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PubMed1998

Subthalamic nucleus or internal pallidal stimulation in young onset Parkinson's disease.

The aim of this study was to compare, retrospectively, the value of chronic bilateral stimulation of the internal globus pallidus (GPi) and the subthalamic nucleus (STN) in patients with young onset Parkinson's disease. We selected 13 consecutive patients with similar characteristics at the time of surgery: age at onset < 40 years, disabling motor fluctuations (Hoehn and Yahr stage 4 or 5 in off-drug phases) and levodopa-induced dyskinesias (LID). Eight patients were operated on in the STN and five in the GPi. The Unified Parkinson's Disease Rating Scale (UPDRS), timed motor tests and a LID scale were compared in on- and off-drug conditions before surgery and 6 months after surgery on stimulation using the chronic electrical parameters found to improve best the motor state of the individual patient, without adverse effects. In off-drug phases, the motor score of the UPDRS was improved by 71% with STN stimulation and by 39% with GPi stimulation on average. This difference was statistically significant (P < 0.05). Whereas rigidity and tremor showed good improvement in both groups, the decrease in the akinesia score was more pronounced in the STN group. In the STN group, the improvement of all motor symptoms was very close, or equal, to the best levodopa response. Thus the levodopa test was predictive of outcome. The improvement in off-drug period motor handicap allowed a decrease in the levodopa-equivalent dose only in the STN group (-56%). The voltage, frequency and pulse width used for chronic stimulation were lower in the STN group. In the on-drug phases there was a marked improvement in LID in the GPi group, as measured by the dyskinesias score during an acute levodopa test, whereas there was only a small decrease in the STN group (P < 0.05). However, in the long term, the reduction of levodopa dosage in the STN group led to an indirect reduction of LID similar to that in the GPi group during activities of everyday life. In conclusion, the overall results favour the neurosurgical treatment of Parkinson's disease by stimulating the STN rather than the GPi.

Adult↗
PubMed1985

Primate globus pallidus and subthalamic nucleus: functional organization.

Neuronal relations to active movements of individual body parts and neuronal responses to somatosensory stimulation were studied in the external (GPe) and internal (GPi) segments of the globus pallidus (GP) and the subthalamic nucleus (STN) of awake monkeys. In GPe (n = 249), GPi (n = 151), and STN (n = 153), 47, 29, and 28% of the cells, respectively, discharged in relation to active arm movements, 10, 11, and 15% to leg movements, and 22, 22, and 18% to orofacial movements. Of the neurons whose activity was related to arm movements, 26, 16, and 21% in GPe, GPi, and STN, respectively, discharged in relation to movements of distal parts of the limb. Of cells whose discharge was related to active limb movements, 37, 22, and 20% in GPe, GPi, and STN, respectively, also responded to passive joint rotation, which was usually specific in terms of joint and direction of movement. Only a small percentage of cells responded to muscle or joint palpation, tendon taps, or cutaneous stimulation. Short-latency, direction-specific neuronal responses to load perturbations confirmed the existence of proprioceptive driving. In both GPe and GPi, leg movement-related neurons were centrally located in the rostrocaudal and dorsoventral dimensions. In contrast, arm movement-related cells were found throughout the entire rostrocaudal extent of both segments, although in greater numbers caudally. In the central portions they were situated largely inferior and lateral to leg movement-related neurons. Neurons related to orofacial movements were largely confined to the caudal halves of both segments, where they were located largely ventral to arm movement-related cells. The STN cells whose activity was related to leg movements were observed largely in the central portions of the nucleus in the rostrocaudal and mediolateral dimensions. Cells whose activity was related to arm movements were found throughout the rostrocaudal extent of the nucleus, but were most numerous at the rostral and caudal poles. Neurons related to movements of the facial musculature and to licking and chewing movements were distributed over the entire rostrocaudal extent of the nucleus, where they generally occupied the ventrolateral regions. In all three nuclei, neurons with similar functional properties were sometimes clustered together. Within the arm and leg areas, however, there was no clear evidence for a simple organization of clusters related to different parts of the limb. These studies provide further evidence for a role of the basal ganglia in the control of limb movements.(ABSTRACT TRUNCATED AT 400 WORDS)

Action Potentials↗
PubMed1990

Subthalamic nucleus of the monkey: connections and immunocytochemical features of afferents.

Retrograde and anterograde transport of wheat germ agglutinin-horseradish peroxidase (WGA-HRP) was studied in 7 squirrel monkeys with discrete injections of the subthalamic nucleus (STN). Injections labeled: (1) the lateral two-thirds of the nucleus (63% and 47%), (2) ventrolateral parts caudally (20%), (3) dorsomedial parts caudally (18%), (4) rostromedial parts (21%), (5) the medial third (38%) and (6) the lateral pole of the nucleus (9%). Afferents to the lateral two-thirds of the STN originated from two parallel cellular arrays in dorsal parts of the middle third of the lateral pallidal segment (LPS) and a single array in the rostral third of the LPS. Medial regions of the STN received input from cells in the rostral LPS. Small numbers of cells were retrogradely labeled in the centromedian-parafascicular (CM-PF) and the pedunculopontine (PPN) nuclei. No cells were labeled in the frontal cortex, the striatum, the substantia innominata (SI), the substantia nigra (SN) or the dorsal nucleus of the raphe. Virtually all pallidal neurons, including identified pallidosubthalamic neurons, were immunoreactive (IR) for gamma-aminobutyric acid (GABA). Pallidosubthalamic neurons were most numerous in regions of the LPS with the lowest density of leucine enkephalin-IR fibers. Substance P-IR fibers, found mainly in the medial pallidal segment, bore no relationship to pallidal afferents to the STN. Choline acetyltransferase-IR cells in the SI and the PPN were not retrogradely labeled with WGA-HRP granules. Anterograde transport in fibers and terminal fields surrounded retrogradely labeled cells in the LPS, suggesting a reciprocal relationship. The caudal third of the LPS and ventral region of the middle third of this nucleus, appeared to project few fibers to, or to receive few fibers from, the STN. A small number of STN efferents entered the medial border of the putamen, but no terminal fields were identified. STN projections to the pars reticulata of the SN appeared to represent about 10% of the projection to the LPS. No STN efferents were identified in the frontal cortex, the SI or the PPN. The hypothesis that STN afferents from the frontal cortex and CM-PF may represent collaterals of projections to other loci is discussed.

Animals↗
PubMed1994

A role for non-NMDA excitatory amino acid receptors in regulating the basal activity of rat globus pallidus neurons and their activation by the subthalamic nucleus.

We have investigated the hypothesis that excitatory amino acid (EAA) receptors in the globus pallidus (GP) play a significant role in maintaining the firing rates of GP neurons under basal conditions and following activation of the subthalamic nucleus (STN). Drugs were infused directly into the GP and/or STN while the extracellular single unit activity of Type II GP neurons was recorded in ketamine-anesthetized rats. Local infusions of the EAA agonists NMDA (30-300 pmol/200 nl) or AMPA (0.1-1 pmol/200 nl) elicited increases in the firing rate of GP neurons in a dose-dependent fashion. Infusion of the GABAA receptor antagonist bicuculline methiodide (1-10 pmol/100 nl) into the STN also elicited dose-related increases in the firing rate of GP neurons. Intrapallidal infusion of the non-NMDA (AMPA/kainate) receptor antagonist NBQX (0.1-1.0 nmol) reduced the basal firing rate of GP neurons by 40%. In contrast, the NMDA antagonist MK-801 (0.01-0.1 nmol) produced no significant effect on basal firing rate. Intrapallidal infusion of the non-selective EAA receptor antagonist kynurenic acid or NBQX reversed or blocked the increase in firing rate of GP neurons following bicuculline-induced activation of the STN. Similar treatment with MK-801, however, had no significant effect on this response. These results indicate that tonic stimulation of non-NMDA receptors plays an important role in maintaining the basal activity of GP neurons and in mediating the effects of increased excitatory input from subthalamic afferent neurons.

Animals↗
PubMedDate not supplied

[Hemiballism as a result of a focal hemorrhagic lesion of the subthalamic nucleus documented by CT].

The authors relate a case of hemiballism with favourable evolution, suddenly arisen in an hypertensive subject, in whom the CT (Computer Tomography) pointed out a small hemorrhage at the level of the subthalamic nucleus (body of Luys), controlateral to hypercinesias. The authors underline the extreme rareness of such clinico-radiologic association since more than 10 years after the introduction of CT only another analogous observation has been related in literature. Cases of hemichorea and/or hemiballism, secondary to ischemic, hemorrhagic or angiomatous lesions, variously situated at the level of basal nuclei have been more often documented through CT.

Cerebral Hemorrhage↗
PubMed1994

Functional metabolic mapping of the rat brain during unilateral electrical stimulation of the subthalamic nucleus.

The alterations in local metabolic activity of several anatomically distinct brain areas were investigated by means of the quantitative autoradiographic 2-deoxy-D-[1-14C]glucose method in awake rats during unilateral electrical stimulation of the subthalamic nucleus (STH). Unilateral electrical stimulation of the STH induced local metabolic activation (by 70% as compared with the control group), as well as distal metabolic activations in the substantia nigra reticulata (by 34%), globus pallidus (by 19%), entopeduncular nucleus (by 18%), deep layers of the superior colliculi (by 15%), and parafascicular thalamic nucleus (by 18%), ipsilaterally to the stimulated side. The ventrolateral motor thalamic nucleus as well as the limbic components, posterior cingulate cortex, and anteroventral thalamic nucleus displayed bilateral metabolic activations (by 20-28%). These results indicate that, in addition to its known ipsilateral motor connections, each STH is functionally related to the limbic system bilaterally. It is suggested that the STH is a site where the central motor information is accessible to the limbic system. Quantitative image analysis of individual serial sections in the STH, substantia nigra, and globus pallidus revealed a consistent dorsoventral pattern of topographic interrelations. Stimulation of either the dorsal or the ventral subdivision of the STH induced always stronger activation in the dorsal compartment of the substantia nigra and in the ventral compartment of the globus pallidus. These results suggest that the earlier-described inversion of the dorsoventral functional correspondence between the substantia nigra and globus pallidus may be partly mediated via the subthalamic nerve cells projecting collateral axons to both these areas.

Animals↗
PubMed1983

Relations between parameters of step-tracking movements and single cell discharge in the globus pallidus and subthalamic nucleus of the behaving monkey.

We describe the relations between the direction, amplitude, and velocity of step-tracking arm movements and the frequency of single cell discharge in the external (GPe) and internal (GPi) segments of the globus pallidus and the subthalamic nucleus (STN) of the behaving monkey. Statistically significant relations to the direction, amplitude, and peak velocity of the movement were found in all structures studied predominantly during the movement but also during the reaction time. For movements in a particular direction, the discharge rate was frequently a linear function of the movement amplitude and/or peak velocity. The slopes of this relation differed for different cells and comprised both positive and negative values. STN differed from both GPe and GPi in that (a) a larger proportion of neurons in STN showed significant relations to the direction of movement and (b) the onset times of changes in neural activity related to movement occurred earlier in STN than in GPe or GPi. The results of these studies suggest that cells in GPe, GPi, and STN may be involved in the control of movement parameters. Loss of the basal ganglia output related to the amplitude or velocity of movement might account for the impairments of step movements observed in Parkinsonian patients. On the other hand, deranged or excessive output related to amplitude or velocity control might result in the excesses of movement observed in other disorders, such as chorea and hemiballismus. These studies also provide direct evidence that the STN exerts a specific influence on basal ganglia output related to the control of movement parameters.

Animals↗
PubMed1992

Excitotoxic acid lesions of the primate subthalamic nucleus result in reduced pallidal neuronal activity during active holding.

1. To gain a better understanding of the pathophysiology of hemiballismus in primates, and to test directly the hypothesis that the subthalamopallidal projection is excitatory, we studied the effects of lesions of the subthalamic nucleus (STN) on neuronal activity in the globus pallidus (GP) of monkeys during performance of a motor behavioral task. 2. Animals were trained to position and hold a manipulandum to which torque pulses were applied, producing elbow flexion and extension. The activity of neurons in the external (GPe) and internal (GPi) segments of GP was recorded in two monkeys during task performance before and after STN lesions. The STN was lesioned by the fiber-sparing neurotoxins ibotenic acid and/or kainic acid. 3. After lesioning, the firing rate of neurons in both segments of GP, which was measured during the period of holding before torque application, was significantly decreased in both animals. The mean of discharge rates of GPi neurons decreased (P < 0.001) from 69.8 (n = 169, SD = 21.6) to 47.4 spikes/s (n = 180, SD = 22.6) after lesioning. The mean of discharge rates of GPe neurons decreased from 63.6 spikes/s (n = 218, SD = 25.1) before lesions to 41.0 spikes/s (n = 208, SD = 18.1) after lesioning. 4. These results provide further evidence that STN gives rise to a major excitatory input to both segments of the GP and support the hypothesis that dyskinesias result from decreased GPi output.

Animals↗
PubMed1985

Non-cholinergic globus pallidus cells that project to the cortex but not to the subthalamic nucleus in rat.

A substantial population of small globus pallidus neurons was demonstrated to have axonal projections to the cerebral cortex using fluorescent retrograde transport techniques. This population was separate from the more numerous population of medium size globus pallidus cells projecting to the subthalamic nucleus and was also separate from the pallidal and especially peripallidal population of large cholinergic cells projecting to the cortex. Some of the small, non-cholinergic cells projecting to the cortex also gave off axonal collaterals to the paraventricular thalamic nucleus.

Acetylcholinesterase↗
PubMed1994

The primate subthalamic nucleus. I. Functional properties in intact animals.

1. The present study tests several key aspects of the current model of the intrinsic circuitry of the basal ganglia, in particular the degree to which basal ganglia-thalamocortical circuits are functionally segregated at the level of the subthalamic nucleus (STN). To this end the responses of STN cells to somatosensory examination (n = 301 cells), the polarity and latencies of neuronal responses to passive and active movements (n = 223 cells), responses to microstimulation (n = 1589 sites), and cross-correlation functions of pairs of neighboring neurons (n = 72 pairs) were studied in STNs of three African green monkeys. 2. The activity of 55% of cells examined in STN was briskly modulated in response to passive movements of individual contralateral body parts. Of these, 86% responded to passive joint rotation of muscle palpation, but in some cases (25% of responding cells) responses were also elicited by light touch. In 91% of the responding cells responses were elicited by manipulations around a single joint only. 3. The caudoventral sector in STN was largely devoid of cells with responses to somatosensory stimulation. Within the rostrodorsal zone a lateral region containing neurons that responded to arm movements and a more medial region with neurons responding to leg movement were found. Cells responding to orofacial movements were located more dorsally and rostrally. Neurons with similar responses to active and passive movements of the limbs tended to be clustered within "arm" and "leg" zones. 4. Of identified arm cells in STN (n = 80), 36% responded to the application of torque pulses to the elbow (43 responses overall). Forty-eight percent of these cells responded to both extension and flexion torques. Ninety-three percent of the responses were initial increases in discharge, which characteristically occurred earlier and were shorter than initial decreases. Fifty-three percent of the responses were biphasic or multiphasic. 5. During active step tracking movements 40% of STN arm cells (n = 53 cells) responded with significant changes in activity. Thirty-six percent of these cells showed responses with both extension and flexion movements. Of the responses, 90% were increases in discharge. Only 14% of all responses were biphasic or multiphasic. Responses tended to occur around the time of movement onset (average latency 2 ms after movement onset). 6. Microstimulation (bipolar pulses, 40 microA, 200-500 ms train duration, 400 Hz) of the core of STN itself did not appear to produce movement.4+ synchronized activity in only 11% of pairs.(ABSTRACT TRUNCATED AT 400 WORDS)

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

Persistent hemiballismus with lesions outside the subthalamic nucleus.

Two patients are reported with hemiballismus due to lesions in the striatum as documented on CT scan. The involuntary movements persisted for one and five years respectively. A third patient with more typical self-limited hemiballismus had no evidence of a causative lesion on CT scan. It is proposed that lesions outside the subthalamic nucleus of Luys may interfere with the compensatory mechanisms which can result in the spontaneous resolution of hemiballistic movements. None of the patients benefited from the use of sodium valproate therapy, however, pimozide reduced the severity of the dyskinesia in the two with longstanding hemiballismus.

Aged↗
PubMed1989

Reduced glutamate decarboxylase activity in the subthalamic nucleus in patients with tardive dyskinesia.

Glutamate decarboxylase (GAD) activity was measured in the nuclei of the basal ganglia in patients with neuroleptic-induced tardive dyskinesia (TD) and controls matched for age and premortem state. In five TD patients, who all had a sudden death, a significant decrease in GAD activity was found in the subthalamic nucleus (STN). The lowered GAD activity in the STN may represent a biochemical substrate for neuroleptic-induced TD.

Aged↗
PubMed1995

Interactions of the subthalamic nucleus and the subpallidal area in oro-facial dyskinesia: role of GABA and glutamate.

Previous studies have shown that lowering the GABAergic activity in the sub-pallidal area (SP) in the cat results in the display of oro-facial dyskinesia (OFD). There exists an intense, mutual anatomical connection between the SP and the subthalamic nucleus and the adjoining lateral hypothalamic area (STH). The present study investigated whether the STH is also involved in OFD. Once this turned out to be true (see below), it was investigated whether the SP-specific OFD is funneled via the STH, or vice versa. Bilateral injections of low doses (50-250 ng) of picrotoxin, a non-competitive GABA antagonist, into the STH were found to elicit OFD. This effect which was quantified in terms of numbers of tongue protrusions, was dose-dependent: a bell-shaped dose-response was found (50-500 ng). The OFD elicited by the most effective dose of picrotoxin (250 ng) was significantly antagonized by muscimol, a specific GABAA agonist, in a dose (50 ng) which itself was ineffective, indicating GABA specificity. In addition, it was found that OFD elicited by local injections of picrotoxin (250 ng) into the STH was significantly attenuated by SP injections of the broad spectrum glutamate antagonist kynurenic acid in a dose (1000 ng) which itself was ineffective, but not by muscimol (100 ng), indicating that the STH-elicited OFD needs an intact and functioning glutaminergic, but not GABAergic, transmission process in the SP for its expression.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1999

Evidence for oxidative stress in the subthalamic nucleus in progressive supranuclear palsy.

Increased free radical production and oxidative stress have been proposed as pathogenic mechanisms in several neurodegenerative disorders. Free radicals interact with biological macromolecules, such as lipids, which can lead to lipid peroxidation. A well-established marker of oxidative damage to lipids is malondialdehyde (MDA). We measured tissue MDA levels in the subthalamic nucleus (STN) and cerebellum from 11 progressive supranuclear palsy (PSP) cases and 11 age-matched control cases using sensitive HPLC techniques. In PSP, a significant increase in tissue MDA levels was observed in the STN when compared with the age-matched control group. By contrast, no significant difference between tissue MDA content was observed in cerebellar tissue from the same PSP and age-matched control cases. These results indicate that lipid peroxidation may play a role in the pathogenesis of PSP.

Aged↗
PubMed1995

Fos immuno-positive neurons in the subthalamic nucleus following reversal of parkinsonian symptoms by antagonism of excitatory amino acid transmission in the entopeduncular nucleus of the monoamine depleted rat.

Drug-induced dyskinesias are a major drawback of the dopaminergic therapies currently employed to treat Parkinson's disease. It is commonly speculated that these dyskinesias may be mediated by functional changes within the striatum. Recent research has, therefore, focused on finding new modes of therapy which will alleviate parkinsonian symptoms without directly altering neurotransmission in the striatum. It has recently been demonstrated that the behavioural symptoms observed in dopamine-depleted rodents can be alleviated by blockade of excitatory neurotransmission in the entopeduncular nucleus. A series of experiments was conducted in order to determine whether this manipulation affected the pattern of Fos immunoreactivity in the basal ganglia elicited by dopamine depletion. The results demonstrated that the most striking change in Fos levels was found in the subthalamic nucleus, indicating that reversal of parkinsonian symptoms in this manner cannot be considered as a simple redress in the balance of activity in the output structures of the basal ganglia.

Animals↗
PubMed1998

Pallidotomy and deep brain stimulation of the pallidum and subthalamic nucleus in advanced Parkinson's disease.

There has been a resurgence in the use of neurosurgical procedures for the treatment of Parkinson's disease (PD). Pallidotomy has become a widely performed procedure on the basis of reports which describe marked reduction of levodopa-induced dyskinesias and variable improvement in parkinsonism. Preliminary reports of the effects of globus pallidus internus (GPi) and subthalamic nucleus (STN) deep brain stimulation (DBS) have also been promising. At 6-month follow up, a cohort of our first 40 patients undergoing pallidotomy demonstrated the following mean improvements when examined after drug withdrawal (off) and under optimal medication (on): total motor off scores-31%; total off activities of daily living scores-30%; and total on dyskinesias-63% (contralateral and ipsilateral dyskinesias improved 82% and 50%, respectively). Although improvements in contralateral dyskinesias and total off parkinsonism were sustained at 2-year follow up (N = 11), benefit for ipsilateral dyskinesias was lost after 1-year follow up (N = 24). and postural stability and gait improvements lasted only 3-6 months. On-period, levodopa-resistant symptoms did not benefit from pallidotomy. Mean improvements in 8 patients undergoing GPi DBS (4 unilateral and 4 bilateral) at 3 months were as follows: total motor off scores-27%; total off activities of daily living scores-26%; and total on dyskinesias-60%. At most recent follow up, 6 patients with STN DBS (5 bilateral and 1 unilateral) showed the following mean improvements: total motor off scores-41%; total motor on scores-27%; total off activities of daily living scores-40%; and total on dyskinesias 41%. Pallidotomy reduces dyskinesias and off disability. GPi DBS may have effects similar to pallidotomy, but might be safer when bilateral procedures are required. Bilateral STN DBS may improve off parkinsonism more than other procedures and might also improve on-period motor function. A randomized trial will be required to determine which procedure is most effective for patients with different clinical features.

Adult↗
PubMed1995

Possible intermixing of neurons from the subthalamic nucleus and substantia nigra pars compacta in the guinea-pig.

A population of cells in the anterior substantia nigra pars compacta (SNPc) of the guinea-pig have been reported previously that differ from classical dopaminergic neurons in terms of their active and passive membrane properties. To investigate this population further, anterior nigral neurons (n = 17) were compared with neurons in the adjacent subthalamic nucleus (STN: n = 26). The anterior nigral neurons were found to be indistinguishable from STN neurons in their action potential characteristics, firing rate, resting membrane potential and input resistance. A low-threshold calcium conductance and anomalous rectification could be demonstrated in cells from both groups. Furthermore, the gross morphological characteristics of anterior nigral neurons and STN neurons were very similar, as assessed following the intracellular injection of biocytin. A further similarity was seen in the response of the two cell groups to cyanide (200 microM) and apomorphine (500 microM). Cyanide hyperpolarised the membrane potential of all STN neurons and the majority (77.8%) of anterior nigral neurons, in both cases producing a concomitant reduction in firing rate. These changes were accompanied by an increase in membrane conductance for potassium ions. Apomorphine depolarised the membrane potential of all STN neurons and anterior nigral neurons, in most cases increasing the input resistance (83.3% of STN neurons and 100% of anterior nigral neurons). In both groups of cells, when firing rate was affected, an increase was usually seen. Given the physiological, morphological and pharmacological similarities of STN and anterior nigral neurons, the most parsimonious interpretation is that the anterior nigral neurons belong to the STN. However, the anterior nigral neurons were found in slices that, when resectioned, contained tyrosine hydroxylase (TH)-immunoreactive cell bodies in every section, in a location corresponding to the SNPc. The implication is that in the guinea pig the SNPc and STN (usually considered to be anatomically distinct nuclei) intermix at this level for several hundred microns. This close association of the STN and the compacta was further demonstrated by the presence of TH-positive varicose and non-varicose neuronal processes within the STN.

Animals↗