observations are reported for the first time: 1) The existence in the outer segment of the human pallidus of neurons with convergent properties, selectively responding with activation to significant “stimulatory” verbal command stimuli initiating the launch and performance of a targeted movement; 2) similarity in the dynamics of concordantly occuring responses of convergent neurons in the integrative centers of the striopallidothalamic circuit in functionally important phases of movement act performance. It is suggested that the similar concordantly developing dynamics of neuronal rearrangements during the performance of a targeted movement act within the structures of this circuit reflects functional interstructural and interneuronal interactions occurring in the striopallidothalamocortical system of the human brain, which is involved in organizing verbally cued targeted forms of activity. Laboratory of Human Cellular Neurophysiology, Institute of Chemical Physics, Russian Academy of Sciences. N. N. Burdenko Institute of Neurosurgery, Russian Academy of Medical Sciences, 4 Kosygin Street, Moscow 117977, Russia. Translated from Rossiiki Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 83, No. 7. pp. 37–44, July, 1997.     

Effect of deep brain stimulation on amplitude and frequency characteristics of rest tremor in Parkinson’s disease

The effect of chronic high frequency deep brain stimulation (DBS) on rest tremor was investigated in subjects with Parkinson’s disease (PD). Eight PD subjects with high amplitude tremor (Group 1) and eight PD subjects with low amplitude tremor (Group 2, used as a reference group) were examined by a clinical neurologist and tested with a velocity laser to quantify time and frequency domain characteristics of tremor. Possible rebound effects in rest tremor when DBS was stopped for 60 min were also explored. Participants received DBS of the internal globus pallidus (GPi) (n=7), the subthalamic nucleus (STN) (n=6) or the ventrointermediate nucleus of the thalamus (Vim) (n=3). Tremor was recorded with a velocity laser under two conditions of DBS (on–off) and two conditions of medication (l-Dopa on–off). Correlations between clinical and experimental results for tremor amplitude was 0.70 with no medication and no stimulation. In Group 1, DBS decreased tremor amplitude but also increased spectral concentration and median frequency significantly. Under medication, the changes in tremor with and without stimulation were not statistically significant (Group 1). When stimulation was stopped for 60 min, a rebound in tremor amplitude was observed and median frequency remained stable in Group 1. None of the comparisons examined produced significant effects in Group 2. Taken together, these results suggest that beyond its effect on tremor amplitude DBS acted also on tremor frequency and did not modify tremor characteristics in subjects with low amplitude tremor.     

Pallidal inputs to thalamocortical neurons projecting to the supplementary motor area: an anterograde and retrograde double labeling study in the macaque monkey

Summary The relationship between thalamocortical neurons projecting to the supplementary motor area (SMA) and pallidothalamic projection fibers was examined with an anterograde and retrograde double labeling technique in macaque monkeys (Macaca fuscata). In each monkey, Fast Blue (FB) was injected into the handarm area of the SMA after mapping the somatotopy using intracortical microstimulation, and horseradish peroxidase conjugated with wheat germ agglutinin (WGA-HRP) was injected into the ipsilateral internal segment of the globus pallidus (GPi). As a result, numerous projection neurons labeled with FB were distributed in pallidal terminal areas labeled with WGA-HRP in the ventral nuclear group of the thalamus. The present findings indicate that the SMA receives strong indirect projections from the GPi via the thalamus.     

Temporal evolution of oscillations and synchrony in GPi/muscle pairs in Parkinson's disease

Both standard spectral analysis and time-dependent phase correlation techniques were applied to 27 pairs of tremor-related single units in the globus pallidus internus (GPi) and EMG of patients with Parkinson's disease (PD) undergoing stereotactic neurosurgery. Over long time-scales (approximately 60 s), GPi tremor-related units were statistically coherent with restricted regions of the peripheral musculature displaying tremor. The distribution of pooled coherence across all pairs supports a classification of GPi cell/EMG oscillatory pairs into coherent or noncoherent. Analysis using approximately 2-s sliding windows shows that oscillatory activity in both GPi tremor units and muscles occurs intermittently over time. For brain/muscle pairs that are coherent, there is partial overlap in the times of oscillatory activity but, in most cases, no significant correlation between the times of oscillatory subepisodes in the two signals. Phase locking between coherent pairs occurs transiently; however, the phase delay is similar for different phase-locking subepisodes. Noncoherent pairs also show episodes of transient phase locking, but they occurred less frequently, and no preferred phase delay was seen across subepisodes. Tremor oscillations in pallidum and EMGs are punctuated by phase slips, which were classified as synchronizing or desynchronizing depending on their effect on phase locking. In coherent pairs, the incidence of synchronizing slips is higher than desynchronizing slips, whereas no significant difference was seen for noncoherent pairs. The results of this quantitative characterization of parkinsonian tremor provide a foundation for hypotheses about the structure and dynamical functioning of basal ganglia motor control networks involved in tremor generation.     

Effects of riluzole on the electrophysiological activity of pallidal neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkey

The effect of riluzole administration, an antiglutamatergic compound, on the electrophysiological activity of the pallidal complex of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys is compared with those induced by two dosages of levodopa (L-DOPA), the first affording the best clinical alleviation, the second sufficient to induce dyskinesias. Both dosages of L-DOPA reduced sharply the firing frequency of globus pallidus pars internalis (GPi) neurons (respectively, 43.8+/-23.0 and 27.4+/-20.2 vs. 111. 2+/-31.4 Hz), decreased the percentage of bursting cells (respectively, 60.7 and 50.0 vs. 80.3%) and augmented the number of regular cells (respectively, 6.5 and 33.0 vs. 4.8%). Riluzole restored the firing frequency (75.0+/-26.9 Hz) and the firing pattern of the GPi (39.7% bursting, 9.5% regular and 50.8% irregular). These results suggest that the emergence of dyskinesia may well be due to a modification of the neuronal messages transmitted from the GPi to the motor nuclei of the thalamus. Riluzole would represent an interesting alternative to dopamine therapy in Parkinson's disease since it regularizes firing but does not cause dyskinesia.     

Quantifying the neural elements activated and inhibited by globus pallidus deep brain stimulation

Deep brain stimulation (DBS) of the globus pallidus pars interna (GPi) is an effective therapy option for controlling the motor symptoms of medication-refractory Parkinson's disease and dystonia. Despite the clinical successes of GPi DBS, the precise therapeutic mechanisms are unclear and questions remain on the optimal electrode placement and stimulation parameter selection strategies. In this study, we developed a three-dimensional computational model of GPi-DBS in nonhuman primates to investigate how membrane channel dynamics, synaptic inputs, and axonal collateralization contribute to the neural responses generated during stimulation. We focused our analysis on three general neural elements that surround GPi-DBS electrodes: GPi somatodendritic segments, GPi efferent axons, and globus pallidus pars externa (GPe) fibers of passage. During high-frequency electrical stimulation (136 Hz), somatic activity in the GPi showed interpulse excitatory phases at 1-3 and 4-5.5 ms. When including stimulation-induced GABA(A) and AMPA receptor dynamics into the model, the somatic firing patterns continued to be entrained to the stimulation, but the overall firing rate was reduced (78.7 to 25.0 Hz, P < 0.001). In contrast, axonal output from GPi neurons remained largely time-locked to each pulse of the stimulation train. Similar entrainment was also observed in GPe efferents, a majority of which have been shown to project through GPi en route to the subthalamic nucleus. The models suggest that pallidal DBS may have broader network effects than previously realized and the modes of therapy may depend on the relative proportion of GPi and/or GPe efferents that are directly affected by the stimulation.